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Infergen
INFERGEN® (interferon alfacon-1), also known as consensus
interferon, is marketed for the treatment of adults with chronic hepatitis C
virus (HCV) infections. It is currently the only FDA approved, bio-optimized
interferon developed through rational drug design and the only interferon
with data in the label specifically for non-responding or refractory
patients. InterMune's sales force re-launched Infergen in January 2002 with
an active campaign to educate U.S. hepatologists about the safe and
appropriate use of Infergen, which represents new hope for the more than 50
percent of HCV patients who fail other currently available therapies.
All alpha interferons, including interferon alfacon-1,
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 symptoms of these conditions should be
withdrawn from therapy. In many but not all cases, these disorders resolve
after stopping interferon alfacon-1 therapy. See WARNINGS, and ADVERSE
REACTIONS in
full
prescribing information
ISLAMABAD, Health experts have conducted a new research which claims
possibility of maximum recovery from chronic hepatitis C through
medication.
The study will be presented in annual conference of Asia Pacific
Association for Study of Liver Diseases (APASL),
being held in Beijing, China in March this year.
According to medical experts this is a very encouraging news for the
patients who are dealing with chronic hepatitis C even after treatment
with Pegylated
Interferon.
This study was conducted at
Maroof
International Hospital and Islamabad Specialists Clinic Islamabad. Prof.
Muzaffar
Gill who supervised the research while talking to APP acknowledged the
work of Dr. UzmaAdeeb and
Dr. Fatima
Khattak, the research fellows who were actively involved in this
research project.
He said hepatitis C is a growing menace in the country and early
detection of the disease and timely intervention in terms of treatment
is still the burning issue.
He said standard care for treatment of chronic hepatitis C is weekly
injection of Peg-interferon and
Ribavirin
and its efficacy is 80% in population.
"Unfortunately we are facing new challenges as a result of this
treatment as there is 15-20% relapse rate (recurrence of diseases) even
after six months of treatment with
Pegylated
Interferon."
He said after new research findings there is a new ray of hope with
newly launched Consensus Interferon (Infergen).
This interferon is used in Europe and United States for the last 2-3
years for chronic Hepatitis C patients who relapse or do not respond
with Peg-Interferon.
Dr. Gill said "We did conduct the first ever clinical study in Pakistan
to evaluate the efficacy of Consensus Interferon (Infergen)
in 40 patients. These patients were treated with Peg interferon before
for six months."
He added after one year of the treatment, the
HCVPCR,
a test to detect live virus was positive in 15% of these patients.
These patients were given 15
ucg of
injection
Infergen thrice weekly for six months and 80% of patients were
HCVPCR
negative which means they were free from disease, he added.
Consensus Interfon plus Ribavirin Produces Sustained Response in Some Prior
Non-responders to Pegylated Interferon
Consensus
interferon plus ribavirin can produce a sustained virological
response (SVR) in a minority of chronic hepatitis C patients who did
not achieve SVR with a prior course of interferon-based therapy,
especially among patients those who initially responded but then
relapsed, according to a study in the
June 2009 issue of Hepatology.
Investigators with the DIRECT study looked at 487
participant who did not achieve
SVR with previous
treatment using
pegylated interferon plus ribavirin,
some who initially responded but then relapsed during or after completion of
therapy and other who never experienced a substantial decrease in HCV viral
load during treatment.
Overall, the study group consisted largely of
"hard-to-treat" patients. Almost all had
HCV genotype 1, 80%
experienced no strong response to earlier treatment, about 70% had high
baseline HCV RNA, about 60% had advanced liver disease, and about 20% were
African-American.
Participants were assigned to receive consensus interferon (245 patients at
9 mcg/daily and 242 at 15 mcg/daily) or else no further treatment. Consensus
interferon is a manufactured product that contains common sequences from
multiple other types of interferon.
At 24 weeks, patients who still had detectable HCV RNA were considered
non-responders and stopped treatment, while responders continued for 24 more
weeks; at the same time, the initial untreated control group was integrated
into the treatment arms. Follow-up continued for 24 weeks after the end of
treatment, and patients who experienced HCV rebound during this period were
considered relapsers.
