Avila
Therapeutics™, Inc., a biotechnology company developing novel
covalent drugs that treat diseases through protein silencing,
presented results of preclinical studies on its highly
selective, small molecule Hepatitis C Virus (HCV) protease
inhibitor, AVL-181.
Nov 2
Avila showed that AVL-181 promoted complete viral
clearance in vitro when used at clinically-relevant
concentrations in combination with other HCV therapies.
Additionally, using an innovative technology for
measuring the extent of covalent bond formation, Avila showed
that AVL-181 bonds selectively and irreversibly to HCV protease
in vivo in a novel rodent model, thus silencing a key protein
necessary for successful viral replication and resulting in a
prolonged duration of action in vivo.
These new data were presented today at
the 60th Annual Meeting of the American Association for the
Study of Liver Diseases (AASLD) international meeting in Boston,
Massachusetts.
"Our clinical candidate, AVL-181, demonstrated inhibition across
multiple genotypes and drug-resistant mutations of the HCV
protease. In addition, the data showing complete viral clearance
in conjunction with other cutting edge therapies are striking,”
said Katrine Bosley, Chief Executive Officer, Avila. "These data
provide additional support for the clinical evaluation of
AVL-181, and we are on track to advance into clinical
development next year.”
In one presentation, “Potential for Rapid and Prolonged
Therapeutic Benefit in HCV through Protein Silencing of NS3
Protease with AVL-181”, the data show that the orally-available,
novel
HCV protease
inhibitor, AVL-181:
selectively bonds the HCV NS3 protease to completely and
irreversibly inactivate proteolytic activity, essentially
silencing the HCV protease complex;
forms a highly specific covalent bond across HCV
genotypes and clinically-described drug-resistant mutant
proteases;
inhibits protease activity in cultured replicon cells for >48
hours after very brief exposure and removal of AVL-181;
demonstrates prolonged pharmacodynamic activity for both
wild-type and drug-resistant mutations (e.g. R155K); and;
results in clearance of HCV RNA from replicon cells in
conjunction with a non-nucleoside polymerase inhibitor,
contributing to a profile that differentiates AVL-181 from
clinically investigated agents.
In a second presentation, “AVL-181 Demonstrates Prolonged
Inhibition of HCV NS3 Protease Activity In Vivo that Directly
Correlates with Prolonged Molecular Target Occupancy”, the data
demonstrate that the orally available, novel HCV protease
inhibitor, AVL-181:
potently and irreversibly silences HCV proteases, and that the
level of protease inhibition is directly correlated with the
extent of target bonding;
durably inhibits the HCV protease for at least 10 hours in vivo
after a single exposure as measured in a novel model in which
NS3/4A is expressed in the mouse liver; and
this duration of action coupled with the low plasma levels of
AVL-181 at this late timepoint confirm that the covalent
mechanism does not depend on the near-continuous drug exposure
such as that required by the reversible HCV protease inhibitors
currently in late-stage clinical trials.
SOURCE Avila Therapeutics, Inc.
Canadian POWeR and
REDIPEN(R) AASLD
Nov 2
Programs presented at the American Association for
the Study of Liver Diseases Annual Meeting -
Results from two significant Canadian studies underscore the growing
scientific evidence of PEGETRON's positive outcomes in the treatment of
chronic hepatitis C virus (HCV) infection.
Canadian investigators across the country collaborated to
generate and analyze clinical data from the Canadian PEGETRON POWeR
(Prospective Optimal Weight-based Dosing Response) and REDIPEN programs,
which were presented at the American Association for the Study of Liver
Diseases (AASLD) Annual Meeting in Boston on November 1, 2009.
The first abstract, Determinants of Virologic Relapse Following Hepatitis C
antiviral Therapy:
Analysis of the Canadian POWeR Program reports Genotype 1
(G1)-infected patients treated with peginterferon alfa-2b plus weight-based
ribavirin (PEGETRON) across 138 Canadian centres, achieved a sustained
virologic response (SVR) rate of 39 per cent, consistent with the 40 per
cent SVR attained with approved peginterferon alfa-2B/ribavirin (PEGETRON)
therapy in the recent United States-based IDEAL Study.
In addition, the relapse rate of G1-infected subjects in
POWeR was 25 per cent, similar to the 24 per cent reported in the IDEAL
Study.
In the second abstract, Outcomes of a Large, Inclusive Population-Based
Hepatitis C Treatment Program are similar to Randomized Controlled Trials:
Interim Results of the
Canadian REDIPEN Program,
a heterogeneous, but representative, population of Canadian
G1 patients treated with peginterferon alfa 2b plus weight-based ribavirin (PEGETRON)
achieved results similar to those treated in randomized, controlled clinical
trials.
The G1 SVR rate was 39 per cent, consistent with both the
above-mentioned Canadian POWeR Program and controlled trials, such as the
IDEAL Study. Similar G1 relapse rates were also reported.
"The results from both the Canadian POWeR and REDIPEN programs support
previous findings from randomized controlled trials of PEGETRON," said Dr.
Curtis Cooper, M.D., Associate Professor of Medicine at the University of
Ottawa, Division of Infectious Diseases and first author of both POWeR and
REDIPEN presentations.
"The encouraging response rates and low relapse rates seen
with PEGETRON therapy are consistent across multiple large Canadian and U.S.
studies and shed important light on hepatitis C treatment outcomes in
real-life clinical practice settings."
These results reinforce the notion that outcomes achieved with PEGETRON
across a large number of clinical trials are consistent and could be
generalized to real-life clinical practice.
Source: SCHERING-PLOUGH CANADA
Drug
Telaprevir Effective in Twice Daily Dosage as Well -
Vertex
Nov 01
After closely observing the hepatitis C drug
Telaprevir in a study, Vertex Pharmaceuticals Inc., has
confirmed that it works well when administered twice daily
as well, instead of the earlier believed dosage of thrice
daily. The study confirmed that the drug worked in over 80%
of the patients when given two times a day as well.
All earlier tests carried out for Telaprevir had reported
that the drug had to be given thrice a day, at regular 8
hour intervals, for it to effectively keep hepatitis C under
control. The new study, however, has confirmed that even
when given twice, at 12 hour intervals, it would work
equally well.
81-85% of the patients involved in the study were earlier on
a three times a day routine, shifting them to the twice
daily routine, in combination with the standard hepatitis C
treatments pegylated-interferon and ribavirin sustained the
response they gave to the dosage when administered thrice.
The data was presented at the meeting of American
Association for the Study of Liver Diseases in Boston.
The study has, according to researchers involved, given much
better results than initially expected. "I was expecting
around 70 percent", Dr Patrick Marcellin, the study's lead
investigator, said. The results of the study are being
viewed as a big step in the history of hepatitis C
treatment.
http://topnews.us/content/28087-hepatitis-c-drug-telaprevir-effective-twice-daily-dosage-well-vertex
More Than 80 Percent of
HCV Genotype 1 Treatment-Naive Patients Achieved
Sustained Virologic Response With
Twice-Daily Telaprevir-Based Regimen
Phase II
telaprevir data from Tibotec featured in oral
presentation at AASLD
Cork, Ireland (October 31, 2009) –Tibotec
announced today results of a new study (VX950-C208),
which showed that sustained virologic response (SVR) was
achieved in more than 80 percent of treatment-naïve
patients with chronic genotype 1 hepatitis C virus (HCV)
who took telaprevir, administered either every 8 hours
or every 12 hours, in combination with standard of
care. Telaprevir, an investigational STAT-C (Specifically
Targeted Antiviral
Therapy for hepatitis C),
is being co-developed by Tibotec in collaboration with
Vertex Pharmaceuticals. The study was presented today
at the 60th Annual Meeting of the American
Association for the Study of Liver Diseases (The Liver
Meeting).
In the phase II study, which enrolled 161
treatment-naïve genotype 1 patients, rates of SVR
(defined as undetectable HCV RNA at 24 weeks after
completion of treatment) ranged from 81 to 85 percent in
patients treated with the every 8 hour telaprevir-based
regimen, and 82 to 83 percent in patients treated with
the every twelve hour regimen. Adverse events (AEs)
were similar to those observed in other trials with
telaprevir and were mainly haematologic (anaemia) and
cutaneous (rash and pruritus) in nature.
For the vast majority of patients, these high SVR rates
were obtained with only 24 weeks of total treatment
(half the duration of current standard of care). Total
duration of treatment was decided using a criteria based
on treatment response. Subjects who achieved
undetectable HCV RNA at week 4 (rapid virologic response
or RVR) and maintained this through week 20, were
allowed to stop all treatment at week 24. Only 18% of
subjects were required to continue standard treatment up
to week 48.
Approximately 180 million people worldwide are infected
with HCV,1 the most common cause of liver
transplant in Europe.2 People with HCV
genotype 1 currently face treatment limitations,
including a standard of care that cures just 40 to 50
percent of patients.3 Without effective
treatment, HCV can lead to serious and fatal diseases of
the liver, including liver cancer4.
“The data presented today show that a significant number
of treatment-naïve genotype 1 HCV patients achieved
sustained virologic response with telaprevir, in
combination with standard of care,” said professor
Patrick Marcellin from Hôpital Beaujon in Clichy,
France. “Telaprevir, which directly targets the virus by
aiming to block its replication, could allow shortening
treatment duration and increasing cure rates in people
with HCV, [compared to standard of care] offering a new
approach to treating HCV.”
About Telaprevir C208 study in Treatment-Naïve
Patients
The phase IIa, open-label, randomised study evaluated
telaprevir administered every eight hours or every 12
hours in combination with standard of care Peg-IFN
alfa-2a (Pegasys®) and ribavirin (Copegus®)
or Peg-IFN alfa2b (PegIntron®) and ribavirin
(Rebetol®) in treatment-naïve patients with
chronic genotype 1 HCV infection.
The objective of the trial was to explore the efficacy,
safety, tolerability, pharmacokinetics, and
pharmacokinetic-pharmacodynamic relationships of
telaprevir when administered as 750 mg every eight hours
or 1125 mg every 12 hours in combination with Pegasys
and Copegus or PegIntron and Rebetol. A total of 161
subjects were randomised to the following groups:
A:
Telaprevir 750 mg q8h with Pegasys/Copegus (Tq8h/Peg2-a)
(n=40)
B: Telaprevir 750 mg q8h with PegIntron/Rebetol
(Tq8h/Peg2-b) (n=42)
C: Telaprevir 1125 mg q12h with Pegasys/Copegus
(Tq12h/Peg2-a) (n=40)
D: Telaprevir 1125 mg q12h with PegIntron/Rebetol
(Tq12h/Peg2-b) (n=39)
All subjects received 12 weeks of
telaprevir treatment in combination with standard
therapy. At the end of Week 12, telaprevir dosing was
completed and subjects continued on standard therapy
only. Most subjects achieved Rapid Virological Response
(RVR) (undetectable at week 4) and remained undetectable
until week 20 and were allowed to stop all treatment at
week 24. Only 18% of subjects were required to continue
standard treatment up to week 48.
Following are the efficacy findings, as measured by
sustained viral response rates (SVRs):
85 percent of patients taking
telaprevir 750 mg q8h with Tq8h/Peg2-a achieved SVR
81 percent of patients taking
telaprevir 750 mg q8h with Tq8h/Peg2-b achieved SVR
82.5 percent of patients
taking telaprevir 1125 mg q12h with Tq12h/Peg2-a
achieved SVR
82.1 percent of patients
taking telaprevir 1125 mg q12h with Tq12h/Peg2-b
achieved SVR
The pharmacokinetic/pharmacodynamic
analysis showed that total exposure to telaprevir
(measured as AUC24h) was similar across all groups.
AEs were similar to those observed in other trials with
Telaprevir. Serious AEs leading to permanent treatment
discontinuation of all drugs were mainly related to rash
(3%, 4/161) and anemia (2%, 3/161).
“For too long, people with HCV have faced treatment
limitations, necessitating a paradigm shift in HCV
therapy,” said Roger Pomerantz, MD, President of Tibotec
Research and Development. “Tibotec is proud to apply
its expertise in virology to discover, develop and make
available new therapies that target HCV in a different
way.”
About Telaprevir
There are currently two fully enrolled, pivotal phase 3
clinical trials examining telaprevir in genotype 1 HCV-infected
adults – REALIZE in treatment-experienced patients and
ADVANCE in treatment-naïve patients. REALIZE is the
only ongoing phase 3 study comparing the efficacy of a
regimen containing a STAT-C to current standard of care
in null responders, while ADVANCE is evaluating the
potential for a 24-week
duration of therapy in treatment-naïve HCV genotype 1
patients. A third phase 3 study, ILLUMINATE, also
fully-enrolled, will provide additional data on
telaprevir in treatment-naïve patients.
Tibotec has the right to develop and commercialise
telaprevir in Europe, South America, the Middle East,
Africa, India, Australia and New Zealand; Vertex will
commercialise telaprevir in the U.S., Canada, and Mexico
and has a collaboration with
Mitsubishi for commercialization in the Far East.
About Tibotec BVBA
Tibotec BVBA is a global pharmaceutical and research
development company. The Company’s main research and
development facilities are in Mechelen, Belgium with
offices in Yardley, PA and Cork, Ireland. Tibotec is
dedicated to the discovery and development of innovative
HIV/AIDS and hepatitis C drugs, and anti-infectives for
diseases of high unmet medical need.
The liver processes almost everything
we take into the body. One of the most important
functions of the liver is to convert medications into
safe levels to treat diseases. This is accomplished by
certain enzymes within the liver—different drugs are
processed by different enzymes. This can be a problem
when people take too much of one medication or an unsafe
combination of medications or herbs that are processed
by the same enzyme or chemical pathway within the
liver. The result can be that too much medicine can be
absorbed, which could lead to a fatal overdose. But
this over-absorption can be used to an advantage when
you want to ‘boost’ the level of another specific drug
without increasing the dose of the medicine that is
being used to treat the condition. This is important
because higher doses of the drug to treat the condition
may produce severe side effects. Another benefit of
using a boosting agent is that you can increase the
levels in the blood or plasma concentrations of the
second drug without a corresponding increase in the side
effects and at the same time decrease chances for the
development of drug resistance.
Ritonavir
An HIV protease inhibitor, ritonavir, is just such a
drug. Ritonavir is metabolized in the liver by an
enzyme called P450 3A (CYP3A). It was discovered that,
when a second HIV protease inhibitor medication was
combined with ritonavir, the plasma concentrations of
the second drug were increased. The boosting properties
of ritonavir were found to greatly enhance overall
successful treatment outcomes, but it also helped to
reduce some of the side effects that would develop if
higher doses of the second drug were given. Also,
because there were higher plasma concentrations of the
second drug in the bloodstream, the chances for
developing drug resistance were lower.
But ritonavir boosting is not without
problems or potential side effects. This could prove
more of a problem in people with liver disease such as
hepatitis C. For instance, ritonavir has been shown to
increase the incidence of certain metabolic disorders
such as fat and carbohydrate (sugar) metabolism and
increase cholesterol levels. Hepatitis C is already
known to increase the chances of metabolic disorders so
adding an agent that would further increase the chances
of developing metabolic disorders could be a problem.
Another potential problem is that the P450 3A (CYP3A)
enzyme metabolizes other drugs, and may inadvertently be
triggered to boost these as well, which could lead to
higher levels that could be unsafe. Careful and
frequent monitoring of all medications would be needed
in people with hepatitis C who use a boosting agent.
The use of ritonavir is now being
studied in combination with HCV protease inhibitors.
Roche’s development program of ITMN191, Pegasys and
ribavirin, and Schering’s (now Merck) SCH900518 are both
using ritonavir as a boosting agent in some clinical
trials. The pharmaceutical company that markets
ritonavir, Abbott, also has a very active early stage
HCV drug pipeline that could eventually be used with
ritonavir.
At the Sixteenth Conference on
Retroviruses and Opportunistic Infection recently held
in Montreal, Canada there were studies presented on two
new boosting agents that are being developed by Gilead
Sciences and Sequoia Pharmaceuticals that may work as
well as ritonavir, but could (hopefully) produce fewer
side effects.
GS 9350 Gilead has developed a
boosting agent, GS 9350, that does not have antiviral
properties against HIV. In test tube and small human
studies it was found to have boosting properties similar
to ritonavir, but with less of the effect on fat and
carbohydrate metabolism that has been found with
ritonavir. In the human studies the drug was found to
be generally well-tolerated.
SPI-452
Sequoia’s boosting agent, SPI-452, has been found to
have no antiviral properties against HIV. In human
testing of HIV negative patients it was found to
increase the levels of a second drug (HIV medication)
with dose proportional effects, but without the type of
metabolic side effects typically seen with ritonavir.
The drug was also generally well-tolerated.
Both boosting drugs are in early
development so it remains to be seen if they are safe
and effective. Down the road after the safety and
efficacy issues have been resolved, the next logical
step would be to combine the new boosters with the newly
developed HCV inhibitors. To this end, Sequoia
announced that another boosting agent, SPI-425, is in
development as a possible boosting drug for HCV
medications.
(NYSE: BMY) and
ZymoGenetics, Inc. (NASDAQ: ZGEN) today presented final
results from a Phase 1b clinical trial of PEG-Interferon lambda
administered with ribavirin in relapsed and treatment-naïve
hepatitis C virus (HCV) patients. The poster included data on 56
patients in the study. Antiviral activity was observed at all
dose levels tested.
The results will be presented at the American
Association for the Study of the Liver Diseases annual meeting
in Boston on November 3.
Interim results were previously presented at the
European Association for the Study of the Liver annual meeting
in April 2009.
"There is a strong need for additional options for hepatitis C
patients,” said Brian Daniels, M.D., senior vice president,
Global Development & Medical Affairs, Bristol-Myers Squibb. "We
are pursuing this investigational pathway to address the fact
that although current interferons have been the backbone of
therapy with meaningful efficacy, they are often poorly
tolerated, leading to dose reductions, poor compliance and
avoidance of treatment.”
"We are excited about the prospects for PEG-Interferon lambda as
a potential HCV treatment,” said Eleanor L. Ramos, M.D., senior
vice president and chief medical officer of ZymoGenetics. "There
is a clear unmet medical need for an interferon with improved
safety and tolerability. We look forward to obtaining additional
clinical data on this promising investigational medicine.”
The Phase 1b clinical trial was designed to evaluate the safety
and antiviral activity of PEG-Interferon lambda when given as a
single agent or in combination with ribavirin in genotype 1 HCV
patients with relapsed disease and in treatment-naïve patients.
In the single agent arm of the study with treatment-relapsed
patients (n=24), PEG-Interferon lambda was administered
subcutaneously at 1.5 mcg/kg and 3.00mcg/kg weekly for four
weeks, and 1.5 mcg/kg and 3.00 mcg/kg every two weeks. In the
combination arm of the study with treatment-relapsed patients
(n=24), PEG-Interferon lambda was administered subcutaneously
weekly at 0.5 mcg/kg, 0.75 mcg/kg, 1.5 mcg/kg and 2.25 mcg/kg
for four weeks, with daily oral ribavirin administered
consistent with the package insert. Patients in the cohort of
treatment-naïve patients (n=7) were given 1.5 mcg/kg of
PEG-Interferon lambda and ribavirin.
PEG-Interferon lambda demonstrated antiviral activity at all
dose levels tested in both relapse and treatment naïve HCV
patients. A majority of patients across all treatment arms
achieved a greater than 2 log reduction in HCV RNA.
Of the patients in the single agent arm of the study, all 12 of
those patients receiving 1.5 mcg/kg and 3.0mcg/kg weekly for
four weeks achieved a greater than 2 log decrease in HCV RNA.
Five of the 12 patients receiving 1.5 mcg/kg and 3.00mcg/kg
every two weeks for four weeks achieved a greater than 2 log
decrease in HCV RNA.
At PEG-Interferon lambda doses of 0.75 mcg/kg, 1.5 mcg/kg and
2.25 mcg/kg administered in combination with ribavirin in
treatment-relapsed patients (n=18), a greater than 3 log mean
maximum decrease in viral load was observed. Of those patients,
eleven (61%) had less than 1,000 HCV RNA copies at Day 29.
Treatment-naive patients, who were treated with 1.5 mcg/kg of
PEG-Interferon lambda in combination with ribavirin (n=7), also
had a greater than 3 log mean maximum decrease in viral load and
two patients (29%) achieved a rapid virologic response (RVR), or
undetectable HCV RNA copies, at 4 weeks.
The most common adverse events were fatigue (29%) and nausea
(13%). There were minimal effects on neutrophil counts. Minimal
constitutional symptoms or hematologic effects were observed
with PEG-Interferon lambda given as a single agent or in
combination with ribavirin. The majority of adverse events and
laboratory changes were grade 1 or 2. Dose-limiting elevations
in ALT or AST, with or without an increase in bilirubin, were
dose-dependent and reversible.
Overall, the results of the study support moving to dose-ranging
Phase 2 studies in treatment-naïve HCV patients.
About Interferon lambda
Interferon lambda (IL-29) is a type 3 interferon that binds to a
unique receptor with more restricted distribution than the
receptors targeted by type 1 interferons, such as interferon
alpha. It is in development for hepatitis C. The native human
protein Interferon lambda is generated by the immune system in
response to viral infection. IL-29 is a member of the type 3
Interferon family, which includes IL-28A and IL-28B, and signals
through the same receptor as IL-28A and IL-28B.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company
committed to discovering, developing and delivering innovative
medicines that help patients prevail over serious diseases. For
more information, please visit
http://www.bms.com/.
About ZymoGenetics
ZymoGenetics is focused on the creation of novel protein drugs
to improve patient care and address unmet medical needs. The
company’s strategy is to discover, develop and commercialize its
products independently, in collaboration with partner companies
or through out-licensing. ZymoGenetics developed and markets
RECOTHROM® Thrombin, topical (Recombinant), a synthetic version
of a human blood-clotting enzyme used to stop bleeding during
surgery. The company is developing a proprietary portfolio of
immune-based product candidates. PEG-Interferon lambda is a
novel type-3 interferon in clinical development for the
treatment of chronic hepatitis C infection. Interleukin-21 is a
novel cytokine in clinical development for the treatment of
metastatic melanoma and renal cell carcinoma. Several other
proprietary product candidates are in preclinical development.
In addition, ZymoGenetics has licensed rights to multiple
clinical and preclinical drug candidates being developed by
other companies. For further information, visit
http://www.zymogenetics.com/.
Bristol-Myers Squibb Forward-Looking Statements
This press release contains "forward-looking statements” as that
term is defined in the Private Securities Litigation Reform Act
of 1995, regarding the research, development and
commercialization of pharmaceutical products. Such
forward-looking statements are based on current expectations and
involve inherent risks and uncertainties, including factors that
could delay, divert or change any of them, and could cause
actual outcomes and results to differ materially from current
expectations.
No forward-looking statement can be guaranteed.
Among other risks, there can be no guarantee that the compound
described in this release will move from early stage development
into full product development, that clinical trials of this
compound will support a regulatory filing, or that the compound
will receive regulatory approval or become a commercially
successful product. Forward-looking statements in the press
release should be evaluated together with the many uncertainties
that affect Bristol-Myers Squibb’s business, particularly those
identified in the cautionary factors discussion in Bristol-Myers
Squibb’s Annual Report on Form 10-K for the year ended December
31, 2008, its Quarterly Reports on Form 10-Q, and Current
Reports on Form 8-K. Bristol-Myers Squibb undertakes no
obligation to publicly update any forward-looking statement,
whether as a result of new information, future events, or
otherwise.
ZymoGenetics Forward-Looking Statements
This press release contains "forward-looking statements" within
the meaning of the Private Securities Litigation Reform Act of
1995. These forward-looking statements are based on the current
intent and expectations of the management of ZymoGenetics. These
statements are not guarantees of future performance and involve
risks and uncertainties that are difficult to predict.
ZymoGenetics' actual results and the timing and outcome of
events may differ materially from those expressed in or implied
by the forward-looking statements because of risks and
uncertainties associated with clinical development.
For example, the results of preliminary studies
do not predict clinical success, and larger and later-stage
clinical trials may not produce the same results as
earlier-stage trials. In addition, the forward-looking
statements in this press release are subject to the other risks
detailed in the company's public filings with the Securities and
Exchange Commission, including the company's Annual Report on
Form 10-K for the year ended December 31, 2008 and Quarterly
Report on Form 10-Q for the quarter ended June 30, 2009. Except
as required by law, ZymoGenetics undertakes no obligation to
update any forward-looking or other statements in this press
release, whether as a result of new information, future events
or otherwise.
erschienen am 31.10.2009 um 21:30 Uhr
CAMBRIDGE, Mass. — Vertex
Pharmaceuticals Inc. said Wednesday its
hepatitis C treatment telaprevir created an
immune system response to the virus in
patients who had not been helped by other
drugs.
The results came from a
midstage trial of the experimental drug.
Vertex said a majority of patients who had
had no response to other drugs, or had only
a partial response or relapsed after
treatment, were free from the virus after
being dosed with telaprevir in the study.
Vertex said virus levels
were undetectable in 90 percent of the
relapsed group and 55 percent of the partial
responders after 24 or 48 weeks of
treatment. Undetectable virus levels are the
main goal of hepatitis C treatment. The
company added that 57 percent of patients
who had not responded at all to other drugs
had a sustained response after 48 weeks.
Four nonresponders, five
partial responders and one prior relapser
experienced a new relapse during the study.
Eight patients left the trial due to bad
reactions to telaprevir.
Wednesday's results came
from an analysis of 94 patients. It did not
include certain other patients who were
unresponsive to previous therapy and which
stopped telaprevir after four weeks because
they were not responding to that drug
either, Vertex said.
Full results from the
study are expected in 2010.
Vertex Pharmaceuticals Reports Third Quarter 2009 Financial
Results and Highlights Recent Business and Clinical Progress
Mon Oct 26, 2009 4:01pm EDT
-Phase 3 registration programs in hepatitis C and cystic
fibrosis on track-
-Vertex to present telaprevir SVR data from Study C208 at AASLD
meeting this week-
CAMBRIDGE, Mass.--
Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today
reviewed recent business and clinical progress and reported
consolidated financial results for the quarter ended September
30, 2009.
"Vertex has made significant advancements across its business
and expects to enter 2010 in a strong financial position that
will enable the continued investment in late-stage development
programs in hepatitis C virus infection and cystic fibrosis,"
said Matthew Emmens, Chairman, President and Chief Executive
Officer of Vertex Pharmaceuticals. "We remain focused on the
completion of the telaprevir Phase 3 registration program and
are on track to submit a telaprevir New Drug Application in the
second half of 2010. In addition, we believe ongoing clinical
trials of telaprevir and of our novel HCV polymerase inhibitor
VX-222 will enable the initiation of the first combination trial
of these two compounds in HCV patients in the coming months -
underscoring our commitment to improve patient care in HCV."
Mr. Emmens continued, "Later this week, we expect to present
final SVR data from Study C208 at the AASLD meeting in Boston
showing the potential for telaprevir to be dosed twice-daily as
part of a response-guided treatment regimen. Our confidence in
telaprevir`s competitive profile remains high, and we look
forward to the presentation of data from C208 and other clinical
trials in the coming days.
"In cystic fibrosis, we recently completed enrollment in a Phase
2 trial of VX-809, our novel CFTR corrector compound, and we
continue to enroll patients across the three trials of the Phase
3 registration program for VX-770, our novel CFTR potentiator.
VX-770 and VX-809 aim to address the underlying defective
protein responsible for this orphan disorder, with the goal of
enabling cystic fibrosis patients to live a more normal life,"
Mr. Emmens said.
Broad Commitment to Hepatitis C
Phase 3 registration program ongoing: ADVANCE, ILLUMINATE and
REALIZE trials
* The ADVANCE, ILLUMINATE and REALIZE trials are evaluating
telaprevir-based regimens as part of a global Phase 3
registration program in more than 2,200 genotype 1
treatment-naïve and treatment-failure patients with hepatitis C
virus (HCV) infection.
* Vertex expects sustained viral response (SVR) data to become
available from ADVANCE and ILLUMINATE in the first half of 2010
and from REALIZE in mid-2010. Vertex plans to submit a New
Drug Application (NDA) for telaprevir in the second half of
2010.
* The Phase 3 ADVANCE trial is evaluating telaprevir, or
placebo, as part of a 24-week telaprevir-based response-guided
treatment regimen in combination with pegylated interferon (peg-IFN)
and ribavirin (RBV) in more than 1,050 treatment-naïve HCV
patients. The response-guided trial design is utilizing rapid
viral response (RVR) criteria to determine which telaprevir
patients can stop all treatment at 24 weeks.
* The Phase 3 ILLUMINATE trial is evaluating response-guided
telaprevir-based regimens, or placebo, in more than 500
treatment-naïve HCV patients. This trial is designed to
supplement SVR data obtained from the pivotal Phase 3 ADVANCE
trial. The aim of the ILLUMINATE trial is to characterize
whether there is an additional benefit to extending treatment
from 24 to 48 weeks in treatment-naïve patients who achieved
undetectable virus levels at weeks 4 and 12 of treatment (eRVR).
* The Phase 3 REALIZE trial is evaluating 48-week telaprevir-based
regimens, or placebo, in more than 650 patients with genotype 1
HCV who did not achieve an SVR with a previous peg-IFN-based
treatment. The REALIZE trial enrolled all major
treatment-failure groups, including null responders.
SVR data from telaprevir twice-daily dosing to be presented
at AASLD this week
* Vertex expects that final SVR data from Study C208, which is
evaluating twice-daily telaprevir dosing, will be presented at a
Presidential Plenary session at the upcoming Annual Meeting of
the American Association for the Study of Liver Diseases (AASLD),
Oct. 30 - Nov. 3 in Boston. The C208 presentation at AASLD
represents the first SVR data for telaprevir-based regimens,
including SVR results from twice-daily dosing of telaprevir, as
part of a response-guided therapy trial design, similar to that
being used in the ADVANCE and ILLUMINATE Phase 3 trials of
telaprevir. Study C208 is an exploratory Phase 2, open-label
clinical study conducted by Tibotec in Europe that evaluated a
twice-daily (1125mg q12h) dosing schedule of telaprevir in
combination with peg-IFN-alfa-2a (PEGASYS¨) or peg-IFN-alfa-2b (PEGINTRON¨)
and RBV, as compared to the current three-times-daily (750mg
q8h) telaprevir dosing schedule.
Additional telaprevir clinical studies in patients who failed
prior HCV therapy
* Vertex has completed PROVE 3, a Phase 2b clinical trial of
telaprevir-based combination therapy in patients with genotype 1
HCV who did not achieve an SVR with a previous peg-IFN-based
treatment. Final PROVE 3 data, including 48-week follow-up SVR
rates (SVR48), will be presented at AASLD.