Results
Overall, about 7% of
patients in the 9 mcg consensus interferon group and 11% in the 15 mcg
group achieved SVR.
Sustained response rates
were higher among participants who were prior relapsers rather than
never-responders.
Response was also more
likely among participants with lower baseline fibrosis scores.
Previous relapsers who
experienced at least a 2 log drop in HCV RNA during their prior course
of treatment and who did not have cirrhosis had the highest SVR rate, at
32%.
Adverse events were
common, with fatigue, depression, nausea, muscle pain, anemia, and white
blood cell deficiencies being reported most often.
Few participants,
however, discontinued treatment for this reason.
"The present study demonstrated that some patients with chronic hepatitis C
who have failed to respond to treatment with [pegylated interferon] and
ribavirin can be successfully retreated with daily [consensus interferon]
and ribavirin," the study authors concluded. "The greatest SVR rate during
retreatment in the present study was observed in [cirrhosis stage] F0-F3
patients who had a partial virologic response during their prior course of
treatment."
7/17/09
Reference B Bacon, M Shiffman, F Mendes, and others. Retreating Chronic Hepatitis
C with Daily Interferon Alfacon-1/Ribavirin after Nonresponse to Pegylated
Interferon/Ribavirin: DIRECT Results. Hepatology 49(6): 1836-1846.
June 2009.
Three Rivers Announces Positive Results
From Phase 3 DIRECT Trial Of Once-Daily INFERGEN(R) With Ribavirin In
Hepatitis C Virus Treatment Failures
June 09
Three Rivers Pharmaceuticals announced positive results of the
U.S.-based, randomized Daily-Dose Consensus Interferon and Ribavirin:
Efficacy of Combined Therapy (DIRECT) clinical trial authored by
Bruce R. Bacon, M.D., of Saint Louis University, and colleagues at
44 centers in the United States. The primary endpoint of increased
sustained virological response (SVR), was achieved demonstrating
that
INFERGEN provides a second chance to those HCV patients failing
to respond to standard, first-line therapy of pegylated interferon
(PEG-IFN) plus ribavirin (RBV). "The retreatment of PEG-IFN/RBV
nonresponders with INFERGEN and RBV is safe and efficacious and can
be considered a retreatment strategy for patients failing previous
therapy with PEG-IFN/RBV, especially in interferon-sensitive
patients with lower baseline fibrosis scores," stated Dr. Bruce
Bacon the lead Investigator for the study.
Among participants who failed initial treatment with PEG-IFN/RBV,
retreatment with INFERGEN in combination with RBV yielded SVR rates
as high as 31.6 % in interferon-sensitive patients with low baseline
liver fibrosis scores, the researchers reported in the June 2009
issue of Hepatology. Overall intent to treat analysis was
6.9% among the 9 mcg/day group and 10.7% in the 15 mcg/day group.
Defining viral response at Weeks 12 and 24 with INFERGEN and RBV in
patients who were prior non-responders to PEG-IFN/RBV therapy can
help predict SVR rates in this difficult-to-treat group of patients.
All patients attaining SVR demonstrated > 2-log drop at Week 12 of
INFERGEN/RBV therapy. Of significant note for these patients was the
analysis regarding viral response at 12 weeks. In the DIRECT trial,
81.3% and 63.6% of patients achieving viral negativity at Week 12
went on to have an SVR in the 9 mcg and 15 mcg arms, respectively.
In addition, slow responders achieved SVR rates of 11.7% and 35.4%
in the 9 mcg and 15 mcg arms. Regardless of treatment dose used,
attaining viral negativity at Week 12 or at Week 24 while on therapy
with INFERGEN and RBV leads to a high sustained virological response
rate.
"These results represent a significant step forward for HCV patients
who deserve a second chance at a potential cure for this chronic
viral infection" stated Donald Kerrish, President and CEO of Three
Rivers Pharmaceuticals.
Approximately 50% of patients with chronic hepatitis C fail to
respond to their initial course of PEG-IFN/RBV therapy. No standard
has yet emerged for second-line therapy, since simply repeating the
same treatment, in well controlled trials, has yielded low response
rates around 2-6%.
The DIRECT trial was a phase 3, randomized, open-label, multicenter,
U.S.-based trial conducted to investigate the efficacy,
tolerability, and safety of daily INFERGEN at dosages of 9 and 15
mcg/day administered with daily weight-based RBV. The study tested 2
dosages of INFERGEN in 487 documented non-responders, of which 80%
did not achieve a 2-log drop on prior pegylated-interferon plus
ribavirin therapy. The best SVR rates were seen in:
-- Patients achieving the greatest reduction in baseline viral load
with peg-IFN/RBV therapy, especially in patients demonstrating >
1-log drop with initial therapy
-- Patients with fibrosis scores of F0 to F3 at baseline
demonstrated SVRs of 7.8% in the 9 mcg arm and 13.1% in the 15 mcg
arm
-- Patients maintaining full dose of INFERGEN/RBV therapy had SVRs
of 7% and 17% for the 9 mcg and 15 mcg arms respectively
-- Patients demonstrating partial response (>2-log drop) with
previous treatment and low fibrosis scores F0-F3 had SVRs of 10.7%
and 31.6% for the 9 mcg and 15 mcg arms
Patients with cirrhosis were less likely to benefit from retreatment
with INFERGEN and RBV unless they displayed previous interferon
sensitivity of at least 1-log drop in viral levels on prior therapy.
About Consensus Interferon (INFERGEN(R))
Consensus Interferon or INFERGEN(R) is a unique, bio-optimized,
selective and highly potent type 1 interferon alpha. INFERGEN is
indicated for the treatment of chronic HCV infection in patients 18
years of age or older with compensated liver disease who have anti-HCV
serum antibodies and /or the presence of HCV RNA. INFERGEN is
currently FDA approved for TIW monotherapy dosing in naive and
previous treatment failure patients.
Important Safety Information
Physicians and patients can obtain additional prescribing
information regarding INFERGEN, including the product's safety
profile and the box warning for all interferon alphas regarding
neuropsychiatric, autoimmune, ischemic and infectious disorders, by
visiting www.infergen.com.
About Hepatitis C
Hepatitis means inflammation of the liver. Hepatitis C is a liver
disease that results from infection with the hepatitis C virus. It
can range in severity from a mild illness lasting a few weeks to a
serious, lifelong illness. Hepatitis C can be either "acute" or
"chronic." Acute hepatitis C virus infection is a short-term illness
that occurs within the first 6 months after someone is exposed to
the hepatitis C virus. For most people, acute infection leads to
chronic infection. Chronic hepatitis C is a serious disease than can
result in long-term health problems, or even death. There is no
vaccine for hepatitis C.
About Three Rivers Pharmaceuticals
Three Rivers Pharmaceuticals is a privately held company
headquartered in Warrendale, Pennsylvania that focuses on
specialized therapies including hepatitis C therapies.
Bruce R. Bacon 1 *, Mitchell L. Shiffman 2, Flavia Mendes 3, Reem
Ghalib 4, Tarek Hassanein 5, Giuseppe Morelli 6, Shobha Joshi 7,
Kenneth Rothstein 8, Paul Kwo 9, Norman Gitlin 10
1Saint Louis University Liver Center, Saint Louis University School
of Medicine, St. Louis, MO
2Hepatology Section, Virginia Commonwealth University Medical
Center, Richmond, VA
3Division of Hepatology, University of Miami Miller School of
Medicine, Miami, FL
4Liver Institute at Methodist Hospital, Dallas, TX
5Division of Gastroenterology and Hepatology, University of
California San Diego, San Diego, CA
6Division of Gastroenterology and Hepatology, University of Florida,
Gainesville, FL
7Division of Gastroenterology and Hepatology, Tulane University
Hospital and Clinic, New Orleans, LA
8Albert Einstein Center for Liver Disease, Philadelphia, PA
9Division of Gastroenterology and Hepatology, Indiana University
School of Medicine, Indianapolis IN
10Division of Gastroenterology and Hepatology, Emory Crawford Long
Hospital, Atlanta, GA
Up to 50% of patients with chronic hepatitis C fail to respond to
initial therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV).