* Vertex is also conducting Study 107, an open-label Phase 2
study to evaluate telaprevir-based combination regimens in
patients who did not achieve an SVR in the 48-week control arms
of the PROVE 1, PROVE 2 and PROVE 3 studies. In Study 107,
telaprevir was given in combination with peg-IFN and RBV for 12
weeks followed by peg-IFN and RBV for 12 weeks or 36 weeks
depending on the patient`s antiviral response to telaprevir in
Study 107 and whether the patient was a prior null-responder,
partial-responder or relapser.
On track to initiate STAT-C combination trial as early as Q4
2009
* Vertex is seeking to advance HCV therapy through the
development of novel combinations of Specifically-Targeted
Antiviral Therapies for hepatitis C (STAT-Cs).
* Vertex is currently conducting a three-day, multiple-dose
viral kinetic study to evaluate the antiviral activity, safety,
tolerability and pharmacokinetics of the HCV polymerase
inhibitor VX-222. In the trial, VX-222 is being administered
at four different doses as a monotherapy in 32 treatment-naïve
patients with genotype 1 HCV infection. Vertex is also currently
conducting a drug-drug interaction study with VX-222 and
telaprevir in healthy volunteers.
* Vertex expects to obtain data from these trials in the fourth
quarter of 2009, which could enable the initiation of a
combination trial of telaprevir and VX-222 in patients with
genotype 1 HCV as early as the fourth quarter of 2009. Vertex
expects data from this first STAT-C combination study of
telaprevir and VX-222 to become available by mid-2010.
Additional HCV compounds in clinical development
* Vertex is also evaluating additional HCV compounds, including
the HCV protease inhibitors VX-813 and VX-985 as well as the HCV
polymerase inhibitor VX-759.
* Vertex also has an NS5A inhibitor program in preclinical
development.
* The goal of these programs is to identify compounds that are
appropriate for further development, including combination
therapy.
AASLD
* The upcoming AASLD meeting, being held Oct. 30 - Nov. 3 in
Boston, is expected to include three telaprevir-related clinical
presentations, including presentations on SVR results from Study
C208, final SVR48 results from PROVE 3 and results from a pooled
analysis of PROVE 1 and PROVE 2 in "difficult-to-cure" patients.
Inhibitex
Announces Data Presentation at the 60th Annual Meeting of the
American Association for the Study of Liver Diseases (AASLD) Mon
Oct 26, 2009 11:29am EDT
INX-189 Exhibits Favorable Pharmacology Profile in Preclinical
Studies
ATLANTA-- Inhibitex, Inc. (NASDAQ: INHX) announced today that a
poster presentation describing preclinical data on INX-189, the
lead compound from its HCV nucleotide polymerase inhibitor
program, will be presented by Dr. Joseph M. Patti, Chief
Scientific Officer and Senior Vice President of R&D, at the 60th
Annual Meeting of the American Association for the Study of
Liver Diseases (AASLD) in Boston, MA. The full abstract can be
viewed at the AASLD website at
www.aasld.org.
The poster (#1611 Patti, et al), entitled "Pharmacological
Properties and In Vitro Characterization of INX-189, a Liver
Targeted Phosphoramidate Nucleoside Analogue Inhibitor of NS5b"
will be presented in the HCV Therapy: Preclinical and Early
Clinical Development session from 8:00 am - 1:00 pm on Tuesday,
November 3rd, 2009.
About HCV and Protides
Hepatitis C is a disease of the liver caused by the hepatitis C
virus (HCV). It is estimated that approximately 4 million
Americans and 170 million individuals worldwide are infected
with HCV. HCV can cause chronic liver disease, cirrhosis and
cancer, and is the leading cause of liver transplant in the
United States. Inhibitex is developing a series of proprietary
phosphoramidates, or protide nucleoside inhibitors, that target
the RNA-dependent RNA polymerase (NS5b) of HCV. Protides are
designed to by-pass the rate limiting first step in the
formation of the active nucleoside triphosphate. INX-189 is a
protide of a 2'-C-methyl guanosine analogue. The Company
believes that its protides possess several pharmacological
advantages over nucleosides alone and potentially other
nucleotide prodrugs. These advantages include greater potency, a
rapid conversion of the protide into its active form in the
liver, and potentially less toxicity due to reduced systemic
exposure of the nucleoside.
About Inhibitex
Inhibitex, Inc., headquartered in Alpharetta, Georgia, is a
biopharmaceutical company focused on developing products to
treat serious infectious diseases. In addition to INX-189, the
Company's pipeline includes FV-100, its clinical-stage
nucleoside analogue in Phase II development for the treatment of
herpes zoster (shingles). The Company has also licensed the use
of its proprietary MSCRAMM® protein technology to Wyeth for the
development of staphylococcal vaccines.
For additional information about the Company, please visit
www.inhibitex.com.
Inhibitex, Inc.
Russell H. Plumb, 678-746-1136
Chief Executive Officer
www.inhibitex.com
October 21, 2009
SciClone
announces enrollment of first patient in its Phase 2 trial of
SCV-07 in hepatitis C
This multicenter, multidose, open-label study is
designed to evaluate the safety and immunomodulatory effects of
SCV-07 as a monotherapy or in combination with ribavirin in
non-cirrhotic patients with genotype 1 chronic HCV who have
relapsed after at least 44 weeks of treatment with pegylated
interferon and ribavirin.
Foster City, Calif. – October 21, 2009 – SciClone
Pharmaceuticals, Inc.
(NASDAQ: SCLN) today announced the enrollment of
its first patient at the Atlanta Gastroenterology Associates in
Atlanta, GA, in a phase 2 trial of SCV-07 for the treatment of
hepatitis C (also known as HCV).
This multicenter, multidose, open-label study is
designed to evaluate the safety and immunomodulatory effects of
SCV-07 as a monotherapy or in combination with ribavirin in
non-cirrhotic patients with genotype 1 chronic HCV who have
relapsed after at least 44 weeks of treatment with pegylated
interferon and ribavirin.
“During our previous phase 2A clinical trial of SCV-07 as a
monotherapy to treat patients with chronic hepatitis C
infections, we were pleased by the safety data and were very
encouraged by the efficacy signal, namely, a reduction of viral
loads and a corresponding increase in neopterin concentration in
some patients after only seven days of SCV-07 administration,”
said Friedhelm Blobel, Ph.D., President and Chief Executive
Officer of SciClone. “SciClone is eager to investigate further
SCV-07's potential to enhance the immune response against
hepatitis C and to determine whether the compound is capable of
improving the current standard of care treatment.”
“Currently approved therapies for the treatment of HCV can have
significant side effects and often fall short of providing the
most important treatment outcome, sustained viral response,”
said Kenneth Sherman, MD, PhD, Gould Professor of Medicine,
Department of Internal Medicine at the University of Cincinnati,
and a principal investigator in SciClone’s study. “We are very
excited by what appears to be SCV-07’s ability to enhance
patients’ immune function without adding significant toxicity.
Should ongoing clinical trials show the benefits of adding
SCV-07 to ribavirin, it has the potential to become incorporated
into standard treatment practices in the future.”
The study, which will monitor biomarkers of immune activation
and HCV viral load dynamics, will include two treatment cohorts
of 20 patients each, who will receive SCV-07 at a dose of either
0.1 mg/kg or 1.0 mg/kg. The treatment period will be
approximately eight weeks long, including four weeks of SCV-07
monotherapy followed by four weeks of SCV-07 in combination with
ribavirin. In addition, there will be three follow-up visits
within seven weeks after the completion of treatment.
For more information on SciClone's phase 2 trial of SCV-07 in
the treatment of HCV, please visit
www.clinicaltrials.gov.
About SCV-07
SCV-07 is a small molecule which stimulates the immune system
through inhibition of STAT3-dependant signaling and the
resulting effects on T-helper 1 cells, which are essential for
clearance of viral infections. SCV-07 has shown a good safety
profile in several early stage clinical trials in healthy
volunteers and subjects with HCV at various doses. SciClone is
also carrying out a phase-2, randomized, double-blinded,
placebo-controlled trial of SCV-07 for the treatment of oral
mucositis in patients with head and neck cancers undergoing
chemo-radiation. The topline results from this trial are
expected to be announced in the first half of 2010.
SCV-07 is protected by composition of matter patents as well as
multiple method of treatment patents. SciClone has exclusive
worldwide rights to SCV-07 outside of Russia, where the molecule
has recently been approved for stimulation of depressed immune
systems.
About the Hepatitis C Virus
HCV is a blood-borne viral disease which causes inflammation of
the liver. The World Health Organization estimates that 170
million people worldwide are infected with HCV, and the Centers
for Disease Control estimates that approximately 8 to 10 million
people are infected with HCV throughout the U.S. and Europe. Of
these patients, approximately 85% are chronically infected, and
the persistent liver inflammation in chronically infected
patients can develop serious complications including cirrhosis
of the liver, liver failure, and hepatocellular carcinoma. Only
about half of all naive patients treated with current therapy
achieve a sustained viral response, and SciClone estimates
nearly 1 million HCV patients in the United States alone have
failed or will fail current therapy. The market for HCV
therapeutics in the three major economic regions of the United
States, Europe and Japan is estimated to total approximately $3
billion currently and is expected to grow to approximately $10
billion by 2014.
About SciClone
SciClone Pharmaceuticals (NASDAQ: SCLN) is a profit-driven,
global biopharmaceutical company with a substantial
international business and a product portfolio of novel
therapies for cancer and infectious diseases. SciClone is
focused on continuing international sales growth, a
cost-containing clinical development strategy, and expense
management.
ZADAXIN (thymalfasin or thymosin alpha 1) is sold
in over 30 countries for the treatment of hepatitis B (HBV) and
hepatitis C (HCV), certain cancers and as a vaccine adjuvant.
SciClone’s pipeline of drug candidates includes thymalfasin, in
preclinical studies as an enhancer of novel H1N1 flu vaccines;
thymalfasin for stage IV melanoma, for which SciClone has
reached agreement with the FDA on the design of a phase 3 trial;
SCV-07 in a phase 2 trial for the delay of onset of severe oral
mucositis in patients receiving chemoradiation therapy for the
treatment of cancers of the head and neck; and SCV-07 in a phase
2 trial for the treatment of HCV.
SciClone has exclusive commercialization and
distribution rights to DC BeadTM in China, where the product is
under regulatory review. The Company also has commercialization
and distribution rights to an anti-nausea drug ondansetron
RapidFilmTM in China and Vietnam, for which it is seeking
regulatory approval.
The information in this press release contains
forward-looking statements including our expectations and
beliefs regarding the timing and results of our clinical trials.
You are urged to consider statements that include the words
"may," "will," "would," "could," "should," "might," "believes,"
"estimates," "projects," "potential," "expects," "plans,"
"anticipates," "intends," "continues," "forecast," "designed,"
"goal," or the negative of those words or other comparable words
to be uncertain and forward-looking. These statements are
subject to risks and uncertainties that are difficult to predict
and actual outcomes may differ materially. These risks and
uncertainties include our forward-looking statements because of
the inherent uncertainties, including in the timing of clinical
trial events such as including patient enrollment, requirements
of, and future actions of, the U.S. Food and Drug
Administration, the fact that experimental data, and clinical
results derived from studies with animals or a limited group of
patients, and as well as comparisons with other clinical trials
may not be predictive of the results of larger studies and,
therefore, such experimental or clinical data are not
necessarily predictive indicative of the efficacy or safety or
the results of larger studies and clinical trials. Please also
refer to the other risks and uncertainties described in
SciClone's filings with the Securities and Exchange Commission.
All forward-looking statements are based on information
currently available to SciClone, and SciClone assumes no
obligation to update any such forward-looking statements.
SciClone Pharmaceuticals
Foster City-based SciClone (NASDAQ: SCLN) signed up the patient
in Atlanta to test SCV-07, a small molecule that stimulates the
immune system.
In this Phase II trial it’s being tested alone or
in combination with ribavirin, another drug.
Two groups of 20 patients will be enrolled in the test and
evaluated over eight weeks, four of them with SCV-07 by itself
and another four where it is combined with ribavirin.
Hepatitis C is a virus carried in the blood that attacks the
liver.
Friedhelm Blobel is president and CEO of SciClone.
"Adding metformin to peginterferon
and ribavirin was safe and improved insulin sensitivity. Although
the study failed to show a statistically significant difference
between arms, it did show an improved SVR in females."
Schering-Plough Highlights Boceprevir, Narlaprevir (SCH 900518)
and PEGINTRON(R) Data at the American Association for the Study
of Liver Diseases (AASLD) 2009 Annual Meeting
Schering-Plough Highlights Boceprevir,
Narlaprevir (SCH 900518) and
PEGINTRON(R) Data at the American Association for the Study of Liver
Diseases
(AASLD) 2009 Annual Meeting
KENILWORTH, N.J., Oct. 15 /PRNewswire-FirstCall/ -- Schering-Plough
(NYSE:
SGP) today announced that data on boceprevir, an investigational
hepatitis C
virus (HCV) protease inhibitor, will be reported in an oral
presentation at
the American Association for the Study of Liver Diseases (AASLD)
Annual
Meeting in Boston, Oct. 30-Nov. 3. Researchers will present
sustained
virologic response (SVR) data on boceprevir triple combination
therapy in
treatment-naive HCV genotype 1 patients who had a null response to
peginterferon and ribavirin (defined as <1>
Patients with null
response to peginterferon and ribavirin are considered to be among
the most difficult to treat successfully. Phase III registration
studies with boceprevir in treatment-naive HCV patients and those
who failed prior treatment have been fully enrolled and are expected
to be completed in mid-2010.
In addition, a
late-breaker oral presentation on narlaprevir (SCH 900518), a
next-generation once-daily HCV protease inhibitor, will report
week-4 rapid virologic response (RVR) and week-12 early virologic
response (EVR) data in treatment-naive HCV genotype 1 patients from
the ongoing NEXT-1 study. Narlaprevir is currently in Phase II
clinical development. Several presentations will report results with
PEGINTRON(R) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP)
combination therapy, an approved treatment regimen for chronic
hepatitis C.
These include a
late-breaker oral presentation on a genome-wide analysis of patients
from the IDEAL study that identified the first genetic marker that
may predict a patient's response to peginterferon and ribavirin
combination therapy for hepatitis C.
Peginterferon and
ribavirin are expected to remain the backbone of HCV treatment
regimens for the next several years. Schering-Plough is in the
process of analyzing options for the development of a genetic test
based on this marker and for making it widely accessible to
providers, patients and diagnostic companies for the advancement of
science and for helping physicians and patients make more informed
treatment decisions.
Hepatitis C is the most
common blood-borne infection in America and the most common form of
liver disease, affecting nearly 5 million people in the United
States and 200 million people worldwide. It is the leading cause of
cirrhosis and liver cancer, and the number one reason for liver
transplants in the United States and Europe. For program
information, please visit the AASLD Web site at
www.aasld.org.
This document is
intended for trade media attending AASLD for their planning
purposes. Key Data Presentations at AASLD 2009 Boceprevir Oral
Presentation High Sustained Virologic Response (SVR) in Genotype 1
(G1) Null Responders to Peg-Interferon alfa-2b plus Ribavirin When
Treated with Boceprevir Combination Therapy; P.Y. Kwo et al.
Abstract 62.
Sunday, Nov. 1, 5:00 pm
to 5:15 pm, Hynes Auditorium Boceprevir Poster Presentations
Response-Guided Therapy (RGT) for Boceprevir Combination Treatment -
Results from HCV SPRINT-1; P.Y. Kwo et al. Abstract 1582.
Tuesday, Nov. 3, 8:00
am to 1:00 pm, Hynes Exhibit Hall C Clonal analysis of mutations
selected in the HCV NS3 protease domain of genotype 1 non-responders
sequentially treated with boceprevir and/or pegylated interferon
alfa-2b; J. Vermehren et al. Abstract 1592.
Tuesday, Nov. 3, 8:00
am to 1:00 pm, Hynes Exhibit Hall C Narlaprevir (SCH 900518)
Late-Breaker Oral Presentation Once-Daily Narlaprevir (SCH 900518)
in Combination with PEGINTRON (Peginterferon alfa-2b)/ Ribavirin)
for Treatment-Naive Subjects with Genotype-1 CHC: Interim Results
from NEXT-1, a Phase 2a Study; J.M. Vierling et al. Abstract LB4.
Monday, Nov. 2, 5:30 pm to 5:45 pm, Hynes Auditorium Narlaprevir
(SCH 900518) Poster
Presentation SVR
Results in Chronic Hepatitis C Genotype 1 Patients Dosed with SCH
900518 and Peginterferon Alfa-2b for 2 Weeks, Followed by
Peginterferon Alfa-2b and Ribavirin for 24/48 Weeks: An Interim
Analysis; J. de Bruijne et al. Abstract 1555.
Tuesday, Nov. 3, 8:00
am to 1:00 pm, Hynes Exhibit Hall C IDEAL Study Late-Breaker Oral
Presentation Genome-wide analysis of patients from the IDEAL study
identifies a polymorphism upstream of the IL28B gene that is
strongly associated with SVR in patients with HCV-1; A.J. Thompson
et al. Abstract LB5. Monday, Nov. 2, 5:45 pm to 6:00 pm, Hynes
Auditorium IDEAL Study Oral Presentation Relationship of the Use of
Statins and Elevated Low-Density Lipoprotein (LDL) or Total
Cholesterol (TC) to Virologic Response in Patients Treated for
Hepatitis C Virus (HCV) in the IDEAL Study; S.A. Harrison et al.
Abstract 120. Monday, Nov. 2, 4:15 pm to 4:30 pm, Hynes Ballroom B
IDEAL Study Poster Presentation Analysis of Reasons for Treatment
Ineligibility in the IDEAL study: African Americans (AA) vs.
non-African Americans (non-AA); M. Melia et al. Abstract 848.
Sunday, Nov. 1, 8:00 am to 5:30 pm, Hynes Exhibit Hall C PEGINTRON
Oral Presentation Interim analysis of a controlled trial of
pre-transplant peginterferon alfa-2b/ribavirin (PEG/RBV) to prevent
recurrent hepatitis C virus (HCV) infection after liver
transplantation (LT) in the Adult-to-Adult Liver Transplantation
(A2ALL) Study; G.T. Everson et al. Abstract 1. Sunday, Nov 1, 8:00
am to 8:15 am, Hynes Auditorium About PEGINTRON PEGINTRON is
indicated for use in combination with REBETOL (ribavirin) for the
treatment of chronic hepatitis C in patients 3 years of age and
older with compensated liver disease. The following points should be
considered when initiating therapy with PEGINTRON in combination
with REBETOL:
(1) These indications
are based on achieving undetectable HCV RNA after treatment for 24
or 48 weeks and maintaining a Sustained Virologic Response (SVR) 24
weeks after the last dose. (2) Patients with the following
characteristics are less likely to benefit from re-treatment after
failing a course of therapy: previous nonresponse, previous
pegylated interferon treatment, significant bridging fibrosis or
cirrhosis, and genotype 1 infection. (3) No safety and efficacy data
are available for treatment of longer than one year.
PEGINTRON is also
indicated for use alone for the treatment of chronic hepatitis C in
patients with compensated liver disease previously untreated with
interferon alpha and who are at least 18 years of age.
The following points
should be considered when initiating therapy with PEGINTRON alone:
Combination therapy with REBETOL is preferred over PEGINTRON
monotherapy unless there are contraindications to, or significant
intolerance of, REBETOL. Combination therapy provides substantially
better response rates than monotherapy. Important Safety Information
on PEGINTRON WARNING: RISK OF SERIOUS DISORDERS AND
RIBAVIRIN-ASSOCIATED EFFECTS Alpha interferons, including PEGINTRON,
may cause or aggravate fatal or life-threatening neuropsychiatric,
autoimmune, ischemic, and infectious disorders. Patients should be
monitored closely with periodic clinical and laboratory evaluations.
Patients with
persistently severe or worsening signs or symptoms of these
conditions should be withdrawn from therapy. In many, but not all
cases, these disorders resolve after stopping PEGINTRON therapy. Use
with Ribavirin: Ribavirin may cause birth defects and death of the
unborn child. Extreme care must be taken to avoid pregnancy in
female patients and in female partners of male patients. Ribavirin
causes hemolytic anemia.
The anemia associated
with REBETOL therapy may result in a worsening of cardiac disease.
Ribavirin is genotoxic
and mutagenic and should be considered a potential carcinogen.
Contraindications PEGINTRON is contraindicated in patients with
known hypersensitivity reactions such as urticaria, angioedema,
bronchoconstriction, anaphylaxis, Stevens-Johnson syndrome and toxic
epidermal necrolysis to interferon alpha or any other component of
the product, autoimmune hepatitis, and hepatic decompensation
(Child-Pugh score >6 [class B and C]) in cirrhotic CHC patients
before or during treatment.
PEGINTRON/REBETOL
combination therapy is
additionally contraindicated in women who are pregnant or may become
pregnant
(see Boxed Warning and Pregnancy section), men whose female partners
are
pregnant, patients with hemoglobinopathies (e.g., thalassemia major,
sickle-cell anemia), and patients with creatinine clearance <50>
If this drug is used
during pregnancy or if a patient becomes pregnant, the patient
should be apprised of the potential hazard to a fetus. A Ribavirin
Pregnancy Registry has been established to monitor maternal-fetal
outcomes of pregnancies in female patients and female partners of
male patients exposed to ribavirin during treatment, and for six
months following cessation of treatment. Physicians and patients are
encouraged to report such cases by calling 1-800-593-2214. I
ncidence of Adverse
Events Most common adverse reactions (>40%) in adult patients
receiving either PEGINTRON or PEGINTRON/REBETOL are injection site
inflammation/reaction,
fatigue/asthenia, headache, rigors, fevers, nausea, myalgia, and
anxiety/emotional lability/irritability. Most common adverse
reactions (>25%)
in pediatric patients receiving PEGINTRON/REBETOL are pyrexia,
headache,
neutropenia, fatigue, anorexia, injection site erythema, and
vomiting.
In a study with PEGINTRON/REBETOL (weight-based) combination therapy
in adult
patients, anemia with weight-based dosing was 29%; however, the
majority of
these cases were mild and responded to dose reductions. The
incidence of
serious adverse reactions reported for the weight-based REBETOL
group was 12%.
In many but not all cases, adverse reactions resolved after dose
reduction or
discontinuation of therapy. Some patients experienced ongoing or new
serious
adverse reactions during the 6-month follow-up period.
Discontinuations for
adverse events were 15% and were related to known interferon effects
of
psychiatric, systemic (e.g., fatigue, headache), or gastrointestinal
adverse
reactions. Dose modifications due to adverse reactions occurred in
29% of
patients.
Most common adverse reactions with PEGINTRON/REBETOL (weight-based)
combination therapy were psychiatric, which occurred among 68-69% of
patients.
These psychiatric adverse reactions included most commonly
depression,
irritability, and insomnia, each reported by approximately 30-40% of
subjects
in all treatment groups. Suicidal behavior (ideation, attempts, and
suicides)
occurred in 2% of all patients during treatment or during follow-up
after
treatment cessation. PEGINTRON induced fatigue or headache in
approximately
two-thirds of patients, with fever or rigors in approximately half
of the
patients. The severity of some of these systemic symptoms (e.g.,
fever and
headache) tends to decrease as treatment continues. There was a
23-24%
incidence overall for injection site reactions or inflammation.
Individual serious adverse reactions occurred at a frequency equal
to or less
than 1% and included suicide attempt, suicidal ideation, severe
depression;
psychosis, aggressive reaction, relapse of drug addiction/overdose;
nerve
palsy (facial, oculomotor); cardiomyopathy, myocardial infarction,
angina,
pericardial effusion, retinal ischemia, retinal artery or vein
thrombosis,
blindness, decreased visual acuity, optic neuritis, transient
ischemic attack,
supraventricular arrhythmias, loss of consciousness; neutropenia,
infection
(sepsis, pneumonia, abscess, cellulitis); emphysema, bronchiolitis
obliterans,
pleural effusion, gastroenteritis, pancreatitis, gout,
hyperglycemia,
hyperthyroidism and hypothyroidism, autoimmune thrombocytopenia with
or
without purpura, rheumatoid arthritis, interstitial nephritis,
lupus-like
syndrome, sarcoidosis, aggravated psoriasis, urticaria, injection
site
necrosis, vasculitis, and phototoxicity.
Additional serious adverse events included suicide, homicidal
ideation,
aggressive behavior sometimes directed towards others,
hallucinations, bipolar
disorders, mania, encephalopathy (usually elderly treated with
higher doses of
PEGINTRON), hypotension, tachycardia, retinopathy including macular
edema,
retinal hemorrhage, cotton wool spots, papilledema, serous retinal
detachment,
ischemic and hemorrhagic cerebrovascular events, bone marrow
toxicity
(cytopenia and very rarely aplastic anemia), thyroiditis, dental and
periodontal disorders, hemorrhagic/ischemic colitis, dyspnea,
pulmonary
infiltrates, pneumonia, interstitial pneumonitis, pulmonary
hypertension,
hepatic failure, increases in serum creatinine in patients with
renal
insufficiency, acute hypersensitivity (angioedema,
bronchoconstriction,
anaphylaxis and cutaneous eruptions), hypertriglyceridemia, and
peripheral
neuropathy.
During the course of therapy lasting up to 48 weeks in patients ages
3 through
17 years receiving PEGINTRON/REBETOL combination therapy, weight
loss and
growth inhibition were common.
Please see full prescribing information at
http://www.spfiles.com/pipeg-intron.pdf.
About Schering-Plough
Schering-Plough is an innovation-driven, science-centered global
health care
company. Through its own biopharmaceutical research and
collaborations with
partners, Schering-Plough creates therapies that help save and
improve lives
around the world. The company applies its research-and-development
platform
to human prescription, animal health and consumer health care
products.
Schering-Plough's vision is to "Earn Trust, Every Day" with the
doctors,
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Hepatitis C drug development at a
crossroads - Comments from the Editors
"In summary, potent viral suppression and shortened duration
of therapy have been shown in the clinical trials with the
addition of protease inhibitors to standard therapy. Although
there is optimism surrounding the new STAT-C agents in the
treatment of HCV, there is also concern regarding how
resistance and new adverse events will impact future therapy. It
also appears that the platform exists to begin to explore non-IFN-containing
regimens, which would be an enormous step forward to
accessing a large proportion of infected patients. However,
this pathway forward is fraught with many hurdles and will need
to be undertaken with deliberation and caution. We clearly stand
at an important crossroads in treatment paradigms for HCV."
David R. Nelson, M.D. *
Section of Hepatobiliary Diseases, University of Florida,
Gainesville, FL email: David R. Nelson (nelsodr@medicine.ufl.edu)
*Correspondence to David R. Nelson, Section of Hepatobiliary
Diseases, University of Florida, 600 SW Archer Road, PO Box
100214, Gainesville, FL 32610-0214
Potential conflict of interest: Dr. Nelson is a consultant and
received grants from Roche, Vertex, Human Genome Sciences,
Bayer, Merck, and Bristol Myers Squibb.
fax: 352-392-7393
Article Text
The introduction of specifically targeted
antiviral therapy (STAT-C) to peginterferon (PEG-IFN) and
ribavirin (RBV) is soon at hand and will offer new treatment
opportunities to patients infected with hepatitis C. The
recently released Protease Inhibition for Viral Evaluation
(PROVE, evaluating telaprevir) and Serine Protease Inhibitor
Therapy (SPRINT, evaluating boceprevir) studies suggest that
protease inhibitors in combination with PEG-IFN/RBV can produce
sustained viral response rates (SVR) approaching 70% to 75% in
genotype 1, treatment-naïve patients and the potential to
shorten treatment duration in those with a rapid viral
response.[1-3] For previous nonresponders and relapsers to
interferon (IFN)-based therapies, there is realistic hope for
retreatment success (approximately 40% and 75% SVR,
respectively, in PROVE 3 data).[4] In addition, there is
early indication that STAT-C drugs may help overcome negative
host factors that have historically been associated with poor
response rates (such as ethnicity, insulin resistance, steatosis,
cirrhosis). A small cohort of African Americans included in
PROVE-1 had a four-fold higher SVR rate with telaprevir (44%
versus 11%), and the presence of cirrhosis did not negatively
impact SVR rates in PROVE-3.
Abbreviations
FDA, Food and Drug Administration; HIV, human immunodeficiency
virus; IFN, interferon; PEG-IFN, pegylated interferon; RBV,
ribavirin; SPRINT, Serine Protease Inhibitor Therapy; STAT-C,
specifically targeted antiviral therapy; SVR, sustained
virological resistance.
However, these trials also emphasize the limitations of protease
inhibitors, and viral resistance data have provided important
new lessons for small molecule drug development. The initial
rapid drop in hepatitis C virus (HCV) viral levels on protease
therapy is attributable to inhibition of the wild-type virus
that then leads to the 'uncovering' of preexisting resistant
variants.[5] The continued replication of these variants can
then lead to a virological breakthrough (ranging from 2%-24%
based on treatment regimen). Most reports have suggested that
resistant variants are present at very low frequencies (<1%) and
are usually detected after near complete suppression of the
dominant wild-type virus. However, a recent analysis has
suggested that naturally occurring drug resistance to protease
and polymerase inhibitors can be seen almost 10% of patients
with genotype 1.[6] Another important finding with significant
clinical implications from the PROVE trials is the different
rates of resistance mutations detected between genotype 1a and
1b (much higher for 1a). The most likely explanation for these
observations is a relative difference in the genetic barrier to
resistance between subtypes. For example, the V36M or R155K
mutation that can confer drug resistance to telaprevir requires
only one nucleotide change from genotype 1a consensus sequence,
whereas two substitutions are required in genotype 1b. Thus, it
appears that HCV subtyping may play an important role in helping
to select future treatment regimens and predict resistance
development.
Perhaps the most relevant conclusion of the PROVE and SPRINT
trials is that PEG-IFN and RBV will remain critical elements in
new treatment regimens. Patients who did not receive RBV in the
PROVE trials and those with low-dose RBV (400-1000 mg) in the
SPRINT-1 trial had increased viral breakthrough, higher relapse,
and lower SVR. These data strongly indicate that
standard-dose RBV is required to optimize response to these
first-generation protease inhibitors. In addition, a 4-week
lead-in phase of PEG-IFN/RBV in the SPRINT-1 trial led to a 50%
reduction in viral breakthrough, likely because of the delivery
of a more steady state of PEG-IFN/RBV and a lower viral load at
the onset of protease inhibitor introduction. Lead-in phase
approaches are now being extensively evaluated in other phase
2/3 programs, and its utility is still uncertain. Unfortunately,
a common theme across all trials was that adverse events such as
rash, pruritus, nausea, diarrhea, and anemia occurred more
frequently in the protease-containing arms versus the standard
of care arm. A higher proportion of both boceprevir-treated and
telaprevir-treated patients discontinued treatment because of
adverse events (1.5-fold to two-fold increase compared with
control arm).