With unsuccessful viral eradication, these patients remain at risk
for developing progression of their liver disease. Retreatment with
PEG-IFN/RBV yields sustained virologic response (SVR) rates that are
under 10%. A wholly synthetic interferon, interferon alfacon-1 or
consensus interferon (CIFN) given with RBV, was evaluated in
patients who failed initial PEG-IFN/RBV therapy. The intent-to-treat
analysis included 487 patients; 245 received CIFN 9 ug/day and RBV,
and 242 received CIFN 15 ug/day and RBV. Within this group of
patients, 59.3% had documented advanced fibrosis at baseline liver
biopsy (stage F3 or F4). SVR rates were 6.9% (17/245 patients) in
the 9 ug group and 10.7% (26/242) in the 15 ug group. In the
intent-to-treat analysis, SVR rates were higher among patients with
a >2-log10 decrease in hepatitis C virus RNA during prior PEG-IFN/RBV
therapy: 11% (4/38) in the 9 ug group and 23% (7/31) in the 15 ug
group. Among patients with lower baseline fibrosis scores (F0-F3),
SVR rates were 7.8% (15/192) in the 9 ug group and 13.1% (23/175) in
the 15 ug group. In this same group of patients (F0-F3), if a
>2-log10 decrease in hepatitis C virus RNA with previous PEG-IFN/RBV
treatment was achieved, SVR rates improved to 10.7% and 31.6% in the
9 ug and 15 ug groups, respectively. CIFN/RBV combination
retreatment was safe and well tolerated. Conclusion: Retreatment of
PEG-IFN and RBV nonresponders with CIFN and RBV is safe and
efficacious and can be considered a retreatment strategy for
patients failing previous therapy with PEG-IFN/RBV, especially in
interferon-sensitive patients with lower baseline fibrosis scores.
Article Text
Since 2001, the standard of care for patients with chronic hepatitis
C has been the combination of pegylated interferon (PEG-IFN) and
ribavirin (RBV).[1][2] This combination has produced sustained
virologic response (SVR) rates of 50%-60% in patients infected with
hepatitis C virus (HCV) genotype 1 who adhere to their therapeutic
regimens and 40% in intention-to-treat populations.[1][2] However,
because only about 65% of patients become HCV RNA-undetectable when
treated with this regimen, more than one-third of all patients are
classified as nonresponders. Some of these patients have relatively
mild liver disease but may have symptoms of HCV viremia, while other
patients have advanced fibrosis and are at risk for developing
complications of chronic liver disease, including decompensated
cirrhosis and hepatocellular carcinoma, and may require liver
transplantation.[3-5]
The optimal approach to PEG-IFN/RBV nonresponders has not been well
defined. Some clinicians have used the watchful waiting approach[6]
and are anticipating new antiviral therapies with either protease
inhibitors or polymerase inhibitors. However, it remains to be
determined just how effective these new agents will be when combined
with PEG-IFN and RBV in the retreatment of PEG-IFN/RBV nonresponders.[7]
Alternative therapies have included retreatment with the alternative
brand of PEG-IFN not used in the initial therapy, although most
results with this approach have been disappointing. Other approaches
have included prolonged treatment with PEG-IFN, maintenance therapy,
or the use of higher dosages of either PEG-IFN and/or RBV.[8-12] The
strategy studied in the current investigation included high doses of
daily consensus interferon (CIFN) (Infergen; interferon alfacon-1) 9
or 15 g/day given with RBV.
Abbreviations
AE, adverse event; bDNA, branched DNA; CIFN, consensus interferon;
DIRECT, Daily-Dose Consensus Interferon and Ribavirin: Efficacy of
Combined Therapy; Hb, hemoglobin; HCV, hepatitis C virus; ITT,
intention to treat; PEG-IFN, pegylated interferon; RBV, ribavirin;
REPEAT, REtreatment with PEgasys in PATients Not Responding to Peg-Intron
Therapy; SVR, sustained virologic response; TMA,
transcription-mediated amplification.