The findings from the PROVE and SPRINT studies have dramatic
implications, because these are the first extensive phase 2 data
to suggest that a new treatment paradigm is on the horizon for
HCV infection. Both protease inhibitors have fully enrolled
phase 3 programs underway, and it is estimated that 2011 will
bring approval of at least one of these agents. However, given
the continued need for PEG-IFN and full-dose RBV, there are many
HCV-infected groups that may not benefit from the addition of
STAT-C agents, including decompensated cirrhosis, renal failure,
posttransplantation, and the IFN-intolerant group (which may
comprise as many as 50%-60% of all HCV-infected patients).[7]
Thus, what is desperately needed is the development of IFN-free
regimens; in other words, a combination of small molecules
similar to human immunodeficiency virus (HIV) therapy. The
groundwork for this strategy has been set, but it is currently
unclear whether HCV can be cured with direct-acting antiviral
agents alone and without IFN-containing regimens. In vitro
studies have confirmed additive/synergistic antiviral efficacy
and the reduction of resistance with combinations of STAT-C
agents, providing the biological plausibility to eradicate HCV
with pure antiviral drug therapy.[8] The first in vivo proof of
principle has been generated in the chimpanzee model, in which
HCV has been eradicated in one animal that was treated with dual
antiviral therapy, including a protease and polymerase
inhibitor.[9] A novel study called INFORM-1 (Interferon-Free
Regiment for the Management of HCV infection), the first
dual-combination clinical trial with oral antivirals in patients
with hepatitis C, is ongoing and evaluates the safety and
combined antiviral activity of R7227 (ITMN-191), a protease
inhibitor, and R7128, a polymerase inhibitor, in 14 days of
combination therapy in treatment-naïve patients infected with
HCV genotype 1.[10] The initial cohorts of this study were
recently reported and appear to lay the foundation for more
aggressive and prolonged non-IFN trial designs. Patients
receiving this combination for 14 days experienced a median
reduction in viral levels of 4.8 log to 5.2 log IU in the higher
doses tested. No treatment-related serious adverse events, dose
reductions, drug-drug interactions, or discontinuations were
reported. But, has this early success moved IFN-free regimens a
step closer to reality for patients?
The answer to this question depends largely on the Food and Drug
Administration (FDA) reaction to these emerging data. The
current regulatory climate in the United States is increasingly
conservative, and there has been limited interest in early non-IFN
regimens in HCV drug development. For an approval pathway,
superiority to standard of care will be required, thus leading
to add-on triple-therapy trial designs for most agents being
tested. It is also clear that FDA concerns of resistance
emergence will limit STAT-C monotherapy testing and place new
challenges before non-IFN drug development pathways. Extensive
preclinical resistance and safety testing are required before
initiating human trials, while duration of exposure to
monotherapy is being minimized (only 2-3 days of monotherapy
allowed in phase 1/2). The Advisory Committee for the FDA has
recommended that STAT-C agents should not undergo combination
with other STAT-C agents until after phase 2b completion of each
single agent.[11] The result of this regulatory climate has led
to the recent outsourcing of aggressive drug development to non-U.S.
territories. The INFORM-1 trial is being enrolled exclusively in
Australia and New Zealand, and one must assume that this is to
bypass the strict FDA regulatory environment.
Recently, this conservative approach for accelerated drug
development has come under fire, and a large number of HCV-infected
patients wonder why the hurdle appears higher than for HIV drug
development. HIV was considered a deadly disease in which
accelerated drug development was crucial, and the regulatory
environment was friendlier to accelerated development. However,
on the surface, HCV does not appear to present such a compelling
argument. Data from the Hepatitis C Antiviral Long-Term
Treatment Against Cirrhosis (HALT-C) study suggests an annual
death rate from those with advanced HCV-related disease of only
1%-2%.[12] However, there are other select groups of patients
who may suffer a much higher rate of mortality, including those
with decompensated cirrhosis, HIV/HCV coinfection, and
posttransplantation patients. Given recent data suggesting
that SVR leads to an improvement in liver-related complications
and mortality,[13][14] the addition of STAT-C agents has the
potential for an immediate impact on morbidity and mortality in
these special populations. However, most of these populations
have not been included in the phase 2 and 3 clinical trials to
date because of the need for extensive safety data and drug
interaction studies. Lost in the excitement around new STAT-C
therapies is the ever-growing list of HCV agents that have been
removed from clinical development in the last few years. At
least 15 drugs have had development halted during clinical
trials, and there are likely many more that have not entered the
public domain. Of note, most of these compounds have been
discontinued not because of lack of antiviral activity, but
rather because of unacceptable adverse event profiles (ranging
from cardiomyopathy to hepatotoxicity). Thus, exposing these
at-risk populations to early drug development may be associated
with challenging adverse event profiles. Lastly, there is
theoretical concern that early and ineffective combination of a
protease and a polymerase inhibitor could lead to multidrug
resistance and compromise future treatment regimens.
In summary, potent viral suppression and shortened duration of
therapy have been shown in the clinical trials with the addition
of protease inhibitors to standard therapy. Although there is
optimism surrounding the new STAT-C agents in the treatment of
HCV, there is also concern regarding how resistance and new
adverse events will impact future therapy. It also appears that
the platform exists to begin to explore non-IFN-containing
regimens, which would be an enormous step forward to accessing a
large proportion of infected patients. However, this pathway
forward is fraught with many hurdles and will need to be
undertaken with deliberation and caution. We clearly stand at an
important crossroads in treatment paradigms for HCV.
References
1 McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski
M, Kauffman R, et al. Telaprevir with peginterferon and
ribavirin for chronic HCV genotype 1 infection. N Engl J Med
2009; 360: 1827-1838.
2 HŽzode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T,
et al. Telaprevir and peginterferon with or without ribavirin
for chronic HCV infection. N Engl J Med 2009; 360: 1839-1850.
3 Kwo P, Lawitz E, Malone J, Schiff E, Vierling J, Pound D, et
al. HCV SPRINT-1 final results: SVR 24 from a phase 2 study of
boceprevir plus pegintron/ribavirin in treatment naïve subjects
with genotype-1 chronic hepatitis C. J Hepatol 2009, 1(50): 54.
4 Manns M, Muir A, Adda N, Jacobsen I, Afdhal N, Heathcote J, et
al. Telaprevir in hepatitis C genotype-1-infected patients with
prior non-response, viral breakthrough or relapse to
peginterferon-alfa2a/b and ribavirin therapy: SVR results of the
PROVE3 study. Program and abstracts of the 44th Annual Meeting
of the European Association for the Study of the Liver; April
22-26, 2009; Copenhagen, Denmark [Abstract 1044].
5 Kieffer TL, Sarrazin C, Miller JS, Welker MW, Forestier N,
Reesink HW, et al. Telaprevir and pegylated interferon-alpha-2a
inhibit wild-type and resistant genotype 1 hepatitis C virus
replication in patients. HEPATOLOGY 2007; 47: 631-639.
6 Kuntzen T, Timm J, Berical A, Lennon N, Berlin AM, Young SK,
et al. Naturally occurring dominant resistance mutations to
hepatitis C virus protease and polymerase inhibitors in
treatment-naïve patients. HEPATOLOGY 2008; 48: 1769-1778.
7 Backus LI, Boothroyd DB, Phillips BR, Mole LA. Predictors of
response of U.S. Veterans to treatment for the hepatitis C
virus. HEPATOLOGY 2007; 46: 37-47.
8 Grunberger C, Wyles DL, Kaihara KA, Schooley RT. 3-Drug
synergistic interactions of small molecular inhibitors of
hepatitis C virus replication. J Infect Dis 2008; 197: 42.
9 Olsen D, et al. A combination of direct antiviral compounds
show synergistic activity in vitro and enhanced efficacy in
vivo. In program and abstracts of the 18th Conference of the
Asian Pacific Association for the Study of Liver, Seoul, Korea,
March 23-26, 2008 [Abstract] [FP149].
10 Gane EJ, Roberts C, Stedman C, Angus PW, Ritchie B, Elston R.
First-in-man demonstration of potent antiviral activity with a
nucleoside polymerase (R7128) and protease (R227/ITMN-191)
inhibitor combination in HCV: safety, pharmacokinetics, and
virology results from INFORM-1. J Hepatol 2009; 50: S380.
11 Sherman KE, Fleischer R, Laessig K, Murray J, Tauber W,
Birnkrant D, et al. Development of novel agents for the
treatment of chronic hepatitis C infection: summary of the FDA
Antiviral Products Advisory Committee recommendations.
HEPATOLOGY 2007; 46: 2014-2020.
12 DiBisceglie AM, Shiffman ML, Everson GT, Lindsay KL, Everhart
JE, Wright EC, et al. Prolonged therapy of advanced chronic
hepatitis C with low-dose peginterferon. N Engl J Med 2008; 359:
2429-2441.
13 Bruno S, Stroffolini T, Colombo M, Bollani S, Benvegnu L,
Mazzella G, et al. Sustained virological response to
interferon-alpha is associated with improved outcome in HCV-related
cirrhosis: a retrospective study. HEPATOLOGY 2007; 45: 579-587.
14 Veldt BJ, Heathcote EJ, Wedemeyer H, Reichen J, Hoffmann WP,
Zeuzem S, et al. Sustained virologic response and clinical
outcomes in patients with chronic hepatitis C and advanced
fibrosis. Ann Intern Med 2007; 147: 677-684.
Idera
Pharmaceuticals Initiates Phase 1 Clinical Trial of IMO-2125, a TLR9
Agonist, in Combination with Ribavirin for Chronic Hepatitis C Virus
Infection
Oct 07 2009
CAMBRIDGE, Mass.--
(BUSINESS WIRE)--Idera
Pharmaceuticals, Inc. (Nasdaq: IDRA) today announced that patient
treatment has been initiated in a phase 1 clinical trial evaluating
IMO-2125 in combination with ribavirin in treatment-naive patients with
chronic hepatitis C virus (HCV) infection. IMO-2125 is a novel agonist
of Toll-like Receptor (TLR) 9.
“We expect that the IMO-2125 trial with ribavirin in treatment-naïve HCV
patients and our ongoing IMO-2125 monotherapy trial in HCV patients who
failed to respond to previous standard of care therapy will provide us
with data in two HCV patient populations on safety, immunological
activity, and effect on HCV RNA levels,” said Tim Sullivan, Ph.D., Vice
President of Development Programs. “We plan to use the data from these
ongoing trials to guide us in further clinical development of IMO-2125
in the treatment of chronic HCV infection.”
About the Trial
The phase 1 randomized, placebo-controlled clinical trial evaluating
IMO-2125 in combination with ribavirin is being conducted in
treatment-naïve patients with genotype 1 chronic HCV infection. IMO-2125
is administered subcutaneously once a week for four weeks in combination
with daily oral administration of standard doses of ribavirin.
The target enrollment is 15 patients per cohort, with 12
randomized to receive IMO-2125 plus ribavirin treatment and three
randomized to receive placebo plus ribavirin treatment. The primary
objective of the trial is to assess the safety and tolerability of
IMO-2125 over an escalating range of dosages in combination with
standard doses of ribavirin. In addition, the effect of treatment on HCV
RNA levels will be monitored.
The clinical trial is expected to be conducted at five or
more sites in France and Russia.
Upcoming Presentations on IMO-2125 at the 60th Annual Meeting of the
American Association for the Study of Liver Diseases
The Company’s two abstracts have been published and can be accessed on
the AASLD website.
The abstracts are:
Abstract 1593: “IMO-2125, a TLR9 agonist, induces Th-1 type cytokines
and interferons with potent anti-HCV activity in human peripheral blood
mononuclear cells and plasmacytoid dendritic cells”
Abstract 1597: “Gene expression profiles induced by IMO-2125, an agonist
of Toll-like receptor 9, in human peripheral blood mononuclear cells”
The posters will be presented on Tuesday, November 3, at 8:00AM ET.
About IMO-2125
IMO-2125 is a novel DNA-based TLR9 agonist being evaluated for the
treatment of chronic HCV infection. IMO-2125 was designed to induce
endogenous interferon-alpha along with other immune response factors to
treat hepatitis C. In preclinical studies, the immune response factors
induced by IMO-2125 have potent activity alone and in combination with
ribavirin in HCV replicon assays. In addition to the announced trial,
IMO-2125 is also being evaluated as a monotherapy in an ongoing phase 1
randomized, placebo-controlled clinical trial for the treatment of
patients with chronic HCV infection who have failed to respond to
previous standard of care combination therapy of ribavirin and pegylated
interferon-alpha.
About the IMO-2125
Monotherapy Trial
In this trial, IMO-2125 is administered subcutaneously once a week with
four weeks of treatment. The target enrollment is ten patients per
cohort, with eight randomized to receive IMO-2125 treatment and two
randomized to receive placebo treatment. The trial is designed to assess
the safety and tolerability of IMO-2125 over an escalating range of dose
levels and to determine the effect of IMO-2125 on HCV RNA levels and
parameters of immune system activation. The trial is being conducted at
six U.S. sites.
About Idera Pharmaceuticals, Inc.
Idera Pharmaceuticals develops drug candidates to treat infectious
diseases, autoimmune and inflammatory diseases, cancer, and respiratory
diseases, and for use as vaccine adjuvants.
Our proprietary drug candidates are designed to modulate
specific Toll-like Receptors (TLRs), which are a family of immune system
receptors that direct immune system responses. Our pioneering DNA and
RNA chemistry expertise enables us to create drug candidates for our
internal development programs and our partnered programs, and generates
opportunities for additional collaborative alliances.
This press release contains forward-looking statements
concerning Idera Pharmaceuticals, Inc. that involve a number of risks
and uncertainties.
For this purpose, any statements contained herein that
are not statements of historical fact may be deemed to be
forward-looking statements. Without limiting the foregoing, the words
"believes," "anticipates," "plans," "expects," "estimates," "intends,"
"should," "could," "will," "may," and similar expressions are intended
to identify forward-looking statements.
There are a number of important factors that could cause
Idera's actual results to differ materially from those indicated by such
forward-looking statements, including whether results obtained in
preclinical studies will be indicative of results obtained in future
clinical trials; whether products based on Idera's technology will
advance into or through the clinical trial process on a timely basis or
at all and receive approval from the United States Food and Drug
Administration or equivalent foreign regulatory agencies; whether, if
the Company's products receive approval, they will be successfully
distributed and marketed; whether the Company's collaborations with
Novartis, Merck & Co., and Merck KGaA will be successful; whether the
patents and patent applications owned or licensed by the Company will
protect the Company’s technology and prevent others from infringing it;
whether Idera's cash resources will be sufficient to fund the Company's
operations; and such other important factors as are set forth under the
caption "Risk Factors" in Idera's Quarterly Report on Form 10-Q for the
three months ended June 30, 2009, which important factors are
incorporated herein by reference. Idera disclaims any intention or
obligation to update any forward-looking statements.
CAMBRIDGE, Mass. (TheStreet)
-- The hepatitis C drug telaprevir from Vertex Pharmaceuticals(VRTX
Quote) is working its way through phase III clinical trials and is
widely expected to be the first new drug in years approved for the treatment
of the chronic liver disease. But how long can telaprevir maintain its "king
of the mountain" status?
And which drug, if any, will be the one to knock telaprevir
from its perch? Questions like these form a recurring subplot for Wall
Street twice a year when liver disease experts gather to present new
research.
Boerhinger Ingelheim's BI-201335 (let's call it '335 for short) seems to be
the telaprevir competitor receiving the most attention as Wall Street gears
up for the American Association for the Study of Liver Disease annual
meeting, Oct. 30 through Nov. 4.
'335, like telaprevir, is a protease inhibitor targeting the hepatitis C
virus, but '335 has the potential to be dosed once daily. Telaprevir will be
dosed three times daily upon approval, although the drug could potentially
be given on a twice-daily schedule.
Research abstracts for the AASLD meeting were released last week and the
early data from '335 appears to place the drug's efficacy squarely in line
with what's been reported from older telaprevir studies. ['335 is still in
phase II studies, so it's year behind telaprevir in terms of clinical
development.]
The debate over '335's safety, however, seems unsettled. Bank of
America/Merrill Lynch analyst Rachel McMinn calls '335's safety profile "not
as clean as feared" due to reports of jaundice and severe rash.
Morgan Stanley's Steve Harr, however, looks at the same '335 data and sees a
potent telaprevir competitor. The rate of severe rash from '335 is less than
that reported with telaprevir and the jaundice reports, while raising
concerns about potential liver toxicity, appear to resolve after a few weeks
of treatment, he says.
More detailed data on '335 will be presented when the AASLD meeting convenes
in a few weeks, so expect to hear a lot more about '335 and its competitive
profile against Vertex's telaprevir.
Avila Presents
Preclinical Data on its Novel, Orally-Available, Pan-Genotype Protease
Inhibitor,
AVL-181, Demonstrating Protein
Silencing of Hepatitis C Virus
Oct 05
A biotechnology company developing novel covalent drugs that
treat diseases through protein silencing, presented results of preclinical
studies on its highly selective, pan-genotype, small molecule Hepatitis C
Virus (HCV) protease inhibitor, AVL-181. The data showed that AVL-181 bonds
selectively, covalently and irreversibly to HCV protease (also known as
“NS3/4A”), thus silencing a key protein necessary for successful viral
replication resulting in a prolonged duration of action.
Furthermore, the data demonstrate that the amount of HCV protease silenced
by AVL-181 can be measured in a dose- and time-dependent manner in an animal
model using Avila’s novel translational technology known as a covalent
probe. With this novel technology, Avila demonstrated that AVL-181
successfully blocked HCV protease enzyme activity and that the HCV protease
target was covalently bonded and silenced in vivo.
These data were presented today at the 16th International
Symposium on HCV and Related Viruses in Nice, France.
"In addition to the ability of AVL-181 to provide sustained inhibition
across multiple genotypes and drug-resistant mutations of the HCV protease,
these data now demonstrate a unique translational advantage. With Avila’s
covalent probe technology, efficacy and target occupancy can be directly
correlated and measured, which is a powerful tool for drug development,”
said Katrine Bosley, Chief Executive Officer, Avila. "These data provide
further support for the clinical evaluation of AVL-181, and we are planning
to advance into clinical development next year.”
In the study, “Protein Silencing of Hepatitis C Virus NS3/4A Protease In
Vitro and In Vivo Using a Novel Drug Design Strategy” (Poster P203), the
data demonstrate that the orally available,
novel HCV protease inhibitor,
AVL-181:
Potently and irreversibly silences wild-type and drug-resistant HCV
proteases;
Durably inhibited the HCV protease, including drug resistant mutants, for
more than 24 hours after a single exposure as measured in a novel in vivo
model in which NS3/4A is expressed and active in the mouse liver; this
prolonged inhibition correlates with the protease half-life and contrasts
with the need for nearly continuous exposure required by the reversible HCV
protease inhibitors currently in late-stage clinical trials;
Occupies the HCV protease target for several hours after the drug had been
cleared, as measured with a novel covalent probe technology; this protease
occupancy correlated directly with sustained inhibition of the protease, and
the return of protease activity was correlated with new synthesis of NS3
protease; and
Has excellent pharmacokinetic properties, including excellent oral
bioavailability in rats as measured in both plasma and liver.
About the Avilomics™ Platform and Covalent Drugs
The Avilomics platform is Avila’s powerful approach to design and develop
covalent drugs that strongly, selectively, and resiliently bond to
disease-causing proteins, thereby silencing their activity and producing
superior pharmacological outcomes.
The approach with covalent drugs inherently provides
prolonged duration of action through this silencing of the disease target.
Covalent drugs can also solve the critical therapeutic challenges of
drugging difficult targets and addressing resistance mutations.
The three components of Avilomics are:
Compositions: Innovative chemical structures for forming highly selective,
not indiscriminate, covalent bonds
Design: Proprietary informatics to uniquely identify sites amenable to
selective covalent modification and target silencing Testing: Empirical methods to
demonstrate covalent specificity at both target and proteomic levels
Together, these components provide a platform for efficient
design and testing of covalent drugs. Avilomics opens up the broad potential
of covalent drugs across target classes and disease areas, as demonstrated
with the company’s emerging pipeline of novel, protein-silencing covalent
drugs.
About Avila Therapeutics™, Inc.
Avila focuses on design and development of covalent drugs to achieve
best-in-class outcomes that cannot be achieved through traditional
chemistries. This approach is called “protein silencing”.
The company is developing a pipeline of novel,
protein-silencing covalent drugs with a current focus on viral infection,
cancer and autoimmune disease. Avila is funded by leading venture capital
firms: Abingworth, Advent Venture Partners, Atlas Ventures, Novartis Option
Fund, and Polaris Venture Partners.
Conatus Pharmaceuticals to Present at the Montgomery
Healthcare Conference
SAN DIEGO, Oct. 5 /PRNewswire/ --
Conatus Pharmaceuticals Inc., a privately
held, clinical stage company developing a treatment for
liver disease associated with Hepatitis C Virus (HCV),
announced today that Steven J. Mento, Ph.D., President
and Chief Executive Officer, will present at the
Montgomery Healthcare Conference being held in Menlo
Park, CA, on October 6, 2009.
Conatus is one of only 30 companies
selected to present to this invitation-only audience of
senior-level private equity and venture capital
investors and corporate industry executives.
Dr. Mento will provide a corporate overview and
highlight Conatus' scientific rationale, progress in
clinical development and business development strategy
of its lead compound, CTS-1027.
Conatus recently initiated a second Phase 2 clinical
trial with its novel drug candidate CTS-1027 for the
treatment of liver disease associated with HCV
infection.
The trial is enrolling patients who have
not undergone therapy with approved standard of care
treatments. Results from an earlier Phase 2 clinical
trial in HCV patients who failed standard of care
treatment are expected to be reported later this year.
CTS-1027 is an oral, small molecule compound that
inhibits the activity of key members of a class of
protease enzymes, the matrix metalloproteinases or MMPs.
CTS-1027 has shown to be effective in multiple
preclinical models of inflammatory liver disease and HCV
infection.
"Preclinical studies suggest that treatment with
CTS-1027 has the potential to impact the second phase of
HCV inhibitory kinetics in patients.
This phase is associated with the
gradual reduction and
replacement of HCV-infected cells by uninfected liver
cells," said Steven J. Mento, President and CEO
of Conatus.
"We believe that CTS-1027 represents a
novel approach to treating HCV disease and look forward
to developing this drug candidate to fill an important
medical need in HCV-infected patients."
Conatus Pharmaceuticals Inc. is a privately-held
specialty pharmaceutical company engaged in the
development of innovative therapeutics to treat liver
disease.
Chronic liver disease affects millions of
people worldwide and can be caused by many different
conditions or "insults" to the liver including Hepatitis
C and other viral infections, obesity, chronic alcohol
abuse or autoimmune diseases.
Conatus was founded by the executive
management team of Idun Pharmaceuticals in July 2005
following the successful sale of Idun to Pfizer. For
additional information, please visit
www.conatuspharma.com
InterMune
Announces Initiation of Ritonavir-Boosted ITMN-191/RG7227 Study
in HCV Patients
BRISBANE, Calif., Sept. 29
/PRNewswire-FirstCall/ -- InterMune, Inc. (Nasdaq: ITMN) today
announced that its partner Roche has begun dosing in a Phase 1b
multiple ascending dose (MAD) study of ITMN-191 (RG7227) boosted
by low-dose ritonavir in patients chronically infected with
hepatitis C virus (HCV) genotype-1.
Ritonavir boosting is an option to enhance and improve
pharmacokinetic profiles of protease inhibitors. It is well
established in the treatment of HIV where it leads to more
convenient dosing, reduced resistance development and high
efficacy.
Not all HCV protease inhibitors are
suitable for ritonavir boosting. However, as InterMune announced
on August 6, 2009, ITMN-191 showed high promise in a Phase 1
single ascending dose (SAD) study in healthy volunteers.
Important PK parameters showed marked improvement and
significant increases in AUC and drug concentrations were
observed. There were no remarkable safety findings.
"We and our partner Roche are very pleased by the performance of
ITMN-191 in twice-daily regimens when un-boosted with ritonavir,"
said Dan Welch, Chairman, Chief Executive Officer and President
of InterMune. "However, if results of ritonavir boosting of
ITMN-191 in human volunteers are replicated in this study of HCV
patients, the approach could lead to achieving more sustained
exposures with lower twice-daily doses of ITMN-191 or perhaps
allow once-daily administration. Either of these two
possibilities could provide patients a regimen with more
convenient administration and with the clinical advantages
associated with sustained drug exposure."
The objective of the MAD study is to determine the
pharmacokinetic (PK), viral kinetic and safety profiles of
ascending doses of once-daily and twice-daily ITMN-191
co-administered with low doses of ritonavir and standard dose
Pegasys® (peginterferon alfa-2a) and Copegus® (ribavirin) in HCV-infected
patients and for 14 days. On August 6, the company announced
results of a Phase 1 study of ITMN-191 co-administered with low
dose ritonavir in healthy volunteers.
About ITMN-191/RG7227ITMN-191/RG7227 is a potent, macrocyclic
inhibitor of HCV NS3/4A protease activity currently in Phase 2b
development. The compound is being developed in collaboration
with Roche. ITMN-191 has produced multi-log10 reductions in HCV
levels in chronic HCV patients, when administered for 14 days as
monotherapy. When ITMN-191 was combined with Pegasys and Copegus,
or the NS5B polymerase in Phase 1b studies, it reduced HCV viral
loads below the limit of quantification in the majority of
study-treated patients. The safety and antiviral activity of
ITMN-191 is also under clinical investigation in combination
with the NS5B nucleoside inhibitor RG7128 in the INFORM clinical
development program. To date, ITMN-191 has been safe and well
tolerated in these studies.
About InterMuneInterMune is a biotechnology company focused on
the research, development and commercialization of innovative
therapies in pulmonology and hepatology. InterMune has an R&D
portfolio addressing idiopathic pulmonary fibrosis (IPF) and
hepatitis C virus (HCV) infections. The pulmonology portfolio
includes pirfenidone for which a Phase 3 program in patients
with IPF (CAPACITY) has been completed and the compound is
currently in the pre-registration stage.
The company also has a research
program focused on a pirfenidone analog named ITMN-520. The
hepatology portfolio includes the HCV protease inhibitor
compound ITMN-191 (referred to as RG7227 at Roche) that entered
Phase 2b in August of 2009 and a second-generation HCV protease
inhibitor research program. For additional information about
Characterization of resistance to the protease inhibitor
boceprevir in hepatitis C virus-infected patients.
Posted : Oct 01
Susser S, Welsch C, Wang Y,
Zettler M, Domingues FS, Karey U, Hughes E, Ralston R, Tong
X, Herrmann E, Zeuzem S, Sarrazin C.
J. W. Goethe University Hospital, Frankfurt, Germany.
Editor’s Note:
This is a small, but important study on the drug resistance and
cross resistance profile of boceprevir used as a monotherapy for a
short period of time. In the conclusions of the study, the authors
state that drug resistance and cross resistance with telaprevir may
have important implications – that is, that the use of boceprevir
may limit the future use of other HCV protease inhibitors such as
telaprevir if treatment with boceprevir is not successful. It is
not clear, however, if the addition of pegylated interferon plus
ribavirin will ultimately prevent resistance.
Alan
Franciscus
Characterization of resistance to the protease inhibitor boceprevir
in hepatitis C virus-infected patients.
Susser S, Welsch C, Wang Y, Zettler M, Domingues FS, Karey U, Hughes
E, Ralston R, Tong X, Herrmann E, Zeuzem S, Sarrazin C.
J. W. Goethe University Hospital, Frankfurt, Germany.
Introduction:
Boceprevir is a hepatitis C virus (HCV) nonstructural protein (NS)
3/4A protease inhibitor that is currently being evaluated in
combination with peginterferon alfa-2b and ribavirin in phase 3
studies. The clinical resistance profile of boceprevir is not
characterized in detail so far.
Methods
The NS3 protease domain of viral RNA was cloned from HCV genotype
1-infected patients (n = 22). A mean number of 47 clones were
sequenced before, at the end, and after treatment with 400 mg
boceprevir twice or three times daily for 14 days
for genotypic, phenotypic, and viral fitness analysis.
Results
At the end of treatment, wild-type an NS3 protease sequence was
observed with a mean frequency of 85.9%. In the remaining isolates,
five previously observed resistance mutations (V36M/A, T54A/S,
R155K/T, A156S, V170A) and one mutation (V55A) with unknown
resistance to boceprevir were detected either alone or in
combination. Phenotypic analysis in the HCV replicon assay showed
low (V36G, T54S, R155L; 3.8- to 5.5-fold 50% inhibitory
concentration [IC(50)]), medium (V55A, R155K, V170A, T54A, A156S;
6.8- to 17.7-fold IC(50)) and high level (A156T; >120-fold IC(50))
resistance to boceprevir.
The
overall frequency of resistant mutations and the level of resistance
increased with greater declines in mean maximum HCV RNA levels. Two
weeks after the end of treatment, the frequency of resistant
variants declined and the number of wild-type isolates increased to
95.5%. With the exception of V36 and V170 variants all resistant
mutations declined by more than 50%. Mathematical modeling revealed
impaired replicative fitness for all single mutations, whereas for
combined mutations a relative increase of replication efficiency was
suggested.
Conclusion:
During boceprevir monotherapy, resistance mutations at six positions
within the NS3 protease were detected by way of clonal sequence
analysis. All mutations are associated with reduced replicative
fitness estimated by mathematical modeling and show cross-resistance
to telaprevir.
"Besides
telaprevir, Vertex has also
begun clinical studies on
next-generation hepatitis C
protease inhibitors....Vertex is
expected to file a new-drug
application for telaprevir in
the second half of next year,
and could launch the product in
2011 if it's approved.....Vertex
on Sept. 24 disclosed that it
will announce data results on
the twice-daily dosing of
telaprevir at the 60th annual
meeting of the American
Association for the Study of
Liver Diseases in Boston on Oct.
30 through Nov. 3, 2009"....
"Vertex could well be a takeover
target of Johnson & Johnson,
Bristol-Myers Squibb, or
Gilead.""
Marcial: Pharma Firms May Vie
for Vertex
Telaprevir is a potential
blockbuster drug for treating
hepatitis C, with a
multibillion-dollar market.
Vertex could get FDA approval
for it next year
Expect merger-and-acquisition
activity to heat up in the
biotechnology sector. That's the
prognostication of many analysts
who have become more upbeat
about the industry, with share
prices now outpacing most other
small-to-mid-cap stock groups.
The Nasdaq biotech stock index
gained 3.15% in the week of
Sept. 14, vs. the broader Nasdaq
composite index's 2.50%, notes
Simos Simeonides, senior biotech
analyst at investment firm
Rodman & Renshaw (RODM), who
believes the biotech rally will
likely persist this year. Both
the profitable biotech companies
as well as those that are still
trying to develop and produce
drugs for approval by the Food &
Drug Administration have been
gaining ground, he adds.
Analysts note that the young
biotechs that have yet to earn a
penny are again attracting
accelerated interest from large
pharmaceutical companies.
Health-care analysts at Credit
Suisse (CS) believe there is a
higher likelihood of large
drugmakers pursuing smaller
biotech outfits to augment their
drug pipelines. They believe
there will be less likelihood of
megamerger deals occurring among
the major drugmakers.
One of the biotechs the Credit
Suisse analysts believe will be
a target of major drug firms:
Vertex Pharmaceuticals (VRTX),
which focuses on the discovery
and development of
small-molecule drugs to treat
viral infections, inflammation,
and cancer. Its chief product is
telaprevir for the treatment of
hepatitis C (HCV).
EXPIRING PATENT PRESSURE
Vertex's name emerges whenever
the subject of merger deals in
the biotech sector pops up, says
Steven Silver, biotech analyst
at Standard & Poor's. (S&P, like
BusinessWeek, is a unit of The
McGraw-Hill Companies (MHP).) He
notes that a number of the major
pharmaceuticals, particularly
those likely to lose huge
revenues because of drugs facing
patent expiration, are eager to
buy biotechs with drugs that
could replace those medicines.
Vertex's attraction: Telaprevir
is a potential blockbuster drug
with a multibillion-dollar
market that could get approval
next year, notes Silver. The
product, he says, is "likely to
emerge as a leader in treating
hepatitis C (HCV), which
afflicts more than three million
people in the U.S." He rates
Vertex a buy with a 12-month
target of 43. However, "My price
objective of 43 doesn't include
a takeover premium," he adds.
Vertex spokesman Cach Barber
declined comment, saying the
company doesn't respond to
market speculation.
Analyst Rachel McMinn of Bank of
America Merrill Lynch (BAC), who
rates Vertex a buy, projects a
higher price target of 48,
mainly based on her "high
expectations" for telaprevir.
Vertex is "well positioned," she
says, to be the first to bring
to market a "novel, highly
potent oral medicine to treat a
broad range of patients with HCV."
She forecasts telaprevir sales
of $3.6 billion in 2013, which
she says would make it "one of
the highest-profile biotech
product launches in the next 18
months." (Bank of America
Merrill Lynch has done business
with Vertex.)
EMBRACED BY J&J
Who could be the potential
suitors? Credit Suisse believes
Vertex could well be a takeover
target of Johnson & Johnson (JNJ),
Bristol-Myers Squibb (BMY), or
Gilead (GILD).
Other biotechs the Credit Suisse
analysts believe could also be
targets of big drugmakers:
Alexion (ALXN), Amylin (AMNL),
Biomarin (BMRN), Rigel (RIGL),
and Salix (SLXP).
But some analysts believe Vertex
may be the more attractive
target as it is already in a
close embrace with Johnson &
Johnson. Vertex partnered with
J&J in 2006 to develop and
commercialize telaprevir in
Europe and several other
regions. Vertex received an
upfront payment of $165 million
from J&J and could potentially
"receive a total of $545 million
in license and milestone
payments," says S&P's Silver.
Shares of Vertex have been on a
roll, hitting a 52-week high of
38.50 a share on Sept. 21 from a
52-week low of 18.43 on Oct. 28,
2008. The stock's advance is in
part ascribed to the takeover
speculation. It climbed as high
as 45 in 2006 when the deal with
Johnson & Johnson was announced.
The stock closed on Sept. 25 at
36.39.
Analyst Maged Shenouda of
investment bank UBS (UBS), who
met with senior executives of
Vertex on Sept. 21 for an update
on telaprevir, says that while
numerous compounds to treat
hepatitis C are in development,
telaprevir "possesses the most
competitive efficacy, safety,
and treatment duration profile."
"SUPERIOR EFFICACY," SHORTER
TREATMENT
Rating Vertex a buy, Shenouda
says the drug is a "major
advance in the treatment of HCV."
The company, he adds, is
studying more competitive dosing
regimens for telaprevir. It has
completed three phase III
clinical studies on dosing.
Vertex on Sept. 24 disclosed
that it will announce data
results on the twice-daily
dosing of telaprevir at the 60th
annual meeting of the American
Association for the Study of
Liver Diseases in Boston on Oct.
30 through Nov. 3, 2009. Drugs
in existence have a three-dose
regimen,
"We believe the drug has shown
superior efficacy to rivals,"
says S&P's Silver, and notes
that telaprevir's treatment
duration of 24 weeks vs. the 48
weeks in current
standard-of-care drugs would be
a big advantage.
Vertex is expected to file a
new-drug application for
telaprevir in the second half of
next year, and could launch the
product in 2011 if it's
approved. Besides telaprevir,
Vertex has also begun clinical
studies on next-generation
hepatitis C protease inhibitors.
It also is studying novel small
molecules for the treatment of
cystic fibrosis in partnership
with the Cystic Fibrosis
Foundation.
On Wall Street, Vertex has been
attracting significant support,
with 16 of 24 analysts who
follow it recommending a buy for
its stock, with 8 others rating
it a hold. Big shareholders
include Fidelity Management,
which holds an 11.7% stake,
Capital World Investors with
5.3%, and Barclays Global
Investors with 4.9%.
Those institutions-and lots of
smaller shareholders-should not
be too surprised if a takeover
bid emerges as drug companies
discover the virtues of Vertex.
Unless otherwise noted, neither
the sources cited in Gene
Marcial's Stock Picks nor their
firms hold positions in the
stocks under discussion.
Similarly, they have no
investment banking or other
financial relationships with
them. Marcial writes the Inside
Wall Street column for
BusinessWeek. In 2008, FT Press
published the bookGene Marcial's
7 Commandments of Stock
Investing.
Unless otherwise
noted, neither the sources cited
in Gene Marcial's Stock Picks
nor their firms hold positions
in the stocks under discussion.
Similarly, they have no
investment banking or other
financial relationships with
them.
Marcial writes the Inside Wall
Street column for BusinessWeek.
In 2008, FT Press published the
bookGene Marcial's 7
Commandments of Stock Investing.http://www.natap.org/2009/HCV/092909_01.htm
ChemDiv and IDialog Announce Completion
of Preclinical Studies of Novel Oral HCV
Inhibitor ID-12
Sep 29 09
A drug development
collaboration recently
announced completion of
preclinical studies of
ID-12, an
investigational oral
hepatitis C virus (HCV)
inhibitor that appears
to blocks the spread of
the virus via
cell-to-cell contact.
The first Phase 1 human
trials are schedules to
start in Russia by the
end of the 2009.
Below is the text of a ChemDiv press
release announcing the recent progress.
ChemDiv and IDialog Nominate
Novel Inhibitor of Hepatitis C for
Clinical Development
San Diego, CA -- September 15, 2009 --
ChemDiv Inc. of San Diego, and iDialog (Intellektualniy
Dialog) of Yaroslavl, Russia, announced
today the successful completion of a
pre-clinical development and the
subsequent nomination of ID-12 as lead
clinical development candidate for the
treatment of chronic hepatitis C. This
novel small molecule orally-bioavailable
inhibitor of hepatitis C virus (HCV)
blocks early stage of viral infection.
Vadim Bichko, PhD, ChemDiv's Vice
President of Virology, stated: "We are
very encouraged by the safety, potency,
PK [pharmacokinetic] profile, and novel
molecular mechanism of action, exhibited
by iDialog's HCV inhibitor in the
preclinical studies. We are quite
excited by the ability of ID-12 to
prevent spread of viral infection
through cell-cell contact, which makes
it superior to the neutralizing
antibodies and other viral entry
inhibitors. This mechanism of action is
complimentary to that of other classes
of HCV inhibitors currently on the
market, or in late stage clinical
development. Thus, ID-12 is a
potentially important component of
therapeutic cocktails for chronic
hepatitis C."
The Phase I study is scheduled to begin
in Q4 2009, and will be conducted in
Russia. The objectives of the trial
include assessment of safety,
tolerability and pharmacokinetics.
iDialog plans to present first clinical
results at a scientific meeting in the
second half of 2010. ChemDiv will
continue supporting R&D programs of
iDialog, including proof of concept
studies in man, through its Chemical
Diversity Research Institute in Moscow,
Russia.
Prof. Dr. Mikhail Dorogov, Director
General of iDialog, confirmed: "We are
happy that our discovery effort over
last 3 years resulted in advancement of
the candidate molecule to clinic. We
shall strive in developing a successful
new therapy for treatment of large
population of hepatitis C patients
worldwide. With its current financing
iDialog is planning to complete the
early development program to obtain
clinical proof of concept. We are
actively exploring options, which will
allow us to accelerate the program with
maximizing our shareholder's return on
investment. We believe our approach is
matching to innovative models of early
partnering, co-development an
co-investment established by pharma and
investment community in the recent
past."
About Hepatitis C
The U.S. Centers for Disease Control and
Prevention estimate that about 4.1
million persons in the United States
have been infected with HCV, and 3.2
million of these people are chronic
carriers. Russian Ministry of Health and
Social Development estimates that over 7
million people in Russia have been
infected with various types of hepatitis
and 2 million of them, chronically.
About ChemDiv
ChemDiv Inc. (Chemical Diversity) is a
global contract research organization
accelerating external discovery and
development of novel therapies through
comprehensive Discovery Outsource
services, including discovery biology,
medicinal and synthetic chemistry,
pre-clinical and clinical development.
About iDialog
iDialog was established in 2006 as an
innovative biopharma start up. It
received over USD$3M of seed investment
from Torrey Pines Investment in 2007 and
subsequently won the research
partnership award of over USD$3 from the
Russian Federal Agency of Science and
Innovation for development of novel
anti-infective agents to match unmet
needs in Russia. iDialog conducted and
continues the broad program to discover
novel therapies for tuberculosis,
hepatitis C and Influenza, in
partnership with Moscow State University
and other academic organizations. In
2008 iDialog established the R&D
collaboration with ChemDiv's Chemical
Diversity Research Institute for
discovery and development of novel small
molecule anti-infective agents, which is
extended to 2011.
9/29/09
Reference
ChemDiv, Inc. ChemDiv and IDialog
Nominate Novel Inhibitor of Hepatitis C
for Clinical Development. Press
release. September 15, 2009.
Achillion Completes Phase 1a
Trial of ACH-1625; Begins Dosing
in Phase 1b Segment With HCV-Infected
Patients
Sept 29 09
ACH-1625 Safe and
Well-Tolerated in Single
Ascending and Multiple Ascending
Dose Trial Segments
NEW HAVEN, Conn., Sept. 28,
2009 (GLOBE NEWSWIRE) --
Achillion Pharmaceuticals, Inc.
(Nasdaq:ACHN), a leader in the
discovery and development of
small molecule drugs to combat
the most challenging infectious
diseases, today announced that
the Company has completed Phase
1a of its ongoing clinical trial
of ACH-1625, a protease
inhibitor for the treatment of
hepatitis C virus (HCV)
infection, and has begun dosing
HCV-infected patients in the
Phase 1b segment of the trial.
ACH-1625 is a potent small
molecule inhibitor of HCV
protease, an enzyme necessary
for viral replication. The drug
candidate was discovered and is
being advanced by Achillion,
with the objective of developing
a best-in-class protease
inhibitor for treatment of HCV
infection featuring potency,
safety, tolerability and
convenient once-daily dosing.
"We are pleased that the
outstanding safety profile
established in preclinical
testing continues to be seen in
this human clinical trial.
ACH-1625 was safe and
well-tolerated in both the
single and the multiple
ascending dose segments," stated
Elizabeth A. Olek, D.O., Vice
President and Chief Medical
Officer of Achillion. "Clinical
data gathered thus far support
our belief that ACH-1625 has the
potential to offer convenient
once-daily dosing and an
improved safety and tolerability
profile compared with other
protease inhibitors being
studied for the treatment of
hepatitis C."
"This first clinical trial of
ACH-1625 has proceeded exactly
as planned and we are quite
pleased and encouraged with the
results to date. The HCV-infected
cohort of the trial has begun,
and we expect it should conclude
within the next few months. We
are eager to demonstrate
ACH-1625's efficacy and
anticipate being able to
announce those data early next
year," added Michael Kishbauch,
Achillion's President and Chief
Executive Officer.
About the Phase 1 Program
The Phase 1a/1b clinical trial
is a randomized, double-blind,
placebo-controlled trial to
investigate the safety,
tolerability, pharmacokinetic
profile and antiviral activity
of ACH-1625 after single and
multiple ascending oral doses in
healthy volunteers, and oral
repeat doses for 5-days in
subjects with hepatitis C
infection. The trial is taking
place in Europe and is designed
to enroll at least 54 subjects,
including both healthy
volunteers and HCV-infected
patients. The trial is
anticipated to be completed in
the first quarter of 2010.
Subjects in the phase 1a single
ascending dose (SAD) segment of
the study received single doses
of ACH-1625 ranging from 50 mg
to 2000 mg. Subjects in the
phase 1a multiple ascending dose
(MAD) segment of the study
received 5 days of ACH-1625 up
to a maximal dose of 2000 mg per
day.
Preliminary data from the SAD
and MAD trial segments
demonstrate:
* No serious adverse events
* No clinically significant
changes in vital signs, ECGs, or
laboratory evaluations
* Adverse events were mild and
transient
About ACH-1625
ACH-1625 is an HCV protease
inhibitor designed and
synthesized based on crystal
structures of enzyme/inhibitor
complex. ACH-1625 is an open
chain, non-covalent, reversible
inhibitor of NS3 protease. In
preclinical studies, ACH-1625
demonstrated high potency,
unique pharmacokinetic
properties and an excellent
safety profile at high drug
exposures. With its rapid and
extensive partitioning to the
liver, as well as high
liver/plasma ratios demonstrated
in preclinical studies,
Achillion believes that ACH-1625
has the potential for once daily
dosing. ACH-1625 has shown low
single-digit nanomolar potency
that is specific to HCV. It is
equipotent against HCV genotypes
1a and 1b at IC50∼1nM.
About HCV
The hepatitis C virus (HCV) is
the most common cause of viral
hepatitis, which is an
inflammation of the liver. It is
currently estimated that more
than 170 million people are
infected with HCV worldwide and
The American Association of
Liver Disease estimates that up
to 80% of individuals become
chronically infected following
exposure to the virus. If left
untreated, chronic hepatitis can
lead to permanent liver damage,
which can result in the
development of liver cancer,
liver failure or death. Few
therapeutic options currently
exist for the treatment of HCV
infection. The current standard
of care is limited by its
specificity for certain types of
HCV, significant side-effect
profile, and injectable route of
administration.
About Achillion
Achillion is an innovative
pharmaceutical company dedicated
to bringing important new
treatments to patients with
infectious disease. Achillion's
proven discovery and development
teams have advanced multiple
product candidates with novel
mechanisms of action. Achillion
is focused on solutions for the
most challenging problems in
infectious disease -- hepatitis
C, resistant bacterial
infections and HIV. For more
information on Achillion
Pharmaceuticals, please visit
www.achillion.com or call
1-203-624-7000.
This press release includes
forward-looking statements
within the meaning of the
Private Securities Litigation
Reform Act of 1995 that are
subject to risks, uncertainties
and other factors, including
statements with respect to
Achillion's expectations
regarding the results of ongoing
clinical trials, and the timing
and duration of clinical trials.
Among the factors that could
cause actual results to differ
materially from those indicated
by such forward-looking
statements are: uncertainties
relating to results of clinical
trials, unexpected regulatory
actions or delays, and
Achillion's ability to obtain
additional funding required to
conduct its research,
development and
commercialization activities.
These and other risks are
described in the reports filed
by Achillion with the U.S.
Securities and Exchange
Commission, including its Annual
Report on Form 10-K for the
fiscal year ended December 31,
2008.
All forward-looking statements
reflect Achillion's expectations
only as of the date of this
release and should not be relied
upon as reflecting Achillion's
views, expectations or beliefs
at any date subsequent to the
date of this release. Achillion
anticipates that subsequent
events and developments may
cause these views, expectations
and beliefs to change. However,
while Achillion may elect to
update these forward-looking
statements at some point in the
future, it specifically
disclaims any obligation to do
so.
ACHN-G
CONTACT: Achillion
Pharmaceuticals, Inc.
Company Contact:
Mary Kay Fenton
(203) 624-7000
mfenton@achillion.com
Lippert/Heilshorn & Associates,
Inc.
Investors:
Anne Marie Fields
(212) 838-3777
afields@lhai.com
Bruce Voss
(310) 691-7100
bvoss@lhai.com
Media:
Megan Rusnack
(212) 838-3777
mrusnack@lhai.com
PSI-7851 is a pro-drug of a
nucleotide analog and is
currently in development for
the treatment of chronic HCV
infection. PSI-7851 has
demonstrated in vitro anti-HCV
activity with EC50 values of
approximately 90 +/- 60 nM,
which is approximately 15-
to 20- fold more potent than
the active metabolite of our
first generation nucleoside
polymerase inhibitor,
PSI-6130. The half-life of
the triphosphate (the
biologically active form of
the molecule) in primary
human hepatocytes is
approximately 38 hours,
which suggests the
possibility for once-daily
dosing. Like RG7128,
PSI-7851 has demonstrated in
vitro activity against HCV
genotypes 1, 2, 3 and 4.
During March 2009, we
initiated a Phase 1 study
for PSI-7851. As part of the
Phase 1 study, we completed
a single ascending dose
study that assessed the
safety, tolerability and
pharmacokinetics of PSI-7851
in healthy subjects at doses
ranging from 25mg to 800mg.
Preliminary results from
this study indicated there
were:
* No serious adverse events
or discontinuations;
* No dose-related adverse
events;
* No grade III/ IV lab
abnormalities; and
* No clinically significant
changes in vital signs or
ECGs.
During June 2009, we
initiated a Phase 1 multiple
ascending dose study in HCV-infected
patients. Subjects were
enrolled at two U.S. centers
and randomized to PSI-7851
(8 per cohort) or placebo (2
per cohort). The primary
objective of this study was
to assess the safety,
tolerability, and
pharmacokinetics of PSI-7851
after once-daily dosing for
three days. The secondary
objective of this study was
to assess antiviral activity
by measuring the change in
HCV RNA. Three dose cohorts
of PSI-7851 (50mg QD, 100mg
QD, and 200mg QD) were
evaluated. Preliminary
results from this study
indicated:
* PSI-7851 was generally
safe and well tolerated
across all cohorts with no
discontinuations, no serious
adverse events, and no
dose-related trends in
adverse events or laboratory
abnormalities.
* PSI-7851 demonstrated
potent antiviral activity
with a mean HCV RNA decrease
of -0.49 log IU/mL, -0.61
log IU/mL, and -1.01 log IU/mL
in patients receiving 50mg
QD, 100mg QD, and 200mg QD,
respectively.
Vertex
Pharmaceuticals Announces
Publication of Telaprevir Abstracts
for Presentation at the 60th AASLD
Meeting
(Nasdaq: VRTX) today
announced that sustained virologic
response (SVR) data from Study C208,
which evaluated twice-daily dosing
of Vertex’s investigational
hepatitis C virus (HCV) protease
inhibitor telaprevir, will be
presented in an oral presidential
plenary session at the 60th Annual
Meeting of the American Association
for the Study of Liver Diseases (AASLD)
taking place Oct. 30 – Nov. 3, 2009
in Boston. Additionally, final
results from PROVE 3 will be
presented in an oral session at the
conference. Results from a pooled
analysis of PROVE 1 and PROVE 2 in
"difficult-to-cure” patients, which
include patients with factors
potentially having an effect on SVR
rates (viral load, race, age, sex,
body mass index, genotype subtype
and liver fibrosis stage), will be
presented in a poster session.
The C208 presentation at AASLD will
include SVR data (defined as
undetectable HCV RNA at 24 weeks
after completion of treatment) and
represents the first SVR data for
telaprevir-based regimens as part of
a response-guided therapy trial
design, similar to that being used
in the Phase 3 trials of telaprevir.
Study C208 is a four-arm,
randomized, open label, Phase 2
clinical trial that was conducted by
Tibotec in Europe in 161
treatment-naïve patients with
genotype 1 HCV infection. Two
different dosing regimens of
telaprevir (750mg three-times daily
or 1125mg twice daily) each were
studied in combination with either
peg-IFN-alfa-2a (PEGASYS®) or
peg-IFN-alfa-2b (PEGINTRON™) and
ribavirin (RBV), the standard
therapies for chronic HCV infection.
The abstracts were published today
and can be accessed on the
AASLD website. In accordance
with the AASLD embargo policy, the
accepted abstract titles are
provided below. Vertex is developing
telaprevir in collaboration with
Tibotec and Mitsubishi Tanabe Pharma.
Telaprevir
Presentations
Twice-daily compared to
three-times daily telaprevir-based
therapy: Study C208
1. "Virological Analysis of Patients
Receiving Telaprevir Administered
q8h or q12h with
Peginterferon-Alfa-2a or -Alfa-2b
and Ribavirin in Treatment-Naïve
Patients with Genotype 1 Hepatitis
C: Study C208” (#194) will be
presented in an oral presidential
plenary session on Nov. 3, 2009 at
8:15 a.m. EST.
The authors of the
study are Marcellin, Patrick; Forns,
Xavier, Goeser, Tobias; Ferenci,
Peter; Nevens, Frederik; Carosi,
Giampiero; Drenth, Joost P.; De
Backer, Koen; van Heeswijk, Rudolf;
Luo Donghan; Picchio, Gaston;
Beumont-Mauviel, Maria.
Telaprevir-based therapy in
treatment-experienced patients:
PROVE 3 Final
Analysis
2. "PROVE 3 Final Results and 1-Year
Durability of SVR with Telaprevir-Based
Regimen in Hepatitis C Genotype
1-Infected Patients with Prior
Non-response, Viral Breakthrough or
Relapse to Peginterferon-Alfa-2a/b
and Ribavirin Therapy” (#66) will be
presented in an oral parallel
session on Nov. 1, 2009 at 6:00 p.m.
EST. The authors of the study are
McHutchison, John G.; Manns, Michael
P.; Muir, Andrew J.; Terrault,
Norah; Jacobson, Ira M.; Afdhal,
Nezam H.; Heathcote, E. Jenny;
Zuezem, Stefan; Reesink, Hendrik W.;
Bsharat, Mohammad; George, Shelley;
Adda, Nathalie; Di Bisceglie, Adrian
M.
3. "Telaprevir, Peginterferon
Alfa-2a and Ribavirin Improved Rates
of Sustained Virologic Response (SVR)
in "Difficult-to-Cure” Patients With
Chronic Hepatitis C (CHC): a Pooled
Analysis From the PROVE 1 and PROVE
2 Trials” (#1565) will be presented
in a poster session on Nov. 3, 2009
at 8:00 a.m. EST. The authors of the
study are Everson, Gregory T.;
Dusheiko, Geoffrey M.; Ferenci,
Peter; Alves, Katia; Bengtsson,
Leif; McNair, Lindsay; McHutchison,
John G.; Muir, Andrew; Pawlotsky,
Jean-Michel; Zeuzem, Stefan.
About
Telaprevir
Telaprevir (VX-950) is an
investigational oral inhibitor of
HCV protease, an enzyme essential
for viral replication, and is one of
the most advanced investigational
antiviral agents in development that
specifically targets HCV. Telaprevir
is being evaluated as part of a
global Phase 3 registration program
in more than 2,200 treatment-naïve
and treatment-failure patients.
Vertex retains commercial rights to
telaprevir in North America. Vertex
and Tibotec are collaborating to
develop and commercialize telaprevir
in Europe, South America, Australia,
the Middle East and other countries.
Vertex is collaborating with
Mitsubishi Tanabe Pharma to develop
and commercialize telaprevir in
Japan and certain Far East
countries.
About
Hepatitis C
Hepatitis C is a liver disease
caused by the hepatitis C virus,
which is found in the blood of
people with the disease. HCV, a
serious public health concern
affecting 3.2 million individuals in
the United States, is spread through
direct contact with the blood of
infected people.1 Though many people
with HCV infection may not
experience symptoms, others may have
symptoms such as jaundice, abdominal
pain, fatigue and fever.1 Chronic
HCV significantly increases a
person's risk for developing
long-term infection, chronic liver
disease, cirrhosis or death.1
Current therapies for HCV typically
provide sustained benefit in less
than half of patients with genotype
1 HCV, the most common strain of the
virus.2 If treatment is not
successful and patients do not
achieve an SVR, they remain at risk
for progressive liver disease.1 In a
recent study, the risk of liver
failure, cancer or death following
unsuccessful HCV treatment was
assessed at 23% after 4 years, and
43% after 8 years.3
About
Vertex
Vertex Pharmaceuticals Incorporated
is a global biotechnology company
committed to the discovery and
development of breakthrough small
molecule drugs for serious diseases.
The Company's strategy is to
commercialize its products both
independently and in collaboration
with major pharmaceutical companies.
Vertex's product pipeline is focused
on viral diseases, cystic fibrosis,
inflammation, autoimmune diseases,
cancer, and pain. Vertex
co-discovered the HIV protease
inhibitor, Lexiva, with
GlaxoSmithKline.
Lexiva is a registered trademark of
the GlaxoSmithKline group of
companies.
PEGASYS® is a registered trademark
of Hoffman La Roche.
2 Strader DB, Wright
T, Thomas DL, Seeff LB, AASLD
practice guideline: diagnosis,
management and treatment of
hepatitis C. Hepatology:
2004(39):1147-1171
3Veldt et al, "Sustained virologic
response and clinical outcomes in
patients with chronic hepatitis C
and advanced fibrosis," Annals of
Internal Medicine, 20 November 2007;
147: 677-684.
Vertex’s press releases are
available at
www.vrtx.com.
(VRTX – GEN)
Clinical Trials of New
Anti-Hepatitis C Drug Began
Sept 15 -09
Russian medics and
engineers report about finishing
preclinical trial stage of a new
candidate drug for treating hepatitis C
and starting clinical trials.
The ID-12 chemical compound is an
original low molecular inhibitor, which
blocks initial stages of virus
expansion. The molecule was developed
within a public private partnership, and
it took its designers three years to
test the series of potential curing
agents to find the ID-12.
First stage of clinical trials,
during which drug’s safety and
pharmacokinetic properties will be
determined, is scheduled for winter 2009
and will take place in Russian
Federation.
http://www.russia-ic.com/news/show/8901/
Additional
Information...................
ChemDiv
and iDialog Nominate Novel Inhibitor of
Hepatitis C for Clinical Development
Sept 15
SAN
DIEGO, CA -- 09/15/09 -- ChemDiv Inc. of
San Diego, and iDialog (Intellektualniy
Dialog) of Yaroslavl, Russia, announced
today the successful completion of a
pre-clinical development and the
subsequent nomination of ID-12 as lead
clinical development candidate for the
treatment of chronic hepatitis C. This
novel small molecule orally-bioavailable
inhibitor of hepatitis C virus (HCV)
blocks early stage of viral infection.
Vadim Bichko, Ph.D,
ChemDiv's Vice President of Virology,
stated: "We are very encouraged by the
safety, potency, PK profile, and novel
molecular mechanism of action, exhibited
by iDialog's HCV inhibitor in the
preclinical studies. We are quite
excited by the ability of ID-12 to
prevent spread of viral infection
through cell-cell contact, which makes
it superior to the neutralizing
antibodies and other viral entry
inhibitors. This mechanism of action is
complimentary to that of other classes
of HCV inhibitors currently on the
market, or in late stage clinical
development. Thus, ID-12 is a
potentially important component of
therapeutic cocktails for chronic
hepatitis C."
The Phase I study is
scheduled to begin in Q4 2009, and will
be conducted in Russia. The objectives
of the trial include assessment of
safety, tolerability and
pharmacokinetics. iDialog plans to
present first clinical results at a
scientific meeting in the second half of
2010. ChemDiv will continue supporting
R&D programs of iDialog, including Proof
of Concept Studies in man, through its
Chemical Diversity Research Institute in
Moscow, Russia.
Prof. Dr. Mikhail Dorogov,
Director General of iDialog, confirmed:
"We are happy that our discovery effort
over last 3 years resulted in
advancement of the candidate molecule to
clinic. We shall strive in developing a
successful new therapy for treatment of
large population of hepatitis C patients
worldwide. With its current financing
iDialog is planning to complete the
early development program to obtain
clinical Proof of Concept. We are
actively exploring options, which will
allow us to accelerate the program with
maximizing our shareholder's return on
investment. We believe our approach is
matching to innovative models of early
partnering, co-development an
co-investment established by pharma and
investment community in the recent
past."
About Hepatitis C
The U.S. Center for
Disease Control and Prevention estimate
that about 4.1 million persons in the
United States have been infected with
HCV, and 3.2 million of these people are
chronic carriers. Russian Ministry of
Health and Social Development estimates
that over 7 million people in Russia
have been infected with various types of
Hepatitis and 2 million of them,
chronically.
About ChemDiv
ChemDiv Inc. (Chemical
Diversity) is a global contract research
organization accelerating external
discovery and development of novel
therapies through comprehensive
Discovery Outsource™ services, including
discovery biology, medicinal and
synthetic chemistry, pre-clinical and
clinical development.
About iDialog
iDialog was established
in 2006 as an innovative biopharma start
up. It received over USD$3M of seed
investment from Torrey Pines Investment
in 2007 and subsequently won the
research partnership award of over USD$3
from the Russian Federal Agency of
Science and Innovation for development
of novel anti-infective agents to match
unmet needs in Russia. iDialog conducted
and continues the broad program to
discover novel therapies for
Tuberculosis, hepatitis C and Influenza,
in partnership with Moscow State
University and other academic
organizations. In 2008 iDialog
established the R&D collaboration with
ChemDiv's Chemical Diversity Research
Institute for discovery and development
of novel small molecule anti-infective
agents, which is extended to 2011.
Contact for ChemDiv:
Ronald Demuth
SVP & General Manager
6605 Nancy Ridge Drive, San Diego, CA
92121
Phone: (858) 794-4860
Fax: (858)794-4931
Email Contact
Contact for iDialog (Intellektualniy
Dialog):
Oleg Korzinov
General Manager
2a Rabochaya St., Moscow Region, Khimki
141400, Russia
Phone: +7 (495) 225 -1192
Experimental Agent ATI-0810 Appears to
Have Novel Mechanism of Action against
Hepatitis C Virus
As background, researchers from
ImQuest Biosciences noted that the
experimental agents have antiviral
activity that results in a
significant reduction of viral RNA
synthesis not related to known
mechanisms including inhibition of
viral entry into cells, initiation
of IRES translation, inhibition of
the HCV NS2/3 or NS3/4A HCV protease
enzyme, or interference with the HCV
NS5B viral RNA-dependent RNA
polymerase.
In previous laboratory studies,
ATI-0810 was 100- to 200-fold less
toxic than ribavirin, and in fact
appeared to reduce the toxicity of
ribavirin when the drugs were
administered together. ATI-0810 was
shown to be non-toxic to fresh human
hepatocytes (liver cells) at the
highest concentration tested (1.33
mM). Furthermore, serial passage of
cells infected with a virus related
to HCV (bovine viral diarrhea virus)
in the presence of escalating doses
of ATI-0810 failed to select for
drug-resistant virus, suggesting a
high genetic barrier to resistance.
In the present study, an HCV
replicon system was used to analyze
the activity of ATI-0810 and 10
chemically related compounds
(PG204057, PG702253, PG702273,
PG702306, PG702307, PG702379,
PG702532, PG702548, PG702617, and
PG703010), and to generate ATI-0810
resistant HCV replicons. The
investigators examined cellular gene
expression in the presence and
absence of ATI-0810.
Results
In vitro antiviral
activity of ATI-0810 and the
related compounds ranged
from 0.21 to 3.4 mcM.
Selection of ATI-0810
resistant replicons revealed
potential
resistance-conferring
mutations in the HCV NS3 and
NS5A enzymes.
A single NS5A mutation,
C446R, conferred a 21-fold
decrease in sensitivity to
ATI-0810.
This mutation is the P2
proximal amino acid at the
NS5A/NS5B junction.
Sensitivity testing of
ATI-0810 in replicons cells
expanded after selection for
this mutation revealed an
approximately 17- to 20-fold
increase in the drug's EC50
value (50% effective
concentration).
The C446R mutation and 3
others -- NS3 D168N, NS5A
L199F, and V296 -- emerged
in replicons cultured with
ATI-0810, but not those
grown without the agent.
Differential gene expression
revealed no significant
changes in cellular RNA
accumulation in the presence
of ATI-0810.
Based on these data, the researchers
hypothesized that ATI-0810 inhibits
HCV replication through a novel
mechanism of action.
"ATI-0810 does not inhibit viral
protease or polymerase activity and
does not appear to inhibit IRES-mediated
translation or NS2 protease
activity," they stated.
They added that in tests combining
ATI-0810 with other anti-HCV agents,
the new agent "reduces the toxicity
of ribavirin and interferon and is
additive with interferon and
additive/slightly synergistic with
ribavirin."
ImQuest BioSci., Frederick, MD.
9/15/09
Reference TB Parsley, l Yang, and RW
Buckheit. ATI-0810 is a Novel Late
Stage Inhibitor of HCV Replicon
Replication. 49th Interscience
Conference on Antimicrobial Agents
and Chemotherapy (ICAAC 2009). San
Francisco. September 12-15, 2009.
Abstract H-215.
Aussies aid
Hepatitis C
'breakthrough'
September
13, 2009
An
Australian-led
team of
international
medical
researchers may
have scored an
important
breakthrough in
the treatment of
hepatitis C.
The team, led by
Sydney molecular
geneticist David
Booth and Sydney
University
hepatitis C
expert Jacob
George, has
identified a
variant in an
interferon gene
which links it
to the treatment
of the chronic
hepatitis C
virus (HVC).
The gene, known
as IL28B, was
found to encode
an interferon
"lambda"
involved with
the suppression
of viruses,
including HCV.
Interferons, or
proteins
inhibiting the
replication of
viruses, are
identified
through the use
of letters from
the Greek
alphabet.
The researchers
said the new
study showed use
of the
interferon-lambda
in treatment
could benefit
those people
identified as
best suited to
receive it and
spare others the
cost and side
effects of their
current
treatments.
Prof George said
the current
standard
treatment
procedure for
chronic HCV was
combined therapy
with pegylated
interferon-alpha
and ribavirin
for about 11
months.
"This treatment
can have side
effects and only
about 40 to 50
per cent of
individuals
infected with
HCV show a
positive
response to it,"
Prof George
said.
"The current
study renews
interest in
therapies which
involve this
type of
interferon, and
suggest that
combined
treatment with
interferon-alpha
and
interferon-lambda
may prove a more
effective
treatment."
Dr Booth, a
molecular
geneticist with
Westmead
Millennium
Institute who is
widely
recognised for
his work with
multiple
sclerosis and
genes that cause
autoimmune
disease, said
the same
principles
applied to
hepatitis C
infection as to
MS.
"We inherit from
our parents
subtle
differences in
the make-up of
our immune
system that can
make a major
difference in
susceptibility
to disease or
how we respond
to treatment,"
he said.
"Finding each of
the few genes
that have such
an impact gives
science an edge
in the eventual
prevention or
control of many
of the major
diseases of
humankind."
He said the
finding that
inherited
differences in
the interferon
lambda gene has
such an impact
on the treatment
of Hep C
provided a
valuable new
lead into
beating "an
infection of
epidemic
proportion
worldwide".
Almost 300
million people
are known to
have been
infected with
hepatitis C,
which is a
leading cause of
liver disease.
Results of the
study into
interferon IL28B
were published
on Sunday's
Nature Genetics
website.
Anadys
Pharmaceuticals Commences Dosing In
Phase II Study Of ANA598
Sep
10 09
Anadys
Pharmaceuticals, Inc. (Nasdaq: ANDS)
announced that dosing has begun in a
Phase II trial of ANA598 in patients
chronically infected with
hepatitis C virus (HCV). The study
will evaluate ANA598 over 12 weeks,
taken in combination with pegylated
interferon-alpha and ribavirin, in
treatment naive HCV patients. ANA598 is
an investigational, oral, non-nucleoside
polymerase inhibitor.
"ANA598 has demonstrated potent
antiviral activity and good tolerability
as a single agent, as well as
preclinical properties indicative of
likely synergy when used clinically in
combination regimens," said James Freddo,
M.D., Anadys' Senior Vice President,
Drug Development and Chief Medical
Officer. "We look forward to building
upon these results to demonstrate the
benefit of ANA598 when used in
combination with interferon and
ribavirin."
About the Phase
II Study
In the Phase II study, naive genotype 1
patients will receive ANA598 or placebo
in combination with Pegasys((R)) (peginterferon
alfa-2a) and Copegus((R)) (ribavirin,
USP) (a current standard of care, or
SOC) for 12 weeks at dose levels of 200
mg or 400 mg twice daily (bid), each
with a loading dose of 800 mg bid on day
one. After week 12, patients will
continue to receive SOC. Patients who
achieve undetectable levels of virus at
weeks 4 and 12 will be randomized to
stop all treatment at week 24 or 48. The
primary endpoint of the study is the
proportion of patients with undetectable
virus at week 12 (defined as complete
Early Virological Response, or cEVR).
Additional endpoints include safety and
tolerability as well as the proportion
of patients with undetectable virus at
week 4 (defined as Rapid Virological
Response, or RVR), weeks 24 and 48, and
24 weeks after stopping all treatment
(defined as Sustained Virological
Response, or SVR).
Ninety patients are planned to be
enrolled in this study -- thirty
patients receiving ANA598 and fifteen
receiving placebo at each dose level.
The study will be managed by the Duke
Clinical Research Institute (DCRI) under
the leadership of John McHutchison, M.D.
and will be conducted at a number of
clinical sites in the United States.
Anadys expects to receive 28-day safety
and response (RVR) data from the 200 mg
dose level by year-end and additional
on-treatment safety and response data
from both cohorts during the first two
quarters of 2010.
About ANA598
ANA598 is a non-nucleoside inhibitor of
the HCV RNA polymerase. Anadys has
completed three Phase I clinical studies
of ANA598 that have demonstrated potent
antiviral activity and good
tolerability. In a monotherapy study in
naive genotype 1 patients, treatment
with ANA598 for three days led to median
declines in viral load ranging from 2.4
to 2.9 log10 in three separate dose
groups. No patient at any dose level
showed evidence of viral rebound while
on ANA598, and there were no serious
adverse events.
Anadys has completed dosing in two
long-term chronic toxicology studies of
ANA598 (26 weeks duration in rats and 39
weeks duration in monkeys). At the
13-week interim, the toxicology profile
of ANA598 in both species was very
favorable. A preliminary assessment of
the results from the 26-week study in
rats indicates a similar profile to that
seen in rats at 13 weeks, in which the
only adverse finding was a marginal
decrease in the rate of weight gain in
females at 1000 mg/kg, the highest dose
tested. Complete results from both
studies, including 39-week data from the
monkey study, are expected at the end of
the third quarter 2009.
Anadys has presented results from
multiple in vitro studies that support
the clinical use of ANA598 in
combination with interferon-alpha. In
particular, data have shown that ANA598
is synergistic in vitro with
interferon-alpha, that mutations
conferring resistance to ANA598 remain
fully sensitive to interferon-alpha, and
that synergy between ANA598 and
interferon-alpha is retained against
mutations conferring resistance to
ANA598. Anadys has also presented in
vitro results supporting future clinical
combination studies with direct
antivirals, including a demonstration of
in vitro synergy between ANA598 and
representative HCV protease and
polymerase inhibitors. Furthermore,
Anadys has presented data that show
ANA598 retains full activity in vitro
against mutations conferring resistance
to protease inhibitors, nucleoside
polymerase inhibitors and non-nucleoside
polymerase inhibitors that act at
binding sites distinct from that of
ANA598, and that protease and nucleoside
polymerase inhibitors retain full
activity in vitro against mutations
conferring resistance to ANA598.
ANA598 has received Fast Track Status
from the FDA for the treatment of
chronic hepatitis C.
About Anadys
Anadys Pharmaceuticals, Inc. is a
biopharmaceutical company dedicated to
improving patient care by developing
novel medicines for the treatment of
hepatitis C. The Company believes
hepatitis C represents a large unmet
medical need in which meaningful
improvements in treatment outcomes may
be attainable with the introduction of
new medicines. The Company is developing
ANA598, a non-nucleoside polymerase
inhibitor for the treatment of hepatitis
C. The Company has also investigated the
potential of ANA773, an oral,
small-molecule inducer of endogenous
interferons that acts via the Toll-like
receptor 7, or TLR7, pathway in
hepatitis C.
Safe Harbor
Statement
Statements in this press release that
are not strictly historical in nature
constitute "forward-looking statements."
Such statements include, but are not
limited to, references to (i) Anadys'
expectation that the Phase II study will
build upon prior results of ANA598
studies and demonstrate a benefit when
ANA598 is used in combination with
interferon and ribavirin; (ii) the
ability for patients in the ANA598 Phase
II study to achieve undetectable levels
of virus at weeks 4 and 12 and to
achieve SVR; (iii) Anadys' expectation
that it will receive 28-day data from
the 200 mg dose level by year end and
additional data during the first two
quarters of 2010; (iv) the antiviral and
tolerability profile of ANA598 seen to
date, which may not be duplicated in the
Phase II study; and (v) preclinical
properties indicative of likely synergy
when used clinically in combination
regimens and in vitro studies which
Anadys believes support the clinical use
of ANA598 in combination with
interferon-alpha and future combination
studies of ANA598 with direct antivirals.
Such forward-looking statements involve
known and unknown risks, uncertainties
and other factors, which may cause
Anadys' actual results to be materially
different from historical results or
from any results expressed or implied by
such forward-looking statements. For
example, the results of preclinical and
early clinical studies may not be
predictive of future results, and Anadys
cannot provide any assurances that
ANA598 will not have unforeseen safety
issues or will have favorable results in
the Phase II trial. In addition, Anadys'
results may be affected by risks related
to competition from other biotechnology
and pharmaceutical companies, its
effectiveness at managing its financial
resources, its ability to enter into
collaborations around its product
candidates, its ability to successfully
develop and market products,
difficulties or delays in its
preclinical studies or clinical trials,
difficulties or delays in manufacturing
its clinical trials materials, the scope
and validity of patent protection for
its product candidates, regulatory
developments involving its product
candidates and its ability to obtain
additional funding to support its
operations. Risk factors that may cause
actual results to differ are more fully
discussed in Anadys' SEC filings,
including Anadys' Form 10-K for the year
ended December 31, 2008 and Anadys' Form
10-Q for the quarter ended June 30,
2009. All forward-looking statements are
qualified in their entirety by this
cautionary statement. Anadys is
providing this information as of this
date and does not undertake any
obligation to update any forward-looking
statements contained in this document as
a result of new information, future
events or otherwise.
Pegasys(R) and Copegus(R) are registered
trademarks of Hoffman-La Roche Inc.
Roche and InterMune Begin Phase 2b Trial
of HCV Protease Inhibitor
RG7227/ITMN-191
Roche and InterMune
announced on August 19,
2009 that they had
started treating the
first patient in a Phase
2b clinical trial of an
experimental hepatitis C
virus (HCV) protease
inhibitor they are
jointly developing. The
compound's Roche
designation is
RG7227 (formerly R7227),
while the InterMune
designation is
ITMN-191. The trial
is evaluating the safety
and efficacy of
RG7227/ITMN-191 in
combination with
pegylated interferon
plus ribavirin in
treatment-naive genotype
1 chronic hepatitis C
patients.
Below is an excerpt from a joint press
release describing the new trial.
Roche and InterMune Initiate Phase 2b
Clinical Trial of RG7227/ ITMN-191 in
Patients With Chronic Hepatitis C
Patients With Chronic Hepatitis C
Study will further define the
safety and efficacy profile
Parallel Phase 1 trial will
assess ritonavir-boosted dosing
INFORM-1 study with polymerase
inhibitor RG7128 ongoing
Basel, Switzerland and Brisbane, Calif.
-- August 19, 2009 -- Roche (SIX: ROG.VX;
RO.S, OTCQX: RHHBY) and InterMune, Inc.
(Nasdaq: ITMN) today announced that the
first patient has been dosed in a Phase
2b study evaluating the hepatitis C
virus (HCV) protease inhibitor,
RG7227/ITMN-191, in combination with
Pegasys (pegylated interferon alfa-2a)
and Copegus (ribavirin).
The study, to be conducted at 45 sites
globally, will further define the safety
and efficacy profile of RG7227/ITMN-191,
for a treatment duration of up to 24
weeks. Approximately 300 treatment-naive
patients chronically infected with HCV
genotype 1 -- the most difficult to
treat form of the virus -- will
participate.
RG7227/ITMN-191 is being developed in
partnership by Roche and InterMune.
Initiation of the Phase 2b trial
triggered a $20 million event payment
from Roche to InterMune under the
companies' collaboration agreement.
Frank Duff, MD, Head of Roche's Clinical
Development for Virology, said, "This
trial represents an important step
forward in the development of this oral
direct-acting antiviral (DAA), and
builds on the encouraging clinical
safety and efficacy data generated to
date."
Dan Welch, Chairman, Chief Executive
Officer and President of InterMune,
said, "We are very pleased to announce
with our colleagues, Roche, the start of
the global Phase 2b program of
RG7227/ITMN-191 in treatment-naive HCV
patients. This study will significantly
expand the clinical efficacy and safety
database for RG7227/ITMN-191, and in the
first quarter of next year provide our
first look at the rapid virologic
response (RVR) rates associated with
this triple therapy."
Phase 2b
Triple Combination Trial Design
The objective of the Phase 2b
randomized, double-blind,
placebo-controlled study is to further
characterize the safety, tolerability,
and antiviral effects of RG7227/ITMN-191
in triple combination, compared with
standard of care (Pegasys and Copegus).
The two-part study will evaluate
treatment regimens of both 12 and 24
weeks. In Part 1 of the study,
approximately 210 patients will be
randomized to one of four study arms --
three of which will receive a 12-week
regimen of RG7227/ITMN-191 at either 300
mg every 8 hours, 600 mg every 12 hours
or 900 mg every 12 hours, in combination
with Pegasys and Copegus, followed by 12
weeks of therapy with Pegasys and
Copegus. The fourth group will be a
control arm receiving Pegasys and
Copegus dosed for 48 weeks.
Part 2 of the study, which is expected
to begin in the first quarter of 2010,
will further evaluate RG7227/ITMN-191 in
a 24-week triple combination regimen
with Pegasys and Copegus. Approximately
90 patients will be randomized to one of
two study arms in Part 2, either a
24-week regimen of RG7227/ITMN-191 in
combination with Pegasys and Copegus, or
a control arm of Pegasys and Copegus
dosed for 48 weeks. Dose selection for
Part 2 will be informed by week 4
results generated in Part 1.
RVR results from Part 1 of the study are
expected in the first quarter of 2010.
RG7227/ITMN-191 -- Next Steps in
Development Program
Roche and InterMune will also initiate
in the third quarter a Phase 1 trial
combining RG7227/ITMN-191 with low dose
ritonavir to examine the virologic
effect of ritonavir-boosted
RG7227/ITMN-191 in once-daily and
twice-daily regimens in combination with
standard dosing of Pegasys and Copegus
in patients chronically infected with
HCV genotype 1.
This study builds on promising drug-drug
interaction data recently generated in
healthy volunteers; a low dose of
ritonavir significantly improved
RG7227/ITMN-191 AUC and plasma
concentrations at later times. There
were no remarkable safety findings.
The Phase 1 study will evaluate the
safety, tolerability, pharmacokinetics
and antiviral activity of once-daily and
twice-daily ritonavir-boosted
RG7227/ITMN-191 regimens administered
with Pegasys and ribavirin for 14 days.
Dr. Duff commented, "Combining
RG7227/ITMN-191 with low dose ritonavir
has the potential to deliver additional
benefits to patients, including the
requirement for less frequent dosing and
fewer tablets per day. Data generated
from this Phase 1 trial may pave the way
for larger studies investigating this
treatment combination."
RG7227/ITMN-191 is also being
investigated in combination with the
NS5B polymerase inhibitor RG7128 in the
INFORM-1 study. This innovative
study has recently been expanded to
examine regimens in which both
RG7227/ITMN-191 and RG7128 are dosed
twice daily in treatment-experienced
patients. Results from all cohorts of
this study will be presented in an oral
presentation in Presidential Plenary
Session III on the morning of November 3
at the 2009 AASLD meeting. Additional
abstracts regarding pharmacokinetic/pharmacodynamics
and resistance have been accepted for
poster presentation.
About
RG7227/ITMN-191
RG7227/ ITMN-191 is a potent,
macrocyclic inhibitor of HCV NS3/4A
protease activity, and has produced
multi-log10 reductions in HCV levels in
chronic HCV patients, when administered
for 14 days as monotherapy. When
RG7227/ITMN-191 is combined with Pegasys
and Copegus, or the NS5B polymerase
inhibitor RG7128, it reduced viral loads
below the limit of detection in a
majority of study-treated patients.
RG7227/ITMN-191 was safe and well
tolerated in these studies.
About
PEGASYS
Pegasys, in combination with Copegus (ribavirin),
is indicated for the treatment of adults
with chronic HCV who have compensated
liver disease and have not previously
been treated with interferon alpha.
Efficacy has been demonstrated in
patients with compensated liver disease
and histological evidence of cirrhosis
(Child-Pugh class A) and patients with
HIV disease that are clinically stable
(e.g., antiretroviral therapy not
required or receiving stable
antiretroviral therapy). In addition,
Pegasys in combination with Copegus is
the first and only FDA-approved regimen
for the treatment of chronic HCV in
patients coinfected with HCV and HIV.
Pegasys is the only pegylated interferon
indicated for the treatment of adult
patients with chronic hepatitis B (HBeAg
positive and HBeAg negative chronic
hepatitis B who have compensated liver
disease and evidence of viral
replication and liver inflammation).
Pegasys is dosed at 180 mcg as a
subcutaneous injection taken once a
week. Copegus is available as a 200mg
tablet, and is administered orally two
times a day as a split dose. Roche has
backed Pegasys with the most extensive
clinical research program ever
undertaken in HCV, with major studies
initiated to advance treatment for HCV
patients with unmet needs, including
patients co-infected with HIV and HCV,
African Americans, patients with
cirrhosis, and patients who have failed
to respond to previous therapy.
About Roche
Headquartered in Basel, Switzerland,
Roche is a leader in research-focused
healthcare with combined strengths in
pharmaceuticals and diagnostics. Roche
is the world's largest biotech company
with truly differentiated medicines in
oncology, virology, inflammation,
metabolism and CNS. Roche is also the
world leader in in-vitro diagnostics,
tissue-based cancer diagnostics and a
pioneer in diabetes management. Roche's
personalised healthcare strategy aims at
providing medicines and diagnostic tools
that enable tangible improvements in the
health, quality of life and survival of
patients. In 2008, Roche had over 80,000
employees worldwide and invested almost
9 billion Swiss francs in R&D. The Group
posted sales of 45.6 billion Swiss
francs. Genentech, United States, is a
wholly owned member of the Roche Group.
Roche has a majority stake in Chugai
Pharmaceutical, Japan.
InterMune is a biotechnology company
focused on the research, development and
commercialization of innovative
therapies in pulmonology and hepatology.
InterMune has a pipeline portfolio
addressing idiopathic pulmonary fibrosis
(IPF) and hepatitis C virus (HCV)
infections. The pulmonology portfolio
includes the completed Phase 3 CAPACITY
program, now in pre-registration, which
evaluated pirfenidone for the treatment
of patients with IPF; RECAP, an
open-label extension study from CAPACITY
and a research program focused on small
molecules for the treatment of pulmonary
disease. The hepatology portfolio
includes the HCV protease inhibitor
compound RG7227/ ITMN-191 in Phase 2b, a
second-generation HCV protease inhibitor
research program, and a research program
evaluating new targets in hepatology.
For additional information about
InterMune and its R&D pipeline, please
visit
www.intermune.com.
9/04/09
Source Roche and InterMune. Roche and
InterMune Initiate Phase 2b Clinical
Trial of RG7227/ ITMN-191 in Patients
With Chronic Hepatitis C Patients With
Chronic Hepatitis C. Press release.
August 19, 2009.
MassBiologics Announces Phase 1 Study of
Monoclonal Antibody Targeting HCV
MassBiologics, a
non-profit drug
developer affiliated
with the University of
Massachusetts Medical
School, announced in
early August that it has
initiated a Phase 1
study evaluating a new
type of hepatitis C
therapy, a monoclonal
antibody known as
MBL-HCV1. In this
early-stage trial,
healthy HCV negative
volunteers will receive
different doses of
MBL-HCV1 to assess its
safety and activity.
Below is a press release from the
University of Massachusetts Medical
School describing the study.
First human gets new antibody aimed
at hepatitis C virus
Phase 1 clinical trial in healthy
subjects designed to advance novel
treatment to prevent
Boston, Mass. -- August 6, 2009 --
Building upon a series of successful
preclinical studies, researchers at
MassBiologics of the University of
Massachusetts Medical School (UMMS)
today announced the beginning of a Phase
1 clinical trial, testing the safety and
activity of a human monoclonal antibody
they developed that can neutralize the
Hepatitis C virus (HCV).
The first volunteer received the
antibody known as MBL-HCV1 on July 28,
2009, and the study is now proceeding
and will eventually involve 30 healthy
subjects in a dose-escalation trial
expected to conclude later this year.
"We are pleased that this program has
now entered the clinical trial phase,"
said Donna Ambrosino, MD, executive
director of MassBiologics and a
professor of pediatrics at the Medical
School. "This trial will test the safety
of the antibody and measure its activity
in the subjects. This will help us
determine the useful dose and other
parameters as we plan for the next step
in this program, which will be a Phase 2
study in liver transplant patients."
HCV attacks the liver and can eventually
lead to liver failure. According to the
U.S. Centers for Disease Control and
Prevention, 3.2 million Americans are
chronically infected with HCV and some
10,000 die annually of the disease.
Globally, as many as 170 million people
are estimated to suffer from HCV
infection. For the most serious cases of
HCV that do not respond to antiviral
drugs, liver transplantation is the only
option.
HCV is the leading indication for liver
transplantation, diagnosed in about half
of the 6,000 liver transplants done each
year in the United States.
Transplantation can be a life-saving
treatment; however, in nearly all cases
the patient's new liver is eventually
infected by HCV because the virus
remains in the patient's bloodstream
during surgery. The powerful antiviral
drugs now used to attack HCV prior to
end-stage liver failure are not
routinely used during surgery due to the
patients' weakened condition and because
of the strong medication that must be
used to prevent the body from rejecting
the new liver. After re-infection with
HCV, nearly 40 percent of patients
suffer rapid liver failure, with
markedly reduced survival rates.
To close that clinical gap, the new
antibody developed at MassBiologics is
designed to be a therapy shortly before
and after transplant surgery. By giving
a patient the new antibody before and
during the time when the donor liver is
implanted, researchers hope the HCV
virus left in the bloodstream will be
neutralized and rendered unable to
infect the new liver. Then, because
monoclonal antibodies are highly
specific and typically have little or no
side-effects, additional dosages of the
new antibody could, theoretically, be
given immediately after transplant
surgery to continue neutralizing any
remaining virus.
It is also possible, researchers
theorize, that the antibody could be
used in combination with new antiviral
drugs for treatment in patients with
newly diagnosed HCV infection. "There is
still more work to be done, but we are
encouraged by the progress of this
program to date," Dr. Ambrosino noted.
"And we are grateful to the people who
have volunteered to participate in this
Phase 1 study. These subjects'
participation will help others and
advance the cause of human health."
About
MassBiologics
MassBiologics, also known as the
Massachusetts Biologic Laboratories, is
the only non-profit FDA- licensed
manufacturer of vaccines and other
biologic products in the United States.
MassBiologics produces 30 percent of the
US tetanus/diphtheria vaccine supply. In
addition to the HCV program,
MassBiologics has discovered and
developed human monoclonal antibodies to
severe acute respiratory syndrome (SARS),
and to Clostridium difficile (C.
difficile), which have shown efficacy in
Phase 2, and to rabies which will be
starting Phase 1 soon in collaboration
with the Serum Institute of India.
MassBiologics traces its roots to 1894,
and since then has maintained a mission
to improve public health through applied
research, development and production of
biologic products. MassBiologics has
been a part of the University of
Massachusetts Medical School since 1997.
About the
University of Massachusetts Medical
School
The University of Massachusetts Medical
School has built a reputation as a
world-class research institution,
consistently producing noteworthy
advances in clinical and basic research.
The Medical School attracts more than
$200 million in research funding
annually, 80 percent of which comes from
federal funding sources. The work of
UMMS researcher Craig Mello, PhD, an
investigator of the prestigious Howard
Hughes Medical Institute (HHMI), and his
colleague Andrew Fire, PhD, then of the
Carnegie Institution of Washington,
toward the discovery of RNA interference
was awarded the 2006 Nobel Prize in
Physiology or Medicine and has spawned a
new and promising field of research, the
global impact of which may prove
astounding. UMMS is the academic partner
of UMass Memorial Health Care, the
largest health care provider in Central
Massachusetts.
Source University of Massachusetts Medical
School. First human gets new antibody
aimed at hepatitis C virus Phase 1
clinical trial in healthy subjects
designed to advance novel treatment to
prevent. Press release. August 6,
2009.
By Crystal
Phend, Staff Writer, MedPage Today Published: July 22, 2009
Reviewed by Dori
F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical
School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
IDEAL Study
The two marketed brands of pegylated interferon alfa
– Pegasys (2a) and PegIntron
(2b) –
are similarly effective for
treating chronic hepatitis C, according to the IDEAL Study,
reported in the July 22 online
edition of the New England Journal of Medicine.
In this trial, sponsored by
PegIntron manufacturer Schering-Plough, J.G. McHutchison and colleagues at 118
U.S. sites enrolled 3070 previously untreated patients with HCV genotype 1.
Participants were randomly assigned to receive 1.5 (standard dose) or 1.0
(low-dose) mg/kg/week PegIntron plus 800-1400 mg/day weight-adjusted ribavirin,
or else 180 mcg/week Pegasys plus 1000-1200 mg/day ribavirin for 48 weeks. Both
regimens were administered according to their label direction, which allowed for
a larger range of ribavirin doses with PegIntron.
Patients receiving Pegasys had
a higher end-of-treatment response rate but were also more likely to relapse, so
sustained virological response (SVR) rates 24 weeks after completing treatment
were similar: 40.9% with Pegasys, 39.8% with standard-dose PegIntron, and 38.0%
with low-dose PegIntron. In all arms, response rates were higher among patients
who achieved rapid or early virological response at weeks 4 or 12. The safety
profile was similar across all three groups, with about 10% experiencing serious
adverse events. The researchers concluded that, "the rates of sustained
virologic response and tolerability did not differ significantly between the two
available peginterferon-ribavirin regimens or between the two doses of
peginterferon alfa-2b."
http://www.hcvadvocate.org/news/newsRev/2009/HJR-6.7.html#1
The European equivalent of the American
Association for the Study of Liver Diseases (AASLD) conference is
the European Association for the Study of the Liver (EASL). This
year’s EASL conference included a wealth of information about
studies that have been conducted on drugs in development to treat
hepatitis C. This article will focus on coverage of the drugs
furthest along in the development cycle—telaprevir and boceprevir as
well some exciting news on the development of HCV therapeutic
vaccines that are in early clinical development.
Telaprevir
In previous Phase II studies of Vertex’s telaprevir, an HCV protease
inhibitor, it has been reported that SVR rates have been as high as
69% in people with HCV genotype 1 who have never been treated
(treatment naïve). Retreatment with pegylated interferon plus
ribavirin in people who did not achieve a sustained virological
response (SVR-undetectable HCV RNA (viral load) 24 weeks post
treatment) with a previous course of pegylated interferon plus
ribavirin is very important because they constitute a large group of
people with HCV who are in the most need for newer HCV medicines
that will improve the chances for successful response to treatment.
At EASL results of a phase II study of patients who did not achieve
an SVR and who were treated with the combination of telaprevir /Pegasys/
ribavirin were reported and the results are very encouraging.
There were three groups in the study:
Group A: telaprevir, Pegasys,
ribavirin for 12 weeks followed by Pegasys plus ribavirin for an
additional 12 weeks (total treatment duration = 24 weeks).
Group B: telaprevir, Pegasys,
ribavirin for 24 weeks followed by Pegasys plus ribavirin for an
additional 24 weeks (total treatment duration = 48 weeks).
Group C: Pegasys plus ribavirin
for a total treatment duration of 48 weeks (standard of care).
A total of 453 patients were enrolled and received
at least one dose of the study drug. (See Table 1 for SVR results)
Definitions of Prior Non-Response
Non-responders: people
who never achieved an undetectable HCV RNA (viral load) during or at
the end of HCV treatment.
Relapsers: people who became HCV viral
load undetectable during to the end of the HCV treatment period, but
who later became HCV RNA (viral load) positive during the follow-up
period.
Breakthroughs: people
who achieved an undetectable HCV viral load during treatment, but
who later had detectable HCV viral load before the end of the
treatment period.
Table 1: SVR results by type of prior
response:
Group A (TVR12/PR24)
Group B (TVR24/PR48)
Group C (PR48)
Non-responders
39% out of 66 patients
38% out of 64 patients
9% out of 68 patients
Relapsers
69% out of 42 patients
76% out of 41 patients
20% out of 41 patients
Breakthroughs
57% out of 7 patients
50% out of 8 patients
40% out of 5 patients
Total
51% out of 115 patients
52% out of 113 patients
14% out of 114 patients
Safety
Vertex reported that the side effects were consistent with prior
studies of telaprevir/Pegasys/ribavirin. Seventeen out of 339
patients (5%) discontinued therapy due to skin rash and three out of
339 patients (1%) due to anemia. Growth factors were allowed in
the study but only two out of 339 patients in the telaprevir groups
were given growth factors to treat anemia.
Comment: Even though the total number of patients in the study was
small, the overall SVR rates are impressive. Another study, the
REALIZE study, has been launched by Tibotec
(Vertex’s European partner) that will enroll about 650
treatment-experienced patients, and the results should give us a
better picture of the effectiveness of a regime that includes the
combination of telaprevir, pegylated interferon and ribavirin, as
well as hopefully confirm the prior results.
Boceprecir
The final results of the SPRINT-1 study of
boceprevir, an HCV protease inhibitor used in combination with
PegIntron plus ribavirin, were also released at EASL. The patients
in the study were HCV genotype 1 patients who had never been treated
(treatment naïve) for hepatitis C.
The study had two parts: Part 1: To evaluate boceprevir (800 mg – three
times a day), PegIntron and ribavirin in standard doses with
different treatment durations. Total of 5 different treatment
groups – two of the arms also had a lead-in phase with PegIntron
plus ribavirin (without boceprevir). In this part of the study the
various treatment regimes were compared to PegIntron plus ribavirin
(standard of care (control group)) for 48 weeks. (520 patients
total)
Part 2: To evaluate boceprevir,
PegIntron and ribavirin treatment: two different doses of ribavirin
(800-1400 mg/day vs. 400-1000 mg/day); 48 weeks of treatment with
the triple combination of boceprevir/PegIntron/ribavirin. No
lead-in phase. (75 patients total)
Part 1 Results
An SVR rate of 75% (77 out of 103 patients) was
highest in the arm that received the lead-in of PegIntron plus
ribavirin for 4 weeks followed by 44 weeks of boceprevir /PegIntron/
ribavirin (total treatment duration = 48 weeks) vs. an SVR of 38% in
the group that received the current standard of care therapy of
PegIntron plus ribavirin. In the group that received the lead-in of
PegIntron plus ribavirin for 4 weeks followed by 24 weeks of the
triple combination of boceprevir/PegIntron/ribavirin (total
treatment duration = 28 weeks) the SVR rates were only 56%, which
confirmed that the optimal treatment duration for the triple
combination (boceprevir, PegIntron, ribavirin) therapy is 48 weeks.
Safety Results
Treatment discontinuations due to side effects in Part 1 of the
study were between 9 and 19% in the boceprevir arms compared to 8%
in the arm without boceprevir. The most common side effects
reported were fatigue, anemia, nausea and headache.
Anemia (hemoglobin decreasing to less than 10
g/dL) occurred in about 50% of people in the boceprevir arms
compared to about 1/3 in the arm without boceprevir. Erythropoietin
(EPO-growth factor) was allowed in the study—26% of patients used
EPO in the arm without boceprevir compared to 39-51% who used EPO in
the groups that received boceprevir.
Part 2 Results
In Part 2 (low dose ribavirin) it was found that the SVR rate was
36% vs. 50% in the standard dose group (both in combination with
boceprevir and PegIntron). This information confirms that standard
doses of ribavirin are needed to increase SVR rates even with the
addition of boceprevir.
Comments
The results are impressive—75% SVR rates. However, the increase in
anemia seen in the patients who received boceprevir is a cause for
concern that could limit the usefulness of boceprevir. Another
concern is that EPO was allowed and used in the clinical trials.
The use of EPO raises many concerns including:
EPO is not currently approved by the FDA to
treat HCV treatment-related anemia. It is unlikely that the
vast majority of patients who develop anemia from HCV treatment
will be able to use EPO since there are strong warnings about
the use of EPO that are now listed on the FDA approved EPO
package insert.
If EPO is used, will it be covered by most
insurance companies? This seems highly unlikely in the light of
the warnings about and the cost of EPO.
How did the use of EPO affect the treatment
outcome? Would more patients have dropped out of the study if
EPO wasn’t used? If so, that could decrease the listed SVR
rates.
Does boceprevir now have an advantage
over the other HCV drugs in development that have not been able
to or rarely used EPO?
Does boceprevir now have a disadvantage
over the other HCV drugs in development because EPO was used in
the clinical trials? Will physicians decide not to prescribe
boceprevir due to anemia if patients do not have access to the
use of EPO?
We may find out some of the answers when phase III
studies are completed, but most likely the real answers will come
when and if boceprevir is approved by the FDA to treat HCV.
Erythropoietin or EPO:
Erythropoietin or EPO is a hormone that is naturally produced by
the kidneys, and to a lesser extent by the liver, that helps
stimulate the bone marrow to produce red blood cells that will
increase the oxygen-carrying capacity of the blood. Synthetic EPO
(brand name Epogen, Procrit) is an injectible medicine that has been
approved by the Food and Drug Administration (FDA) to treat anemia
caused by kidney failure, the HIV medication AZT, and cancer. Most
people have heard of EPO related to its illegal use as a
performance-enhancing drug by some athletes. In 2007, the FDA
issued a Public Health Advisory and required a black box warning on
the product information labeling about the potential health risks of
using EPO.
Box
HCV Vaccines
The discovery of protective or therapeutic vaccines has proven
difficult, but reports from EASL on various therapeutic vaccines are
encouraging. Therapeutic vaccines work to stimulate the immune
system to fight an infection and may have a use in ‘boosting’ the
effectiveness of current and future medications to treat hepatitis
C.
TG4040: Results from a phase I
study were released and it was found that 6 out of 15 patients given
the therapeutic vaccine, TG4040, had a viral load reduction of 0.5
to 1.4 log10 IU/mL from baseline. The next step in the development
process is a new clinical trial of TG4040 in combination with
pegylated interferon plus ribavirin. The new trial is expected to
begin in 2010.
GI-5005: Treatment with GI-5005,
a therapeutic HCV vaccine (plus pegylated interferon/ribavirin) was
compared to pegylated interferon/ribavirin (without GI-5005). The
combination that included GI-5005 was found to produce 8% to 12%
higher rates of HCV viral load reductions at twelve weeks in HCV
genotype 1 treatment-naïve patients compared to those in the group
who did not receive GI-5005.
ChronVac-C DNA vaccine: Data on
the first DNA vaccine was released at EASL. In a proof of concept
study, 12 HCV genotype 1 treatment-naïve patients were given various
doses of the therapeutic vaccine. In 4 out of 6 patients who
received the two highest doses there were viral load reductions
exceeding 0.5 log10 that lasted for 2 weeks to greater than 10
weeks. The HCV viral load reductions correlated with specific
immune response thereby satisfying the proof of concept.
In the trials of HCV vaccines listed above, the
vaccines were safe and well-tolerated.
In addition to the above studies, there were many
reports on drugs being developed to treat hepatitis C. These drugs
are in very early development and a summary of the results can be
found on the
HCV Advocate Drug Pipeline web page.
Although often dismissed as
non-crucial medical jargon, understanding the stages of development
provides a more realistic appreciation of potential new Hepatitis C
drugs. Keeping current on the potential arrival of new, improved
Hepatitis C drugs is a regular research venture for many who are
living with the Hepatitis C virus (HCV). Because the current
standard of care for HCV works for less than 50 percent of those
infected, doctors, scientists and pharmaceutical companies are
feverishly searching for a solution that is more effective and has
fewer side effects than interferon combination therapy. However,
keeping up with the seemingly endless announcements of discoveries
and successes demands a layman’s road map for deciphering what it
all means.
The testing of new drugs is a long
process that typically takes about 12 years from pre-clinical
testing, through clinical trials, to U.S. Food and Drug Association
(FDA) approval until it can finally reach the general public.
Pre-Clinical
Drug companies continuously analyze thousands of compounds, seeking
ones of therapeutic value. During the average six to seven years of
pre-clinical testing, the manufacturer completes synthesis and
purification of the drug and conducts limited animal testing. Under
FDA requirements, a drug company must first submit data showing that
their drug is reasonably safe before it can be evaluated by humans
in initial, small-scale clinical studies.
Only after proving its safety and
efficacy in vitro (in a test tube) or in laboratory animal testing
can a drug be administered to humans in clinical trials. During
pre-clinical drug development, the following is evaluated:
Toxicity
Pharmacologic
effects
Genotoxicity –
genotoxic substances cause cancer, through genetic mutation or
contribution to tumor development
Absorption and
metabolism
Speed of excretion
If any evidence surfaces that it is
unsafe or ineffective, the drug will likely never make it to human
testing. Actually, only about 1 in 1,000 investigational compounds
survives pre-clinical testing favorably and proceeds to clinical
studies. Of those drugs that make it to human testing, approximately
1 in 5 will persevere through the many steps and receive FDA
marketing approval. Therefore, a person living with HCV who hopes to
find a new medicine may be disappointed if he/she gets too excited
about drugs in the pre-clinical testing phase.
When a company is ready to proceed
to clinical trials, it files an investigational new drug application
with the FDA. Most clinical trials are designated as Phases I, II or
III, and sometimes IV based on the type of questions that the study
is seeking to answer. Although the phases of human clinical studies
are generally conducted sequentially, there are cases when the
phases overlap.
Clinical Trial: Phase I
Once granted approval by the FDA as an investigational new drug,
testing can begin on humans. Phase I studies are typically conducted
in healthy volunteer subjects, with the intent of determining:
Metabolic and
pharmacologic actions
Side effects with
increasing doses
If possible, early
insight into drug effectiveness
Typically considered to be smaller
trials, Phase 1 studies generally recruit between 20 to 80 human
subjects. Typically the drug remains in Phase I for one to two
years.
Clinical Trial: Phase II
Instead of recruiting solely healthy people, Phase II clinical
trials begin to evaluate the drug’s effectiveness in the target
population. This stage of testing is where the preliminary data on a
potential drug’s effectiveness for HCV emerges. Additionally, Phase
II helps determine the common short-term side effects and risks
associated with the drug. Several hundred people are usually
enrolled in a Phase II clinical study. At the end of this round of
studies, the manufacturer meets with FDA officials to discuss the
development process, continued human testing, any concerns the FDA
may have and the protocols for Phase III.
Clinical Trial: Phase III
Usually the most extensive and expensive part of drug development,
Phase III studies are intended to evaluate the overall benefit-risk
relationship of the drug. By gathering additional information about
the drug’s effectiveness, safety, side effects and comparison to
commonly used treatments, Phase III studies involve large groups of
participants. Usually tested on several thousand people, Phase III
studies also provide the basis for extrapolating results for
physician labeling should the drug be granted FDA approval.
Once Phase III is complete, the
manufacturer may file a new drug application. Review of the new drug
application typically lasts one to two years, bringing drug
development time after pre-clinical trials to approximately nine
years. If the FDA approves the new drug, it may be marketed with FDA
regulated labeling. The FDA also gathers safety information as the
drug is used and adverse events are reported, and it will
occasionally request changes in a labeling or will submit press
releases as new contraindications arise. If adverse events appear to
be systematic and serious, the FDA may withdraw a product from the
market at any time.
Clinical Trial: Phase IV
In Phase IV studies, the drug is already on the market for a
particular indication, but is now being tested for a different
indication, use or disease.
Fast Track Status
During the phases of investigational drug development, the
manufacturer can obtain accelerated development or review of its
drug. If granted fast track status by the FDA, the timelines for
clinical trials can take some shortcuts. Geared towards facilitating
the development and expedition of new drugs that have the potential
to address an unmet medical need for serious or life-threatening
conditions, many HCV potential drugs are granted fast track status.
Once a drug receives fast track
designation, early and frequent communication between the FDA and a
drug company is encouraged throughout the entire drug development
and review process. The frequency of communication assures that
questions and issues are resolved quickly, often leading to earlier
drug approval and access by patients.
Having a general concept of the
many steps and length of time involved in the approval of a new
medication gives us a greater appreciation of what it takes to
develop a drug. Patience is definitely required to see a potential
cure come to fruition. While it may be premature to place all of
your hope in a compound with promising pre-clinical trial results,
go ahead and visualize how a drug emerging positively from Phase III
will help you defeat HCV.
Comments:
In healthy volunteers MK-3281was found to be safe and
well-tolerated and plasma concentrations indicate a
potential for twice daily dosing.
(May 18, 2009)
Comments:
On March 31, 2009 Pharmasset, INC, announced the start (and
first patient dosed) of PSI-7851 in healthy volunteers. The
data from this study is expected in the second quarter of
2009. (April 21,
2009)
Comments:
Abbott and Enanta Pharmaceuticals announced the initiation
of a double-blind, placebo-controlled study of ABT-450 HCV
in healthy volunteers.
(February 20, 2009)
Comments:AASLD 2008:
A small study of 19 prior HCV genotype 1
treatment-experienced patients were divided into three
groups and were given once-a-day dosing of either 48, 120 or
240 mg of BI 201335 a day in combination with pegylated
interferon and ribavirin for 28 days. The drug was found to
produce a virologic response in all treatment doses through
day 28. The higher dose of 240 mg/day produced the highest
virologic response. There were no serious side effects
reported – the side effects experienced were consistent with
the side effects seen in pegylated interferon plus ribavirin
therapy. One patient discontinued treatment due to anxiety.
Boehringer announced that further development is being
planned.
(Feburary 10,2009)
Comments:
Phenomix announced that it had begun enrolling patients in
the Netherlands. 24 healthy subjects and 6 HCV patients will
be given PHX1766 to test the safety, tolerability and
pharmacokinetcs.
(October 28, 2008)
Comments:
On January 13, 2009 Idenix announced that it will begin a
study of IDX184 in HCV genotype 1 treatment-naive patients
who will receive one of four doses (25 to 100 mg
once-per-day). The study will include 10 patients who will
receive the study drug and 2 patients who will receive a
placebo drug. (January 26, 2009)
Comments:On December 1, 2008
ANA598 received fast-track designation from the FDA.
EASL 2009:It
was reported that ANA598 produced rapid and sustained
reductions in HCV RNA with median reductions at the end of
treatment (Day 4) exceeding 2 log10 (>99%) at all dose
levels. At 200 mg bid (twice-daily) the median viral load
reduction was 2.4 log10 (range of 0.4 to 3.4); at 400 mg
bid, 2.3 log10 (range of 1.6 to 3.5); and at 800 mg bid, 2.9
log10 (range of 2.2 to 3.4). Genotype 1a patients
demonstrated median reductions of 1.4 log10, 1.8 log10, and
2.5 log10 at 200, 400 and 800 mg bid, respectively. In 10 of
the 12 genotype 1a patients who received ANA598, viral load
was still declining at the end of the three days of
treatment. Genotype 1b patients demonstrated median
reductions of 2.6 log10, 2.5 log10, and 3.2 log10, at 200,
400 and 800 mg bid, respectively.
In a separate study of healthy
volunteers (14 day study) three people developed a severe
rash and discontinued therapy.
(May 5, 2009)
Comments:On
June 11, 2008, Abbott announced the initiation of a Phase I
study to test the safety, tolerability, antiviral activity
and pharmacokinetics of ABT-333 in healthy volunteers and in
HCV positive individuals. (June
11, 2008)
EASL 2009: In a
study of healthy adults ABT-333 was found to safe and
generally well-tolerated in doses of 200, 400, 600, and 100
mg BID (twice a day) when given for 10 days.
(May 5, 2009)
Comments:
In a small study of healthy volunteers, VCH-916 was found to
be generally safe and well-tolerated and achieved plasma
concentrations proportional to the dose given. Based on
these results a 14-day study of HCV genotype 1
treatment-naïve subjects is being planned.
On March 12, 2009, Vertex announced that it had completed
acquisition of ViroChem and will be developing ViroChem’s
HCV polymerase inhibitors in combination with their drug and
will study ViroChem’s drugs in combination with pegylated
interferon plus ribavirin.(March
13,2009)
Comments:
EASL 2009: Week 4 data from a study of 35 patients
treated with 200, 300, 500 mg (plus placebo) BID (twice a
day) plus pegylated interferon/ribavirin found that up to
75% were viral load negative at week 4. The drug was
generally well-tolerated.
(May 5, 2009)
Comments:
On September 2, it was announced that InterMune, according
to the agreement with Roche, had met certain milestones and
that further clinical development would be transitioned over
to Roche.
EASL 2009: The final results
from a phase I study were announced – 14 days of ITMN-191
(six treatment arms; one placebo arm) with Pegasys plus
ribavirin found that there was a 5.3 to 5.7 log drop in HCV
RNA. The drugs were generally well-tolerated with 4 serious
adverse events, but 2 of the events were not attributed to
the study drug and the other 2 events were similar to those
seen in the non-ITMN-191 arm. (May 5,
2009)
Comments:AASLD 2008: HCV genotype 2 and
3 prior non-responders were treated with R7128 (1500 mg
twice a day) in combination with Pegasys plus ribavirin for
28 days. There was a mean viral log reduction of 5.0 log10.
R7128 was generally well-tolerated and further development
in genotype 2 and 3 patients is being planned.
On January 12, 2009, Pharmasset, announced the FDA approval
of a phase 2b study of R7128 in combination with Pegasys and
ribavirin. The study is expected to enroll 400 HCV genotype
1 or 4 treatment-naïve patients. The study subjects will be
enrolled into 4 arms – R7128 (500 or 100mg bid) plus Pegasys
and ribavirin for a treatment durations of 24 or 48 weeks
and one control arm – Pegasys plus ribavirin – for a
treatment duration of 48 weeks.
On April 25, 2009, it was announced that the first patient
had been dosed. (May 5, 2009)
Comments: EASL
2009: The results of a study of 95 treatment-naïve
patients with HCV genotype 1 who were randomized into 5
groups (including one placebo group) were presented. All
doses of MK7009 were found to have potent antiviral effects
and was generally well-tolerated with no serious adverse
events or discontinuations.
(May 18, 2009)
Comments:EASL 2009: In an ongoing study,
48 HCV genotype 1 (treatment-naïve & treatment-experienced)
patients were treated with various doses of BI 207127
monotherapy (one group received placebo). Preliminary
results found that there was significant reduction of HCV
viral load after 5 days of treatment. The drug was generally
well-tolerated. A minor rash and redness of skin was
reported but managed effectively. (May
18, 2009)
Comments:A-832
is a NS5A inhibitor that was found (in a test tube) to
prevent the HCV IRES-dependent translation process. A phase
I study of A-831 has been initiated in healthy volunteers.
In 2007, AstraZeneca acquired Arrow Therapuetics, Ltd. There
has been no further news about the development of A-831.
(February 10,
2009)
Comments:
Gilead has begun recruitment for a clinical trial to study
the safety, tolerability and effectivenss of GS-9190 in
combination with Pegasys plus ribavrin for a treatment
duration of 24 or 48 weeks.
(February 10, 2009)
Comments:
In a phase I study of healthy volunteers, BMS-790052 was
found to be safe and well-tolerated and the absorption and
distribution properties of the drug appeared to suggest a
once-a-day dosing. In a study of HCV genotype 1 patients it
was found to produce a rapid reduction in HCV RNA in the 1,
10, and 100 mg doses. BMS is currently recruiting patients
for a phase II study in HCV genotype 1 treatment
non-responders and naive patients. BMS-790052 will be dosed
from 1-100 mg (once or twice a day).
(January 26, 2009)
Comments:
On November 24, 2008 Schering announced the results from a
Phase I clinical trial of 518 in treatment-naïve patients
and HCV patients who did not respond to a previous course of
HCV treatment. SCH518 was given as either monotherapy or in
combination with peginterferon and demonstrated enhanced
antiviral activity, with up to 4log10 and 5log10 decreases
in HCV RNA respectively. A phase IIa study is currently
on-going, but no further details have been released.
On March 9, 2009, it was announced that Merck would buy
Schering-Plough. The sale of Schering to Merck is contingent
on the approval of Merck and Schering stockholders as well
as government regulatory agencies. Merck announced that they
expect the transaction will be completed by the end of 2009.
EASL 2009: In a trial of SCH518
in combination with PegIntron, with and without ribavirin
and with and without ritonavir (used to boost antiviral
effects of SCH518) was found to be generally well-tolerated
with no serious side effects and it was shown to have potent
antiviral activity in treatment-naïve and
treatment-experienced patients. The results of the study
also suggest that SCH518 could be a once-a-day dose.
(May 18, 2009)
Comments:AASLD 2007: In a 10 day phase I
study in which 32 treatment naïve HCV patients received
different doses of VCH-759 (400 mg TID, 800 mg BID, and 800
mg TID) all patients achieved a 1 log10 decrease
in HCV RNA but the higher dose arm of 800 mg TID achieved
2.5 log10 decrease. The drug was generally
well-tolerated. A Phase 2, Multicenter, Randomized,
Double-Blinded, and Placebo-Controlled Study of the
Antiviral Activity, Safety and Pharmacokinetics of VCH-759
is underway.
On March 12, 2009, Vertex announced that it had completed
acquisition of ViroChem and will be developing ViroChem’s
HCV polymerase inhibitors in combination with their drug and
will study ViroChem’s drugs in combination with pegylated
interferon plus ribavirin.
(March 13, 2009)
Comments:
iTherx will commence a phase 2a study that will enroll 40
patients (European study sites) to test ITX5061 as a single
agent for viral load reductions, safety and tolerability.
(February 9,
2009)
Comments:
TMC435 (formerly TMC435350-C201) is a phase IIa
proof-of-concept, blinded, randomized, placebo-controlled
trial to assess the effectiveness, safety, tolerability, and
pharmacokinetics of four different dose regimens of
TMC435350 (25 mg daily, 75mg daily, 200mg daily, 400mg
daily). 96 treatment-naïve and 24 treatment-experienced
patients with chronic genotype-1 HCV infection will be
enrolled in the trial which will be conducted at more than
20 sites in Europe. Patients will receive either TMC435350
or placebo once daily (qd) for 28-days. Standard of Care
(SoC) treatment, peginterferon alpha-2a (Pegasys®) and
ribavirin (Copegus®), will be provided for 48 weeks or,
optionally, for 24 weeks for those patients with an
undetectable HCV viral load at Week 4 and who remain
undetectable at Week 20. Patients will be followed-up for 24
weeks after the end of standard of care (Peg/ribavirin) to
allow evaluation of sustained virologic response (SVR).
EASL 2009: TMC435 given to HCV
genotype 1 treatment-naïve patients at doses of 25, 75 or
200 mg qd (once a day) for 4 weeks was generally well
tolerated and showed impressive viral load reductions. The
trial in treatment experienced-patients is ongoing.
In another study of 37 HCV genotype 1 treatment-experienced
patients, the triple combination of TMC435 plus Pegasys and
ribavirin was found to produce strong antiviral activity and
to be safe and well tolerated.
(May 5, 2009)
Comments:
On May
21, 2008, Schering announced that they would begin 2 phase
III studies to evaluate boceprevir in combination with
PegIntron plus ribavirin in treatment-naïve and
treatment-experienced patients.
On January 27, Schering Plough announced that it had
completed enrollment in their Phase III (HCV SPRINT-2
study).
On March 9, 2009 it was announced that Merck would purchase
Schering-Plough. The acquistation must first be approved by
the Merck and Schering stockholders and they expect the
transaction to be completed by the end of 2009.
EASL 2009: In the five arm
study of boceprevir, the arm that included 103 patients
achieved an SVR of 75% – this regime included a 4 week
lead-in phase of PegIntron plus ribavirin followed by triple
combination therapy of boceprevir, PegIntron and ribavirin
for 44 weeks. Total duration of treatment was 48 weeks. The
side effects in the boceprevir arms were similar to side
effects that are usually seen in pegylated interferon and
ribavirin except there was a higher incidence of
anemia—about 50% in the boceprevir arms vs. about 33% in the
group without boceprevir.
(May 5, 2009)
Comments:
On January 23, 2008, Vertex
announced that they will
begin recruitment into a
phase III clinical trial in
March 2008. The ADVANCE
trial will be conducted in
about 100 centers in the
U.S., Europe and certain
other countries. The study
will enroll approximately
1050 HCV genotype 1
treatment naïve patients.
There will be 3 treatment
arms comparing telaprevir in
combination with pegylated
interferon plus ribavirin
for a treatment duration of
24 weeks. The control arm
will be patients treated
with pegylated interferon
plus ribavirin for 48 weeks
(current standard of care).
This is the pivotal Phase
III study that will be used
to apply for FDA marketing
approval, which Vertex
expects to seek in late
2010.
On October 15, 2008 Tibotec
(Vertex’s European Partner)
announced that it has begun
enrollment into its phase
III study called REALIZE to
evaluate telaprevir in
combination with pegylated
interferon plus ribavirin in
prior treatment null
responders, partial
responders, and relapsers.
The study will enroll about
650 treatment experienced
HCV patients in the US,
Europe and other countries
throughout the world.
Phase II Clinical
Trials:
PROVE 2:
The study results of 323 HCV
genotype 1 treatment-naïve
patients (never been
treated) was released at
this year’s (2008) AASLD
conference. The results
found that the arm that
received the 24 weeks of
treatment (12 weeks of
telaprevir plus pegylated
interferon plus ribavirin
followed by 12 weeks of
pegylated interferon plus
ribavirin (without
telaprevir) had the highest
SVR rate – 69% (56 out of 81
patients) compared to 46%
(38 out of 82 patients) in
the arm that received 48
weeks of pegylated
interferon plus ribavirin
(control arm).
EASL
2009: PROVE
data of 453 patients who did
not achieve a sustained
virological response (SVR)
with a previous course of
pegylated interferon plus
ribavirin was released.
Non-responders by type of
non-response was:
non-responders (38-39%);
relapsers (69-76%); viral
breakthroughs (51-52%).
Study 107:
Interim results from another
study of people who failed
to achieve an SVR with a
previous course of pegylated
interferon plus ribavirin
therapy was released at
AASLD and found that 24 week
response rates were
null-responders (43%),
partial responders (82%),
relapsers (83%), and viral
breakthroughs (0%). The
safety profile is consistent
with other studies of
telaprevir, pegylated
interferon and ribavirin.
Study C208
is a new study that is
evaluating different doses
of telaprevir – 750 mg every
8 hours (q8h or three times
a day) compared to 1125 mg
dose every 12 hours (q12h or
twice a day) in HCV genotype
1 treatment-naïve patients.
Week 12 data found that 93%
of patients who received the
q8h were HCV undetectable
and 83-85 % who received the
q12h dose were HCV
undetectable.
(May
5, 2009)
The European Association of the Study of
Liver Disease wrapped up on Sunday in Copenhagen. Here are some
of the hightlights of all things hepatitis C:
INFORM-1 Data
Roche, InterMune(ITMN
Quote) and Pharmasset(VRUS Quote) provided the most eagerly
anticipated clinical data of the conference Saturday with
results from a 14-day trial combining two experimental direct
antivirals -- InterMune's ITMN-191 with Pharmasset's R7128 --
given to patients with treatment-naïve hepatitis C. Roche is a
development partner on both drugs.
The companies called the INFORM-1 study
"ground breaking" and rightly so in that this trial was the
first time that two oral drugs -- both of which stop the
hepatitis C virus from replicating itself, albeit in different
ways -- were shown to be safe and effective in lowering viral
loads in patients when taken in combination.
However, the viral load reductions and number
of patients with undetectable levels of virus achieved by
various dose combinations of ITMN-191 and R7128 over 14 days
fell short of past studies combining a more potent oral drug
like Vertex Pharmaceuticals'(VRTX Quote) telaprevir with
standard of care for hepatitis C (long-acting injectable
interferon and ribavirin).
The INFORM-1 study is a solid proof of concept
that an all-oral combination therapy for hepatitis C is
possible, but Roche, InterMune and Pharmasset are going to have
to show that higher doses of the drugs, especially of
InterMune's ITMN-191, produce stronger antiviral efficacy in
order to make it possible to eliminate the use of interferon and
ribavirin.
Vertex's Telaprevir
Vertex had a fairly quiet EASL conference,
mainly because telaprevir is in the middle of phase III studies
that won't have data available until next year. Still, the
company did present previously disclosed data showing that
telaprevir is capable of significantly improving cure rates in
the most difficult-to-treat patients who had failed prior
treatment with the current standard drug regimen for hepatitis C
-- a 48-week course of long-acting interferon plus ribavirin.
This data keeps telaprevir ahead of its
hepatitis C rivals because no other drug has yet shown the
ability to improve the cure rates for both patients new to
therapy as well as those who have failed prior therapy.
Telaprevir was the "butt" of some negative
EASL chatter due to an anecdotal report that the drug was
causing severe anal itching in patient(s). One EASL attendee
described the side effect as "fire in the hole."
All jokes aside, itchy rash is a well-known
and documented side effect of telaprevir, but there have been no
confirmed reports of anal pruritis (the medical term for anal
itching) in any of the telaprevir studies presented to date. In
fact, patient discontinuation rates due to telaprevir-induced
rash appear to be on the decline, as doctors and patients learn
how to better manage the side effect.
This should lead to higher cure rates for
telaprevir in the ongoing phase III studies compared to the
already high rates seen in the phase II trials.
New England Journal Of Medicine Publishes
Landmark Clinical Studies Of The Investigational
Hepatitis C Virus Protease Inhibitor Telaprevir
http://www.medicalnewstoday.com
Two clinical studies published
in this week's New England Journal of Medicine
demonstrate that treatment with the investigational oral
hepatitis C virus (HCV) protease inhibitor telaprevir dosed in
combination with pegylated-interferon (peg-IFN) and ribavirin (RBV)
as part of a 24-week treatment regimen resulted in a significant
improvement in the rate of sustained viral response (SVR),
considered a cure of the viral infection, in treatment-naïve
genotype 1 HCV patients, as compared with the SVR rate for
standard therapy dosed for 48 weeks. The data are from two Phase
2b (mid-stage) clinical trials of telaprevir known as PROVE 1
and PROVE 2. In these trials, patients who received a 24-week
telaprevir-based treatment regimen achieved SVR rates of up to
69 percent, as compared to SVR rates of up to 46 percent in
patients in the control arms of these trials who received peg-IFN
and RBV for a standard duration of 48 weeks. Telaprevir is being
developed by Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX)
in collaboration with Tibotec and Mitsubishi Tanabe Pharma.
Telaprevir is currently in Phase 3 (late-stage) clinical
development.
HCV is the most common
blood-borne infection in the U.S., four times more common than
HIV infection, and is the leading cause of liver
transplantations and liver cancer in the U.S.
"Currently available therapies
for patients infected with HCV can be difficult to tolerate and
less than half the patients who start the yearlong treatment
regimen achieve the ultimate goal of having an undetectable
level of virus in their bodies," said John McHutchison, M.D.,
Lead Investigator for the PROVE 1 trial and Associate Director
of the Duke Clinical Research Institute. "In these Phase 2
clinical trials, up to 69 percent of patients in the 24-week
telaprevir-based treatment arm had undetectable virus levels
after 24 weeks, and even though telaprevir does produce side
effects of its own, its addition to standard therapy allowed us
to shorten the duration of treatment. This 24-week regimen was
half the duration of currently approved therapies and, if
confirmed to be this effective in larger Phase 3 studies, could
one day become a very important treatment option for hepatitis C
patients."
"In the PROVE 1 and PROVE 2
trials, telaprevir significantly improved the proportion of
patients who were cured of their disease and also shortened the
duration of HCV therapy from 48 to 24 weeks for the majority of
treatment-naïve patients - an exciting achievement and a
potentially meaningful advance in the treatment of this
disease," said Robert Kauffman, M.D., Ph.D., Senior Vice
President of Clinical Development for Vertex. "Based on data
from these trials, as well as from the PROVE 3 trial in patients
who failed prior HCV therapy, telaprevir is being evaluated in a
comprehensive Phase 3 registration program in more than 2,200
treatment-naïve and treatment-failure patients. Assuming
successful completion of this program, we expect to file an
application for approval of telaprevir with the U.S. FDA in the
second half of 2010."
PROVE 1 and PROVE 2
Study Results
The primary endpoint of the PROVE 1 and PROVE 2 trials was the
proportion of patients who had no detectable hepatitis C virus
in their blood (undetectable plasma HCV RNA) 24 weeks after the
completion of therapy, also known as a sustained viral response
(SVR). Patients who achieve an SVR are considered to be cured of
their HCV infection.
Final results from the PROVE 1
and PROVE 2 trials showed that the 24-week treatment arm, which
consisted of 12 weeks of telaprevir dosed in combination with
peg-IFN and RBV followed by an additional 12 weeks of peg-IFN
and RBV alone, resulted in a significant improvement in SVR
rates, an increased rate of rapid virologic response (RVR,
defined as undetectable levels of HCV RNA by the end of week 4)
and low rates of viral relapse (defined in patients as
undetectable HCV RNA at the end of treatment but detectable
viral levels during the post-treatment follow-up period), as
compared with the SVR, RVR and relapse rates observed in
patients in the control arms who received peg-IFN and RBV for 48
weeks.
Of the small sub-group of
African American patients enrolled in PROVE 1, 44 percent
achieved an SVR in the telaprevir arms, while 11 percent
achieved an SVR in the control group. SVR rates in African
Americans are typically lower than in other ethnic groups.
African Americans are also disproportionately infected with HCV
as compared to other ethnic groups.
Together, these data suggest
that a 24-week telaprevir-based treatment regimen may be
sufficient for treatment-naïve patients who achieve an RVR.
These findings are being confirmed in Vertex's ADVANCE Phase 3
clinical trial in treatment-naïve patients, focusing on 24-week
response-guided regimens that consist of either 8 or 12 weeks of
telaprevir in combination with peg-IFN and RBV. Treatment-naïve
patients in the ADVANCE Phase 3 trial who achieve an RVR and who
stay undetectable through week 12 of treatment will receive 24
weeks of treatment. Patients who do not meet the RVR criteria
but are undetectable at week 24 will continue on peg-IFN and RBV
for a total duration of 48 weeks. This Phase 3 trial is designed
to maximize the number of patients who can achieve SVR while
offering a large proportion of treatment-naïve patients the
benefit of a 24-week treatment duration.
Telaprevir Safety &
Tolerability Across PROVE 1 and PROVE 2
More than 400 patients received a telaprevir-containing regimen
as part of the PROVE 1 and PROVE 2 clinical trials, and the
adverse event profile was generally consistent across these
trials. Telaprevir was evaluated in combination with
Peginterferon alfa-2a and ribavirin. In these placebo-controlled
studies, the most common adverse events reported more frequently
in the telaprevir treatment arms compared to the placebo arms
were gastrointestinal events, skin events (rash, pruritus) and
anemia. Other adverse events reported were similar in type and
frequency to those seen with currently approved peg-IFN and RBV
treatment. The most common adverse event leading to
discontinuation in the telaprevir arms was rash in approximately
7 percent of patients across both PROVE 1 and PROVE 2.
Investigators have reported that rash adverse events were
reversible upon discontinuation of treatment, and a rash
management plan was implemented as part of subsequent telaprevir
clinical trials, including ongoing Phase 3 trials.
PROVE 1 Study Design
PROVE 1 was a Phase 2b, randomized, double-blind,
placebo-controlled trial that enrolled and treated 250
treatment-naïve genotype 1 HCV patients at 37 clinical trial
sites in the U.S. Of the patients enrolled in PROVE 1, the mean
age was 48.1 years, 63 percent were men and 77 percent were
white. Patients in PROVE 1 received 750mg of telaprevir (or
placebo) orally every eight hours, based on treatment arm, and a
once-weekly 180ug injection of Peginterferon alfa-2a, as well as
a 1,000mg or 1,200mg weight-based daily oral dose of ribavirin.
PROVE 1 consisted of four treatment arms: (1) a 24-week
telaprevir-based arm consisting of 12 weeks of telaprevir in
combination with peg-IFN and RBV, followed by an additional 12
weeks of peg-IFN and RBV alone, (2) a 48-week telaprevir-based
arm consisting of 12 weeks of telaprevir in combination with
peg-IFN and RBV, followed by an additional 36 weeks of peg-IFN
and RBV alone, (3) a 12-week telaprevir-based arm consisting of
12 weeks of telaprevir in combination with peg-IFN and RBV, and
(4) a control arm consisting of 12 weeks of placebo in
combination with peg-IFN and RBV, followed by 36 weeks of peg-IFN
and RBV alone.
PROVE 2 Study Design
PROVE 2 was a Phase 2b, randomized, partially double-blind,
placebo-controlled trial that enrolled and treated 323
treatment-naïve genotype 1 HCV patients at 28 clinical trial
sites in France, Germany, the United Kingdom and Austria. Of the
patients enrolled in PROVE 2, the mean age was 44.3 years, 59.4
percent were men and 94.1 percent were white. Patients in PROVE
2 received 750mg of telaprevir (or placebo) orally every eight
hours, based on treatment arm, a once-weekly 180ug injection of
Peginterferon alfa-2a, as well as a 1,000mg or 1,200mg
weight-based daily oral dose of ribavirin. PROVE 2 consisted of
four treatment arms: (1) a 24-week telaprevir-based arm
consisting of 12 weeks of telaprevir in combination with peg-IFN
and RBV, followed by an additional 12 weeks of peg-IFN and RBV
alone, (2) a 12-week telaprevir-based arm consisting of 12 weeks
of telaprevir in combination with peg-IFN and RBV, (3) a 12-week
telaprevir-based arm consisting of 12 weeks of telaprevir in
combination with peg-IFN (no RBV), and (4) a control arm
consisting of 12 weeks of placebo in combination with peg-IFN
and RBV, followed by 36 weeks of peg-IFN and RBV alone.
About Telaprevir and
Vertex's HCV Development Portfolio
Telaprevir (VX-950) is an investigational oral inhibitor of HCV
protease, an enzyme essential for viral replication, and is one
of the most advanced investigational antiviral agents in
development that specifically targets HCV. Telaprevir is being
evaluated as part of a global Phase 3 registration program in
more than 2,200 treatment-naïve and treatment-failure patients.
Vertex retains commercial
rights to telaprevir in North America. Vertex and Tibotec are
collaborating to develop and commercialize telaprevir in Europe,
South America, Australia, the Middle East and other countries.
Vertex is collaborating with Mitsubishi Tanabe Pharma to develop
and commercialize telaprevir in Japan and certain Far East
countries.
Vertex is also developing
VCH-222, an oral inhibitor of the HCV NS5B
polymerase. HCV polymerase inhibitors represent an additional
class of drug candidates that are aimed at inhibiting viral
replication.
Source: Vertex
Pharmaceuticals Incorporated
Anadys' ANA598 and Rash
Anadys Pharmaceuticals'(ANDS Quote) share
price has not yet recovered from the emergence last week of a
rash associated with its experimental drug ANA598. The company
contends that investors are more worried about rash than doctors
using the drug in clinical trials and the emergence of this
potential side effect will not derail the drug's development.
However, Anadys only has another quarter or
two of cash left and doesn't have enough money on hand to begin
the next round of ANA598 clinical trials. Anadys is negotiating
with potential partners for ANA598 but if talks are delayed, the
company could be forced to raise money though another dilutive
financing.
-- Highlights include
Anadys Pharmaceuticals Inc. (ANDS), Roche Holding AG (RHHBY),
Schering-Plough (SGP), Gilead Sciences (GILD), Vertex
Pharmaceuticals (VTRX) and Valeant Pharmaceuticals International
(VRX).
-- Strong efficacy data
observed in early phase Ib studies for ANA598, but a severe rash
raises safety concerns
ANA598
is Anadys’ (ANDS) lead anti-HCV (hepatitis C Virus) drug
candidate currently under phase I studies. The company’s share
price got a boost recently on its strong efficacy data from a
phase Ib study.
Anadys presented the final
antiviral and safety data from all three dose levels (200, 400
and 800 mg bid) at the 44th annual meeting of the European
Association for the Study of the Liver (EASL) on April 23, 2009.
The trial enrolled total 35 subjects. ANA598 treatment resulted
in rapid and sustained reductions in HCV RNA with median
reductions at end of treatment
(day 4) exceeding 2 log10
(>99%) at all dose levels.
At 200 mg bid, the median viral
load reduction was 2.4 log10 (range of 0.4 to 3.4); at 400 mg
bid, 2.3 log10 (range of 1.6 to 3.5); and at 800 mg bid, 2.9
log10 (range of 2.2 to 3.4). Genotype 1a patients demonstrated
median reductions of 1.4 log10, 1.8 log10, and 2.5 log10 at 200,
400 and 800 mg bid, respectively. Genotype 1b patients
demonstrated median reductions of 2.6 log10, 2.5 log10 and 3.2
log10, at 200, 400 and 800 mg bid, respectively. Genotype 1b is
the most common subtype of hepatitis C found in North America
and Europe.
No patient showed evidence of
viral rebound while on ANA598. The drug seemed well-tolerated in
this short-term study and there were no serious adverse events
reported.
However, later in a separate
study from healthy volunteers in a 14-day study conducted to
extend the safety and pharmacokinetic profile of ANA598, a
severe rash was observed in some ANA598 treated subjects. Thirty
subjects participated in the study, with eight subjects
receiving ANA598 and two subjects receiving placebo at each dose
level (400 mg once-daily, 800 mg once-daily and 600 mg bid).
Preliminary results from the
study suggested that ANA598 was generally well-tolerated in all
cohorts with no serious adverse events, but three subjects (two
subjects in the 800 mg once-daily cohort and one subject in the
600 mg bid cohort) developed grade II rash and discontinued
treatment after either six or seven days of consecutive dosing.
Competition is fierce
in anti-HCV market
Although ANA598 showed encouraging efficacy, this was only
conducted in an early phase I trial with a very small number of
patients. We remind investors that competition will be fierce in
the anti-HCV market.
HCV is a serious infection
afflicting about 3.2 million people in the U.S. and
approximately 170 million people worldwide -- fatal in some
cases -- and is the primary cause of liver transplants in the
U.S. and Europe. This market is currently dominated by two
players: Roche (RHHBY), which commands a majority of the U.S.
and global pegylated interferon market share through the sale of
Pegasys/Copegus, and Schering-Plough (SGP), through the sale of
Peg-Intron / Rebetrol. The global HCV market in 2008 was between
$2 and $3 billion and is expected to grow to $4.4 billion in
2010 and $8.8 billion in 2015.
Due to the asymptomatic nature
of HCV infection, it often goes undetected for up to 20 years
following the initial infection. Each year, 8,000 to 10,000
people in the U.S. die from complications of HCV. The current
standard of care is a combination of pegylated interferon and
ribavirin.
Even if Anadys is able to bring
ANA598 to the market, it will face tough competition from other
big players like Schering Plough, Roche, and Gilead (GILD) in
the HCV market. In addition, a number of companies are
developing oral formulations for the treatment of HCV.
Vertex (VTRX) has set a new
benchmark for the treatment of HCV. Its HCV candidate,
Telaprevir, demonstrated significant reduction in viral load
with 4.4-log reduction in viral load compared to 1-2 log
reduction seen in other standard of care interferon therapy.
We believe that this data sets
the bar very high, and we are unsure whether Anadys can reach
it. Currently, Telaprevir is undergoing phase III studies.
Valeant’s (VRX) Taribavirin (previously known as Viramidine) is
in advanced clinical development.
Meanwhile, Schering’s
Boceprevir is in phase III. Hence, they are already ahead of
Anadys in terms of development. So we believe competition will
remain a challenge for Anadys in the years to come.
Cash burn is a matter
of concern
The company is still in the development stage, with no products
on the market.
Net cash burn in the first
quarter of 2009 was $7.1 million. The company had only $21
million in cash, cash equivalents and investment as of March 31,
2009, which should last for about three quarters, according to
our model. Anadys, therefore, needs to enter into an agreement
on a partnership or acquisition relatively quickly otherwise it
will have to raise additional cash to fund its operations in
2009.
Currently all eyes are on the
ANA598 data and potential partnership agreement the company may
enter into in the near future. We are happy to see the very
positive efficacy data in the phase Ib trial, but are concerned
about the severe rash side effect. Since the phase I trial is
only tested in a small number of subjects, we remain skeptical
if the company can find a partner with favorable terms.
Schering-Plough's(SGP Quote) boceprevir made
some headlines last week with phase II cure rates numerically
higher than what's been reported by Vertex's telaprevir in its
phase II studies. But boceprevir still doesn't look competitive
because the drug is causing significant rates of anemia in
patients and requires dosing up to 48 weeks compared to 24-week
dosing for telaprevir. Boceprevir is also ineffective for
patients who have failed prior treatment.
The other challengers to telaprevir also
presented new data at the EASL conference, but none seemed ready
yet for a full fight. Johnson & Johnson's(JNJ Quote) TMC-435
appears to have at least a signal for liver toxicity;
Merck's(MRK Quote) MK-7009 reported high rates of vomiting;
while InterMune's ITMN-191 isn't very potent on its own,
especially when dosed twice daily.
2009 Annual
Meeting of the
European
Association for
the Study of the
Liver*
April 22-26,
2009 |
Copenhagen,
Denmark
*CCO is an
independent
medical
education
company that
provides
state-of-the-art
medical
information to
healthcare
professionals
through
conference
coverage and
other
educational
programs.
I returned from Copenhagen on April 27 after enjoying a
very exciting meeting and talking with many researchers
about the development of the many promising new oral HCV
drugs.
There were about 25 new HCV drugs that new data was
reported on at EASL in Copenhagen
April 23-26 2009.
The biggest story was the INFORM Study which is the
first study of 2 oral HCV drugs in combination in
patients, the study showed short-term efficacy/potency
and safety for the combination of Roche's protease
ITMN191 (R7227) and their polymerase NRTI R7128.
This was the first proof of concept study for showing
you can combine 2 oral HCV drugs, and the study
importantly showed additive antiviral activity and
safety.
Of course further studies are planned to move this
ahead.
Of interest also was a poster on an early study of
lambda interferon in patients which is a peginterferon
that shows little or no interferon side effects. A major
question is whether or not interferon and ribavirin can
be eliminated from therapy.
I have my doubts they can be and still achieve a 'cure'
with time limited duration of therapy but many others
are confident they can eliminate peg/RBV; many
researchers and companies are planning the studies to
answer this question, but if interferon is still needed
at least for some patients a peginterferon like lambda
without side effects would obviously be a tremendous
breakthrough. Every major drug company has oral HCV
drugs in development and presented data at EASL
including Boerhinger who has a protease now in phase 2 &
for the first time presented new data in patients on
their polymerase inhibitor.
Merck presented for the 2nd time on their protease this
time in combination with peg/RBV with interesting and
positive results, and for the first time presented new
data on their polymerase. Tibotec presented 2 studies in
naives and treatment-experienced patients on their
once-a-day protease which looks potent. Of note,
Schering presented for the first time their new
protease, not boceprevir, that looks potent and will be
boosted by ritonavir. '
Abbott has a comprehensive HCV drug program and they
presented interesting preclinical data showing their
protease to be potent and they had 2 posters on their 2
polymerase inhibitors. Of note there are 2 types of
polymerase inhibitors, NNRTIs and NRTIs, and their are
at least 2 types of NNRTIs. NNRTIs that can bind at
different places may be able to be combined in a regimen
and also along with a NRTI. At AASLD BMS presented their
first data in patients on their NS5A inhibitor and it
looked potent, and at this EASL Presidio, a biotech,
presented preclinical data on their NS5A candidates.
Of course as expected Vertex presented phase 2 data on
telaprevir and Schering presented phase 2 data on
boceprevir, and both of these proteases are now in phase
3 and expected to be ready for launch in mid 2011.
Pfixer presented at EASL with a poster on their new HCV
NNRTI filibuvir and it looks promising. HCV drug
resistance appears to be of concern. With monotherapy
drug resistance to the protease can emerge quickly, in 2
days.
Combining peg/RBV with the protease can prevent
resistance but if a patient develps viral failure, just
like in HIV, drug resistance can emerge. In naives the
results from phase 2 when using telaprevir+peg/RBV was
about 65% SVR rate with 24 weeks therapy, in
treatment-experienced prior nonresponders the SVR rate
was 39% and this included both null and nonresponders.
Also, 75% of prior relapsers and 57% of prior
breakthroughs achieved SVR in phase 2 study.
For boceprevir the data was 56% with 24 weeks with or
without 4 week peg/RBV lead-in, and with 48 weeks 75%
with 4 week lead-in and 67% without 4 week lead-in.
So drug resistance is an important point to bear in mind
as the proteases so far in development appear to be
cross-resistant.
So far there are no 2nd generation proteases that will
be active against resistance like in HIV with for
example darunavir. Researchers are looking for such
proteases but they have not yet emerged. So be careful
about acquiring drug resistance to a protease but it
does appear as though other drugs will at some point in
the future provide a regimen.
For example, combining an NS5A inhibitor with 2 NNRTIs
or an NNRTI+NRTI will be possibilities in the future.
All in all, future therapy for HCV is promising for
patients.
After the expected launch in 2011 of telaprevir+peg/RBV
and boceprevir+peg/RBV right behind that by perhaps 2
years will be Roche's 2 orals plus peg/RBV but the other
companies are also developing their own multiple drug
regimens and perhaps the companies will collaborate and
do cross-company studies with their drugs.
Vertex acquired ViroPharma's polymerase inhibitors and
presented interesting data at EASL on VCH-222 which in
early study showed a potent 3.7 log viral load
reduction.
So you can see we are headed towards regimens with 2, 3
and perhaps 4 oral HCV drugs in combination with peg/RBV
and perhaps later without peg/RBV.
With 2 orals plus peg/RBV I estimate 75-80% SVR rates
and close to that for African-Americans and with 3 orals
plus peg/RBV I estimate 85%-95% SVR rates for all
including African-Americans. But to get to this point it
will take some time.
Briefly, regarding hepatitis B BMS reported entecavir
resistance data out to 7 years and Gilead reported 2
years efficacy and resistance data on tenofovir and the
data for both drugs looks good.
The reports on all these presentations are linked to
below and on the NATAP website.
Jules Levin
Thursday April 23, 2009, Copenhagen Denmark
Reported by Jules Levin
So we see very potent protease inhibitors at various stages
of development, boceprevir & telaprevir in phase III and
others in earlier studies in patients. We are seeing nice
potency also in patients with polymerase inhibitors. Of note
some of these polymerase inhibitors will be able to be
combined, so we can foresee 2 and 3 drug oral regimens that
will be in studies soon. Roche is reporting at this meeting
the first results from a combination of 2 oral drugs, R7128
the polymerase inhibitor plus ITMN-191 their protease
inhibitor. So Roche is the furthest along in a study of 2
oral drugs. For the near future peg/RBV will be used in
combinaton therapy with oral drugs. A combination of 2 orals
plus peg/RBV will I expect provide SVR rates of 75-90%, and
rates in African-Americans may be a little lower but still
good. Vertex acquired 3 Virochem NNRTI polymerase inhibtors
2 months ago with one of them VCH-222 showing in early data
about I recall 3.50 viral load reductions. So they are
planning a study combining VCH-222 plus telaprevir and peg/RBV.
Taken together soon to be coming HCV therapy will provide
nice SVR or "cure" rates. Combining 2 orals plus peg/RBV
should be much more effective in preventing HCV drug
resistance from developing and this regimen should be very
effective for prior nonresponders, prior null responders,
more effective than 1 oral plus peg/RBV. Below is a brief
review of study data presented today and I will follow with
more detailed studies. At AASLD in Nov 2008 BMS reported
initial data in patients for their NS5A inhibitor and this
drug looks potent to. There are 2 HCV entry inhibitors being
presented here and several cyclophilin inhibitors and a
presentation on intravenous silymarin, and there are
presentations on nitazoxanide, and there are 2 phase III
presentations for albuferon the interferon taken every 2
weeks.
I am writing this report at the first morning of EASL. I am
reporting this to you by wireless sponsored by Gilead, the
first time EASL has had wireless at the poster session or
the conference I think I am in the Schering symposium after
sitting through the Roche symposium which was on HBV and
Pegasys and based on the effect of Pegasys on HBsAg decline
in predicting HBV DNA and HBsAg loss it looks like Pegasys
may have a more significant role in HBV therapy. The HCV
Late Breaker posters were put up this morning and some
interesting results on new HCV drugs were reported.
Boerhinger Ingelheim reported for the first time on their
new HCV polymerase inhibitor. They reported 5 days oral
treatment with BI 207127 800 mg every 8 hours and other
lower doses. The 800mg dose showed a 4 og viral load
reduction. Two patients developed a rash, they had the
highest pk exposures. The only serious adverse event related
to the intake of the drug was a moderate generalized
erythema with facial involvement. this patient was receiving
800mg every 8 hrs and the SAE resolved within 2 days after
discontinuation of the drug lab parameters did not show any
relevant changes from baseline. there were no signs of
liver, kidney or hematotoxicity. further clinical
development is planned. Boerhinger also has a protease
inhibitor currently in phase II in patients, they reported
initial potency in patients at AASLD in Nov and the drug
showed good potency.
Pfizer presented a poster for their NNRTI polymerase
inhibitor in combination with pegasys and ribaviin. In
previous monotherapy study for 8 days 2 log viral load
reduction was seen. Patients received 200, 300 or 500 mg bid
in combination with peg/RBV. The drug appeared safe and
tolerable. The mean viral load reduction was at day 4 was
-0.58 Placebo), and -2.29, -2.72, and -2.83 for the 3 doses
of drug. At day 28, the viral load reductions were -2.10
(placebo), and -4.46, -4.67, and -3.62 for the 3 drug doses.
The percent of patients achieving RVR (undetectable HCV RNA
by week 4) was 0% (placebo), and 60%, 75% and 63% for the 3
doses of drug.
Merck presented the first data on their protease inhibitor
in naives in combination with peg/RBV. Previously at AASLD
last year they reported -4.55 log reduction with monotherapy.
In this study the about 75% of patients had undetectable
viral load at I think it was 4 weeks, I don't have right in
front of me but will report it all later. There was GI upset
in some patients over the patients who took only peg/RBV.
Merck is planning a study in treatment-experienced patients.
Tibotec reported data for the first time on their protease
inhibitor TMC435 in combination with pegasys/RBV for 28
days, a total of 40 patients in study receiving placebo or 1
of 3 doses. Previously they reported -4.35 log reduction in
monotherapy. In this study mean decreases in viral load were
4.3, 5.5 and 5.3 for 75, 150, and 200 mg once daily. At day
28 4/9 (44%), 7/9 (78%), and 7/10 (70%) of patients achieved
<25 IU/Ml undetectable viral load. Of note in this study,
the OPERA Study, these patients were treatment-experienced,
patients were classified as prior nonresponders and prior
relapsers. For nonresponders (6 or 7 patients in each group)
receiving 150 mg once daily about 30% had <10 IU/ml and
about 65% had <25 IU/ml; for nonresponders receiving 200 mg
once daily about 30% achieved <10 IU/ml and about 50%
achieved <25 IU/ml; for nonresponders receiving 75 mg qd
about 25% achieved <25 with no one achieving <10 IU/ml. For
prior relapsers those receiving 150 mg qd 100% achieved. <10
IU/ml (n=3), for those receiving 75 mg qd (n=2) they all
achieved <10 IU/ml, for patients in the 200 mg group (n=4)
90% achieved <25 IU/ml and 20% < 10 IU/ml). For these
patients who I reported are <25 IU/ml they are between 10
and 25 IU/ml. There were no discontinuations due to
safety.Bilirubin elevations were observed in some patients
receiving TMC435 (total, direct & indirect), mostly with the
200 mg dose. These elevations were generally mild and
reversible in nature. Future studies are planned.
I am sitting in the Schering symposium where they are
previewing the results for boceprevir phase II results being
presented later today. Of note for patients with RVR 82%
receiving 28 weeks therapy in combination with peg/RBV
achieve undetectable, I think it is SVR I just saw slide but
not sure, and with 48 weeks it is 94%. This is with I recall
4 week peg/RBV lead-in. I will report exact data later today
to you.
Schering will be presenting at this meeting SCH90518, a new
protease inhibitor that will be boosted with ritonavir, and
it will be dosed twice daily, so Schering is saying blood
levels with this drug will be higher and their early
thinking is they hope it might suppress protease resistance
mutations. But this will of course have to be proven in
patients. I think they said in the abstract that this PI has
some similar mutations as other PIs but the high bood levels
may be good enough to suppress PI resistance.
A
Step Forward in Therapy for Hepatitis C EDITORIAL -
NEJM
April 30 2009
Jay H. Hoofnagle, M.D.
From the Division of Digestive Diseases and Nutrition, National
Institute of Diabetes and Digestive and Kidney Diseases, National
Institutes of Health, Bethesda, MD.
"An obvious question is why
telaprevir was given for only 12 weeks and not continued with the
peginterferon and ribavirin for a total of 24 or 48 weeks. The
reason was the side effects. In both studies, telaprevir was
associated with an increased rate of anemia, nausea, diarrhea,
pruritus, and rash. The rashes tended to be severe, to arise after 8
weeks of treatment, and to increase in frequency thereafter. The
nature and cause of the rashes were not elucidated....
...A second question is why the rate of
sustained virologic response to the combination of telaprevir,
peginterferon, and ribavirin was not higher. In preliminary studies,
this combination led to decreases of the HCV RNA to undetectable
levels within a few weeks in almost all patients.11,12,13
Nevertheless, at the end of the treatment period in these two
trials, only 57% and 70% of patients had undetectable HCV RNA
levels, end-of-treatment response rates that can be achieved with
the use of peginterferon and ribavirin alone.5,6,7 Because the
relapse rates were lower among patients receiving telaprevir than
among those receiving standard therapy, the sustained virologic
response rates were higher with telaprevir. Therefore, the enhanced
response rates with telaprevir may be due to the prevention of viral
breakthrough and relapse and may occur only in patients who have at
least a partial response to peginterferon....
....Telaprevir appears to be a material advance in the therapy of
hepatitis C, beginning a new era of treatment - an era of antiviral
agents developed specifically to target this virus. Other HCV-specific
agents, including other protease inhibitors,14 helicase and
polymerase inhibitors, and molecular
agents that interfere with viral replication,15 are likely to
follow. Combinations of these new agents with drugs currently in use
may ultimately provide effective therapy for all patients with
hepatitis C, the promised goal of decades of research."
The therapy of hepatitis C began almost 25 years ago with a small
trial of recombinant human interferon alfa.1 The rationale for using
interferon was its broad antiviral effects and the suspicion that it
might be active against the still-undiscovered agent of non-A, non-B
hepatitis. Indeed, interferon had striking effects, lowering serum
aminotransferase levels and, in a proportion of patients, inducing a
lasting improvement in serum enzyme levels. Not until the discovery
of the hepatitis C virus (HCV) were the effects of interferon
understood; treatment resulted in a decrease in HCV RNA levels,
which led to a sustained absence of virus in a proportion of
patients.2 The difficulty was that interferon required parenteral
injections, had multiple adverse effects, and resulted in a poor
overall response rate. Nevertheless, interferon was approved for use
for hepatitis C treatment in the United States in 1992.
The second important advance in hepatitis C therapy came with the
use of ribavirin. Ribavirin is a nucleoside analogue known to have
activity against several flaviviruses. When HCV was identified as a
flavivirus, ribavirin was an obvious treatment choice. Ribavirin had
little effect on serum HCV RNA levels but led to improvements in
aminotransferase levels and histologic characteristics of the
liver.3 More importantly, when combined with interferon, ribavirin
increased the rate of sustained virologic response.4 Interferon and
ribavirin given in combination for 48 weeks yielded rates of
sustained virologic response of 40 to 50%, two to three times those
obtained with interferon alone.3 Ribavirin was approved for use as
an adjunct to interferon therapy of hepatitis C in 1998.
A third advance in therapy of hepatitis C came soon thereafter, with
the introduction of pegylated forms of interferon that allowed for
once-weekly (rather than thrice-weekly) injections. Peginterferon
yielded higher rates of sustained virologic response than standard
interferon: 45 to 55% after a 48-week course of peginterferon and
ribavirin.5 The response rates varied according to HCV genotype.
Among patients infected with genotypes 2 and 3 (approximately 25% of
patients in the United States), rates of sustained virologic
response were 70 to 80% and were achieved with a 24-week course and
reduced doses of ribavirin.6 In contrast, rates of sustained
virologic response among patients infected with genotype 1
(approximately 70% of patients in the United States) were less
satisfactory, ranging from 40 to 50% and requiring 48 weeks of full
doses of ribavirin. In some populations, response rates were even
lower, with rates of approximately 25 to 30% among blacks.7 Higher
doses and longer courses of therapy increased rates of sustained
virologic response minimally and usually were associated with
increased side effects.3 Peginterferon was approved in the United
States in 2001.
Almost 10 years later, a fourth advance in hepatitis C therapy is
still awaited but now may be close at hand. Two articles in this
issue of the Journal describe results of phase 2 trials involving
telaprevir (formerly known as VX-950).8,9 Telaprevir is a specific
inhibitor of the HCV protease and is one of several molecules
developed according to a rational drug design based on the molecular
structure of HCV.10 Telaprevir is peptidomimetic, meaning that it
resembles the HCV polypeptide that is cleaved by the viral protease,
a necessary step in replication. However, telaprevir has an
electrophilic "serine-trap warhead" that forms a covalent bond with
the catalytic serine residue of the protease, blocking its activity.
Telaprevir, an agent developed specifically to target HCV,
represents a new era of therapy for hepatitis C.
Telaprevir has profound effects on HCV replication in cell culture
and in animal models.10 In phase 1 studies of chronic hepatitis C, a
1-to-2-week course of telaprevir lowered HCV RNA levels by 2 to 5
log10 IU per milliliter.11 As expected,
this short-term therapy was followed by a rebound in viral levels
after the drug was stopped. Furthermore, telaprevir resistance
appeared rapidly, and viral levels trended upward during the last
days of treatment. The combination of telaprevir and peginterferon
appeared to provide more profound viral suppression and less viral
resistance.12,13 Some patients treated with peginterferon and
ribavirin for a full 48 weeks after the short course of therapy with
telaprevir, peginterferon, and ribavirin had a sustained virologic
response.
These phase 1 studies led to the design of the two trials reported
here, by McHutchison et al. in the United States (ClinicalTrials.gov
number, NCT00336479 [ClinicalTrials.gov] )8 and HŽzode et al. in
Europe (NCT00372385 [ClinicalTrials.gov] ).9 The trial designs were
somewhat complex. Telaprevir was given for 12 weeks only, in
combination with peginterferon alfa-2a with or without ribavirin,
which were given for either for the same 12 weeks or for a total of
24 or 48 weeks. The control group received the standard therapy of
peginterferon and ribavirin for 48 weeks. Standard therapy yielded
rates of sustained virologic response of 41% and 46%, respectively.
In comparison, telaprevir given for 12 weeks combined with
peginterferon and ribavirin given for 24 weeks yielded response
rates of 61% and 69%, both significant increases over the responses
to standard therapy.
The other regimens tested had less satisfactory results. The
stopping of all therapy at 12 weeks yielded lower rates of sustained
virologic response than seen with continuation of therapy through 24
weeks, and the use of peginterferon and telaprevir without ribavirin
was associated with high rates of relapse. Finally, in the study by
McHutchison et al., the continuation of peginterferon and ribavirin
for a total of 48 weeks, including the initial 12-week course of all
three agents, was no more effective than the 24-week regimen (rate
of sustained virologic response, 67% and 61%, respectively). These
phase 2 trials suggest that the addition of telaprevir to the
combination of peginterferon and ribavirin will increase rates of
sustained virologic response in patients with chronic hepatitis C
due to infection with HCV genotype 1 from approximately 45% to as
high as 65% and will permit therapy to be limited to 24 weeks, thus
avoiding the expense and side effects of prolonged therapy.
An obvious question is why telaprevir
was given for only 12 weeks and not continued with the peginterferon
and ribavirin for a total of 24 or 48 weeks. The reason was the side
effects. In both studies, telaprevir was associated with an
increased rate of anemia, nausea, diarrhea, pruritus, and rash. The
rashes tended to be severe, to arise after 8 weeks of treatment, and
to increase in frequency thereafter. The nature and cause of the
rashes were not elucidated.
A second question is why the rate of sustained virologic response to
the combination of telaprevir, peginterferon, and ribavirin was not
higher. In preliminary studies, this combination led to decreases of
the HCV RNA to undetectable levels
within a few weeks in almost all patients.11,12,13 Nevertheless, at
the end of the treatment period in these two trials, only 57% and
70% of patients had undetectable HCV RNA levels, end-of-treatment
response rates that can be achieved with the use of peginterferon
and ribavirin alone.5,6,7 Because the relapse rates were lower among
patients receiving telaprevir than among those receiving standard
therapy, the sustained virologic response rates were higher with
telaprevir. Therefore, the enhanced response rates with telaprevir
may be due to the prevention of viral breakthrough and relapse and
may occur only in patients who have at least a partial response to
peginterferon.
Telaprevir appears to be a material advance in the therapy of
hepatitis C, beginning a new era of treatment - an era of antiviral
agents developed specifically to target this virus. Other HCV-specific
agents, including other protease inhibitors,14 helicase and
polymerase inhibitors, and molecular agents that interfere with
viral replication,15 are likely to follow. Combinations of these new
agents with drugs currently in use may ultimately provide effective
therapy for all patients with hepatitis C, the promised goal of
decades of research.
No potential conflict of interest relevant to this article was
reported.
HCV SnapShots/April Alan Franciscus, Editor-in-Chief
It’s all about the mega buy-outs &
buy-in of HCV drug manufacturers!
Vertex / ViroChem: In early March 2009, Vertex
announced that it will acquire Canadian
biotech ViroChem for $100 million in cash
and about 10.7 million shares of Vertex
common stock. ViroChem has two HCV
non-nucleoside polymerase inhibitors,
VCH-222 and VCH-759. ViroChem’s HCV
polymerase inhibitors are in early
development and will now be developed by
Vertex and combined with Vertex’s HCV
development pipeline. Vertex announced that
it expects to begin a combination study of
telaprevir with a ViroChem HCV polymerase
inhibitor in the second half of 2009. In
addition to the combination study with
telaprevir, Vertex announced that it is also
planning additional studies of ViroChem’s
HCV polymerase inhibitors in combination
with pegylated interferon plus ribavirin. Source: Company Press Release.
Merck / Schering-Plough:
On March 9, 2009 Merck announced that it had
offered to buy Schering-Plough for 41.1
billion dollars. The deal has been years in
the making and is seen as a cost-saving
purchase which will allow Merck to increase
the numbers of drugs already on the market
as well as acquire Schering’s extensive
pipeline, which includes boceprevir and
Schering’s approved HCV medications – Intron
A, PegIntron and Rebetol (brand name for
ribavirin). It is also a move by Merck to
diversify their product line with medicines
to treat other diseases such as hepatitis
C. The buy-out is contingent upon Merck and
Schering-Plough stockholder approval but is
expected to be completed by the end of
2009. Schering’s Board of Directors has
approved the buy-out. Source: Company Press Release.
Roche /
Genentech:
On March 13, 2009 a deal between Roche and
Genentech was finally approved by
Genentech’s Board of Directors. In the
$46.8 billion deal, Roche purchased the
remaining 44% of Genentech stock. The
take-over will mean that Roche will be the
7th largest U.S. pharmaceutical company in
terms of market share with an employee
payroll of 17,500 people. Interestingly
Roche (at least the United States portion of
Roche Holding AG), will move from Nutley,
N.J. to Genentech’s operating site in South
San Francisco. Roche will also assume
Genentech’s name. Source: Company Press Release.
This month’s SnapShots article will focus on
the recent news about drugs in development
to treat hepatitis C – including the start
of a new study of R7128, results from a
small phase I study of ITMN-191, a new HCV
polymerase inhibitor being developed by
Idenix (IDX184), Anadys’ impressive results
with ANA598, a new clinical study to
evaluate a once-a-month dose of albuferon,
and a few new developments on Bristol-Myers’
bold new entrance into the HCV drug
treatment arena.
R7129 Pharmasset and Roche announced on
January 12, 2009 that they will launch a
large phase 2b study of R7128, an HCV
nucleoside polymerase inhibitor, in
combination with Pegasys and ribavirin. The
new study will enroll about 400 HCV
genotypes 1 and 4 treatment-naïve patients
into five different treatment arms. The
trial will evaluate different doses of R7128
(500 mg to 1000 mg twice a day (bid)) in
combination with standard doses of Pegasys
plus ribavirin. Treatment durations will be
either 24 or 48 weeks based on a patient’s
rapid virological response.
In the previous Phase I study of R7128 in
combination with Pegasys plus ribavirin, 81
HCV treatment-naïve patients who were
treated for 4 weeks achieved viral load
reductions of 3.8 log10 IU/mL to 5.1 log10
IU/mL in the R7128 combination arms compared
to 2.9 log10 IU/mL in those who received
Pegasys plus ribavirin (without R7128).
Primary data from the new study is expected
to be released late in 2009.
INFORM-1 R7128 and ITMN-191 (listed above)
together with ribavirin (without interferon)
are being tested as the first
interferon-free combination therapy. The
results should give us a lot of information
about the effectiveness of these drugs and
also tell us if there are any synergistic
effects from combining these antiviral
compounds.
IDX184
Idenix Pharmaceuticals announced on January
12, 2009 that it was initiating a small
Phase I/II proof-of-concept study of IDX184,
an HCV nucleotide polymerase inhibitor.
This will be a double-blinded,
placebo-controlled, dose-escalation study to
evaluate the safety, tolerability and
antiviral activity of IDX184 in HCV genotype
1 treatment-naïve patients. The doses will
range from 25 to 100 mcg once-a-day dosing
(SID). Eight patients will receive IDX184
and 2 will receive placebo.
ANA598 In a small phase I study of Anadys’
ANA598, an HCV polymerase inhibitor, it was
found that in the 8 patients who received
200 mg of ANA598 for 3 days there was a
range of viral load reductions from 1.4 to
3.4 log10. The 8 patients were either HCV
genotype 1a or 1b. The drug was generally
well-tolerated. The decline in HCV viral
load is impressive, but more studies with
more patients and a longer duration of
treatment are needed to determine if the
viral load reductions can be sustainable and
more importantly if there are any drug
toxicities.
ITMN-191
On January 12, 2009 InterMune reported on
the results from a small phase I study of
ITMN-191 in combination with Pegasys and
ribavirin. In this study, there were six
arms of ITMN-191 (either 100, 200, 300 mg
every 8 hours or 400, 600, 900 mg every 12
hours) combined with Pegasys plus ribavirin.
There was also one placebo arm. A total of
57 HCV genotype 1 treatment-naïve patients
were treated for 14 days. After 14 days of
treatment, the log drop in HCV RNA (viral
load) was from 5.5 to 5.7 log10.
There were two levels of detection limits: <
25 IU/mL and < 9.3 IU/mL. The group that
received 200-300 mg every 8 hours (50 and
57% respectively) achieved the best
results.
The medications were generally
well-tolerated. There were 4 serious
adverse events (AEs) reported: two were
sciatica (nerve pain from a compressed back
disc) which the researchers believed were
unrelated to the study drug; the other two
AEs were neutropenia and indirect bilirubin
elevation, but it was noted that the
frequency and severity was similar to that
seen in the placebo arm.
A phase 2b study is expected to begin in the
second quarter of 2009 using various doses
of ITMN-191, dosed every 8 or every 12 hours
with treatment durations of 12 or 24-weeks.
Albuferon – New Study
Human Genome Sciences announced that
Novartis has initiated a new study of
albuferon to treat 375 HCV genotype 2 and 3
patients with a once-a-month injection of
albuferon (900, 1200, or 1500 mcg) in
combination with ribavirin for a 24 week
duration. The trial will also include a
control arm using Pegasys plus ribavirin.
The study will assess the safety,
tolerability and effectiveness of albuferon
compared to Pegasys – both interferons in
combination with ribavirin.
BMS Bristol-Myers Squibb (BMS) is
jumping into the HCV drug research arena big
time with various announcements over the
last couple of months. In January BMS
announced that it has struck a 1.2 billion
dollar deal with ZymoGenetics to codevelop
ZymoGenetics’ long-acting type III
interferon, PEG-interferon lambda. Under
the agreement, BMS will help to codevelop
the longer acting form of interferon and
will jointly sell and share in the profits
in the United States and Europe. BMS
announced in December that it has signed an
agreement with Arris Pharmaceutical
Corporation to develop HCV protease
inhibitors. Under the agreement, BMS will
have exclusive rights to the development and
marketing of any protease inhibitors that
are discovered during the terms of this
agreement.
In addition to these stories, BMS also has
three HCV drugs currently in phase I/II
studies.
This year’s American Association
for the Study of Liver Disease (AASLD) conference included information on many
new drugs under development to treat hepatitis C, so much in fact that it is
difficult to include all the new drugs that were presented at AASLD – the result
being that I will not report on the pre-clinical data presented at AASLD. Even
excluding the pre-clinical trials, there is so much information to include that
the report will be divided into two parts that will appear in the December 2008
and the January 2009 HCV Advocate newsletter.
It’s amazing how far HCV drug
development for treating hepatitis C has advanced over the years. Just 5 years
ago at the November 2003 AASLD conference I reported on the first HCV protease
inhibitor that entered into human trials – BILN 2061. I also reported on the
pre-clinical data on VX-950 (telaprevir), early data on a long acting type of
interferon (Albuferon) and a prodrug of ribavirin called viramidine.
Since 2003, the clinical
development of BILN 2061 has been halted due to safety concerns, and so far
viramidine has not been shown to be as effective as ribavirin. However, the
good news is that telaprevir is still going strong, is now in Phase III clinical
trials and has been shown to be safe, well-tolerated, and more effective than
current treatments. Albuferon is also in Phase III studies, but, unfortunately,
the once a month dosing arms of the clinical trials had to be discontinued due
to pulmonary (lung) problems. It looks like the once every 2 weeks dosing is
still a viable option although the effectiveness of albuferon does not seem to
be any better than pegylated interferon. But all in all the data presented at
this year’s conference on HCV drugs in development are very encouraging.
Telaprevir
The final and interim results from various studies of Vertex’s telaprevir, an
HCV protease inhibitor, were released at this year’s conference.
PROVE 3:
interim data on 453 patients who did not achieve a sustained virological
response (SVR) with a previous course of pegylated interferon plus ribavirin –
non-responders, relapsers and viral breakthroughs – was presented. This
included the interim results from the arms that received 12 weeks of telaprevir
in combination with pegylated interferon plus ribavirin followed by 12 weeks of
pegylated interferon plus ribavirin (without telaprevir). HCV RNA negative was
defined as less than 10 IU/mL).
Note:
the results given are SVR12 (12 weeks after treatment ends) and SVR24 (24 weeks
after treatment ends) and the totals are combined:
Overall SVR results
52% (60 out of 115 patients-total)
Non-responders
41% (27 out of 66 patients)
Relapsers
73% (29 of 40 patients)
Breakthroughs
44% (4 of 9 patients)
Results for the control arm group
(48 weeks of pegylated interferon plus ribavirin) are still pending.
The side effect profile is
consistent with pegylated interferon except there were higher incidences of
pruritus (itching) and rashes, including severe rashes. Sixteen percent of
patients in the telaprevir-based arms discontinued treatment due to adverse
events (side effects) compared to 4% in the group that received pegylated
interferon plus ribavirin (without telaprevir).
Study 107 Study 107 is another clinical trial that is
evaluating the use of telaprevir in HCV prior non-responders, partial
responders, relapsers and viral breakthroughs. The patients in this study were
people who were enrolled in the control arm (pegylated interferon/ribavirin
without telaprevir) of a previous telaprevir study.
The interim results at week 24 are
listed below by type of prior response. HCV RNA negative is defined as <10
IU/mL:
Null-reponders
43% (18 of 42 pts)
Partial responders
82% (18 of 22 pts)
Relapsers
83% (5 of 6 pts)
Breakthroughs
0% (0 of 1 pt)
The safety profile is consistent
with other studies of telaprevir, pegylated interferon and ribavirin.
Prove 2
The final PROVE 2study results of 323 HCV genotype 1
treatment-naïve patients (never been treated) were also released at this year’s
AASLD conference. HCV RNA negative was defined as < 10 IU/mL. The results
showed that the 24-week arm (12 weeks of telaprevir plus pegylated interferon
plus ribavirin followed by 12 weeks of pegylated interferon plus ribavirin
without telaprevir) had the highest SVR rate, 69%, (56 out of 81 patients)
compared to 46% (38 out of 82 patients) in the arm that received 48 weeks of
pegylated interferon plus ribavirin (control arm). The side effect profile was
consistent with the side effects reported above. Fourteen percent of patients
discontinued treatment due to adverse events compared to 7% in the control group
who received pegylated interferon plus ribavirin (without telaprevir).
Study C208
Study C208 is a newer study that is evaluating different doses of telaprevir –
750 mg every 8 hours (q8h or three times a day) compared to a 1125 mg dose every
12 hours (q12h or twice a day) in HCV genotype 1 treatment-naïve patients. In
addition, the two different brands of pegylated interferon – alfa-2a (Pegasys)
and alfa-2b (PegIntron) – were used. The previous studies of telaprevir only
included Pegasys.
The very preliminary results of
patients who were undetectable (less than 10 IU/mL) at week 12 are listed below
by dose and pegylated product:
q8h alfa-2a
93% (37 out of 40 pts)
q8h alfa-2b
93% (39 out of 42 pts)
q12h alfa-2a
83% (33 out of 40 pts)
q12h alfa-2b
85% (33 out of 39 pts
To date 13 patients have
discontinued therapy due to adverse events – 6 patients in the q8h and 7
patients in the q12h arms. A total of 9 patients had viral breakthrough – 4
patients in the q8h and 5 patients in the q12h.
If the results between the
different dosing schedules can be carried through to the end of the trial and
the results of this trial can be replicated in a larger study, a twice-a-day
dose of telaprevir may be a future option.
The results from these studies are
very encouraging, showing higher treatment response rates in a variety of
populations with HCV genotype 1 including treatment-naïve patients and patients
who have not achieved an SVR with a prior course of pegylated interferon and
ribavirin therapy. Telaprevir began Phase III studies in March 2008 and it is
believed that Vertex will apply to the Food and Drug Administration for approval
to market telaprevir for the treatment of chronic hepatitis C in 2010-2011.
New
Study – 3 Antivirals, No
Interferon: Roche, InterMune, Inc, and Pharmasset jointly
announced on November 10 a new study called INFORM-1 to evaluate the safety and
antiviral activity of three antivirals – R7227 (ITMN-191) an HCV protease
inhibitor, R7128 an HCV polymerase inhibitor and ribavirin.
This will be the first clinical
trial combining three antiviral medications without the use of interferon
as a possible treatment of hepatitis C.
The study will evaluate the three
antiviral medications in HCV genotype 1 treatment-naïve patients. The clinical
study will be conducted in Australia and New Zealand. Hopefully, this first of
its kind study for treating hepatitis C will usher in a new era that will
include many combinations of antivirals to treat hepatitis C, and which may
ultimately lead to therapies that do not contain interferon or ribavirin.
Boceprevir Interim results from Schering’s HCV protease
inhibitor, boceprevir, were also presented at AASLD. The SPRINT-1
study was a very complex study that included 5 treatment arms. The
study population consisted of HCV genotype 1 treatment-naïve patients. The
results below are listed by treatment arm.
Sustained Virological Response
(SVR12 & SVR24)
Treatment Arm
All patients
a) No lead-in, 28 weeks
55% SVR 24 (59 out of 107 pts)
b) Lead-in, 28 weeks
56% SVR 24 (58 out of 103 pts)
c) No lead-in, 48 weeks
66% SVR 12 (68 out of 103 pts)
d) Lead-in, 48 weeks
74% SVR 12 (76 out of 103 pts)
e) P/R control, 48 weeks
38% SVR 12 (39 out of 104 pts)
a) Boceprevir, PegIntron, ribavirin
(no lead-in phase) – total treatment duration = 28 weeks.
b) PegIntron, ribavirin for 4 week
lead-in followed by boceprevir, PegIntron, ribavirin for 24 weeks – total
treatment duration = 28 weeks
c) Boceprevir, Pegintron, ribavirin
(no lead-in phase) – total treatment duration = 48 weeks.
d) PegIntron, ribavirin for 4 weeks
followed by boceprevir, PegIntron, ribavirin for 44 weeks – total treatment
duration = 48 weeks.
e) Control group that received only
PegIntron, ribavirin – total treatment duration = 48 weeks.
*Dosing: PegIntron 1.5 ug/kg
once a week, ribavirin 800-1400 mg/day & boceprevir 800 mg/3 times a day.
Results for the boceprevir arm and
control arm that included low-dose ribavirin are still pending.
The side effects reported were
similar in the d) group (lead-in, 48 weeks) compared to the
e) control group except for higher prevalences of fatigue (71%
vs. 55%), Anemia (56% vs. 34%), neutropenia (low white blood cells, 30% vs.
12%), taste changes (27% vs. 9%) and muscle pain (26% vs. 16%).
The increase in the SVR rates in
group d (boceprevir lead-in phase,48 weeks treatment duration)
is very impressive. Schering began their Phase III studies in May 2008 and they
are expected to apply to the FDA for marketing approval sometime in 2010 or
2011.
Nitazoxanide
At last year’s AASLD nitazoxanide (brand name Alinia) burst upon the HCV
treatment scene with impressive results as an add-on to Pegasys and ribavirin
therapy. Nitazoxanide is approved to treat diarrhea that is caused by
Cryptosporidium parvum and Giardia lamblia, and has been found to
have only mild side effects. A last year’s conference, a 12 week lead-in phase
of nitazoxanide followed by 36 weeks of nitazoxanide, Pegasys and ribavirin in
genotype 4 treatment-naïve patients produced a 79% SVR (in the triple combo
arm) for treatment-naïve patients and 25% SVR in the treatment-experienced
patients. Since this time, Romark has launched a study on HCV genotype 1
patients.
At this year’s conference,
information about a small study of 44 patients to evaluate effectiveness of a 4
week lead-in phase of nitazoxanide dosed at 500 mg twice a day (taken with food)
followed by the combination of nitazoxanide and pegylated interferon (no
ribavirin used) for 36 weeks was released. The SVR results are listed below:
100% SVR
3 of 3 HCV genotype 1 patients
100% SVR
1 of 1 HCV genotype 2 patient
78% SVR
31 of 40 HCV genotype 4 patients
The authors commented that a
12-week nitazoxanide lead-in phase can be reduced to 4 weeks without
compromising SVR rates. It was also concluded that more studies are needed to
compare the effectiveness of nitazoxanide in combination with pegylated
interferon with and without ribavirin in treatment-naïve and
treatment-experienced patients. Imagine that – a possibility of eliminating
ribavirin from combination treatment. Of course, much larger studies are needed
to confirm these findings.
Drugs in
Early Clinical Development
R7128
is an HCV polymerase inhibitor that is being developed by
Pharmasset and Roche. Preliminary results from studies on HCV genotype 1
treatment-naïve and treatment-experienced patients have resulted in impressive
HCV RNA (viral load) reductions. Based on various studies, Pharmasset will
further develop the 1000 mg dose BID (twice a day) in HCV genotype 1
treatment-naïve patients and the 1500 mg dose TID in HCV genotype 1
treatment-experienced patients – both doses in combination with Pegasys plus
ribavirin.
What about HCV genotypes 2 or 3?
At this year’s conference a study of R7128 in people with HCV genotype 2 or 3
who either were prior treatment non-responders or relapsers was released at
AASLD. Patients were given R7128 (1500 mg twice a day) in combination with
Pegasys plus ribavirin for 28 days or placebo/Pegasys/ribavirin. At the end of
the treatment period there was a mean decrease in HCV RNA of 5.0 log10 in the
R7128 arm compared to a 3.7 log10 in the placebo arm. No serious adverse events
were reported and the side effects reported in the R7128 group were similar to
the group that did not receive R7128. More studies are being planned.
ITMN-191
is an HCV protease inhibitor being developed by InterMune and
Roche. The results from a monotherapy study of HCV genotype 1 treatment-naïve
and treatment-experienced patients were released. In the study there were 50
patients who received doses up to 600mg (every 12 hours or every 8 hours) or
placebo for 14 days. The mean reduction in the 200 mg every 8 hours group by
day 14 was 3.8 log10 in treatment-naïve. In the treatment-experienced patients
the median viral load reduction was 2.5 log10. The reduction in HCV RNA was dose
dependent. The doses were considered safe and were well-tolerated with only one
serious adverse event reported – vertigo – that was not considered related to
the study drug.
AASLD
2008—Drugs in Development: Part 2 Alan Franciscus,
Editor-in-Chief
In
last
month’s HCV Advocate newsletter I wrote about many new drugs in
development to treat hepatitis C that were presented at the American Association
for the Study of Liver Diseases (AASLD) conference. The report included four
studies on telaprevir as well as the results on boceprevir, nitazoxanide, R7128,
and ITMN-191. This month I will report on studies of drugs that are in an
earlier phase of clinical development: TMC435, BI 201335, PF-00868554, GI-5005
(a DNA based HCV vaccine) and farglitazar (anti-fibrotic).
TMC435
TMC435
(formerly TMC435350) is a new HCV protease inhibitor that is
being developed by Tibotec Pharmaceuticals Ltd. One poster presented data on
cloned HCV genotype 1 through 6 proteases that found TMC435 was a potent
inhibitor of the serine protease in all genotypes tested.
In another poster two groups of
patients were studied – healthy patients and patients infected with hepatitis
C.
In the group of healthy volunteers
the once-a-day 200 mg dose was to evaluate the safety, antiviral activity and
pharmacokinetics (absorption, distribution, metabolism and excretion) of
TMC435. The 200 mg capsule formulation reached a steady state in 7 days.
In yet another study, 48
HCV-infected patients received either the 25 mg or 75 mg dose (once a day) given
as a monotherapy or in combination with pegylated interferon plus ribavirin.
After 7 days of treatment there was a mean viral load reduction of 2.63 log10
IU/mL in the 25 mg arm and 3.43 log10 IU/mL in the 75 mg/day arm both given as
monotherapy. The triple combination arm (TMC435, pegylated interferon,
ribavirin) given for 28 days produced a mean viral load reduction of 3.47 log10
IU/mL in the 25 mg arm and 4.55 log10 IU/ml in the 75 mg/day arm.
The most common adverse events
reported were nausea, diarrhea, and headache – no serious adverse events were
reported.
BI 201335
Boehringer Ingelheim’s BI
201335 is an HCV protease inhibitor that is in early clinical
development. Information about the safety, antiviral activity and
pharmacokinetics of BI 210335 in HCV genotype 1 treatment-naïve patients and
treatment-experienced patients were presented.
The treatment-naïve study was
divided into two parts, the first part of which was a monotherapy study
evaluating 4 doses of BI 201335 (20, 48, 120, 240 mg or placebo) for 14 days.
If a patient had ≥ 1 log10 decrease in HCV RNA they were rolled over to the
second part of the study that included BI 201335 plus Pegasys and ribavirin from
day 15 through day 28. All of the patients in the study (except one patient in
the 20 mg arm) achieved greater than 2.8 log10 drop in HCV RNA. The maximal HCV
RNA reduction was 2.9 log10 (20 mg) to 4.0 log10 (240 mg) which was achieved
within 2-4 days. The drug was generally safe and well-tolerated with no dose
dependent increase in adverse events. The only case for concern was a dose
dependent change in bilirubin.
The second study included 19
treatment experienced patients who did not achieve more than a 2 log10 reduction
in HCV RNA with a previous course of pegylated interferon plus ribavirin. The
patients were given doses of 48, 120, or 240 mg (once daily) in combination with
Pegasys plus ribavirin for 28 days. The maximal HCV RNA reduction was 5.0 log10
(48 mg) to 5.3 log10 (240 mg) during the 28 days of treatment. BI 201335 was
found to be safe and well-tolerated with no severe adverse events except the
usual side effects seen in people who receive pegylated interferon plus
ribavirin.
The antiviral activity of the once
a day dose of BI 201335 was remarkable and further clinical trial development is
expected.
PF-00868554
Pfizer’s entry into HCV drug
development is an HCV polymerase inhibitor PF-00868554. Two
studies were released at AASLD – one was on the safety, tolerability and
pharmacokinetics of PF-00868554 dosed in healthy volunteers, and the other
poster measured the antiviral activity in HCV genotype 1 infected patients.
In the first study of healthy
volunteers, 33 male patients were randomized to receive 50,100, and 300 mg BID
(twice a day), and one group received 300 mg TID (three times a day) for 14
days. The researchers found that the drug was safe and well-tolerated at all
doses and drug plasma concentrations were achieved that would be expected to
inhibit HCV RNA replication.
The second study included 32 HCV
treatment-naïve genotype 1 male patients who received the same doses listed
above for 7 days. The drugs were found to be safe and well-tolerated and the
HCV antiviral activity was dose dependent with mean reductions in HCV RNA from
-0.97 to -2.13 log10. Based on these results Pfizer has initiated a study of
PF-0086854 in combination with pegylated interferon alpha-2a and ribavirin.
GI-5005
GlobeImmune’s therapeutic vaccine
study of GI-5005, used with and without pegylated interferon
plus ribavirin in 140 HCV genotype 1 treatment-naïve and non-responders was
presented in a poster. In the monotherapy phase of the study no patients
discontinued therapy due to adverse events. In the pegylated interferon/ribavirin
therapy (without GI-5005), 5 patients discontinued therapy due to side effects.
In the triple therapy arm 3 patients discontinued therapy due to side effects,
but the investigators did not attribute the side effects to GI-5005.
The authors reported that in the
triple therapy arm that was given to HCV patients with a high viral load
(>600,000 IU/mL) the patients showed a 2.6-fold improvement in RVR rates
compared to those who received just pegylated interferon/ribavirin. Based on
these results the authors suggested that GI-5005 may increase the rate of HCV
clearance.
Farglitazar
Given the amount of people who do
not respond to current HCV therapies it is of the utmost importance that other
options to help with HCV disease progression are developed. An area that is
vitally important is the development of anti-fibrotic medications to treat
moderate to severe HCV disease progression. There are currently clinical trials
underway on a variety of anti-inflammatory and anti-fibrotic drugs such as
PF-03491390, MitoQ, CTS-1027, and farglitazar. Unfortunately, the results from
a trial of farglitazar (G1262570) in 177 people with chronic
hepatitis C who had moderate fibrosis did not show any benefit when given
various doses of Farglitazar. Hopefully, the other drugs in current clinical
development and new anti-fibrotic drugs will be developed to help stop or
reverse disease progression.
There are
currently clinical trials underway on a variety of anti-inflammatory and
antifibrotic drugs such as PF-03491390, MitoQ, CTS-1027, and farglitazar.
2009 Annual
Meeting of the
European
Association for
the Study of the
Liver*
April 22-26,
2009 |
Copenhagen,
Denmark
*CCO is an
independent
medical
education
company that
provides
state-of-the-art
medical
information to
healthcare
professionals
through
conference
coverage and
other
educational
programs.