Patients and Methods
This study, referred to as the DIRECT (Daily-Dose Consensus
Interferon and Ribavirin: Efficacy of Combined Therapy) trial, was
designed by the sponsor and by several of the academic
investigators. The data were managed by the sponsor and the academic
investigators. The sponsor performed the statistical analysis. The
academic investigators were responsible for the development of the
final manuscript and had unrestricted access to the data. An author
involved with the design or execution of this study either wrote or
edited every section of the manuscript. Both an academic author (B.
R. B.) and an industry representative (Michael Beckloff, Three
Rivers Pharmaceuticals, Cranberry Township, PA) attest to the
completeness and accuracy of the data.
Study Design.
This was a phase 3, randomized, open-label, multicenter, U.S.-based
registration trial conducted to investigate the efficacy,
tolerability, and safety of daily CIFN at dosages of 9 and 15 g/day
(interferon alfacon-1, Infergen; Three Rivers Pharmaceuticals, LLC,
Cranberry Township, PA) administered with daily RBV (Ribasphere,
Three Rivers Pharmaceuticals, LLC) compared with no treatment in
patients who did not respond to prior therapy with either PEG-IFN
alfa-2a or alfa-2b and RBV. The trial was divided into 2 sections:
DIRECT-001 and DIRECT-002 (Fig. 1).
Patients were randomized at a 1:1:1 ratio into three study groups:
CIFN 9 ug/day (group 1), 15 ug/day (group 2) plus oral RBV
1,000-1,200 mg/day (based on body weight), or a control,
no-treatment group (group 3). The no-treatment group was mandated by
the U.S. Food and Drug Administration in order to provide a
comparison of safety for the two treatment groups. It was not
anticipated that any of the patients randomized to the control group
would have a spontaneous response. After 24 weeks of observation,
all patients in the control group of DIRECT-001 were offered
randomization into DIRECT-002 to receive CIFN 9 or 15 g/day plus RBV.
At week 24, patients who had undetectable plasma HCV RNA by branched
DNA (bDNA) assay, confirmed by transcription-mediated amplification
(TMA) assay, or who had a 2-log10 decrease from baseline in HCV RNA
were assigned to continue therapy to week 48. Patients with a
<2-log10 decrease from baseline in plasma HCV RNA (bDNA assay) were
considered nonresponders and were withdrawn from treatment. At week
48, patients with undetectable plasma HCV RNA (by bDNA and TMA
assays) were assigned to return for regular visits in the follow-up
period (weeks 52, 60, 68, and 72) until 24 weeks after their last
dose of study drug (week 72). Patients with detectable plasma HCV
RNA (bDNA or TMA assay) at any time between weeks 48 and 72 were
classified as relapsers.
All patients who discontinued therapy early at any time were
instructed to return for a single follow-up visit 30 days after
their last dose of study drug to complete early
termination/discontinuation assessments. Patients who had
undetectable plasma HCV RNA by bDNA and TMA assays at the time of
stopping therapy or at the early termination/discontinuation visit
were to return for follow-up plasma HCV RNA assessments through week
72, as long as their plasma HCV RNA levels remained undetectable by
both bDNA and TMA assays. Patients who discontinued for nonresponse
at weeks 12 or 24 did not undergo a follow-up HCV RNA measurement.
Patients in the no-treatment group in DIRECT-001 were given the
option to enroll in DIRECT-002 under the following conditions: if
they achieved a <2-log10 decrease in plasma HCV RNA at week 24
compared with baseline or if they had detectable plasma HCV RNA by
bDNA or by TMA at week 48. These patients were then treated
according to the same protocol followed in DIRECT-001. The results
of DIRECT-001 and DIRECT-002 were pooled for the purpose of this
analysis.
Patients.
Men and women were eligible for enrollment if they were chronically
infected with HCV of any genotype. Chronic infection was identified
based on a history of being positive for serum anti-HCV and/or HCV
RNA. A liver biopsy performed within 3 years of screening must have
demonstrated evidence of chronic HCV infection. Hepatic fibrosis was
interpreted by local pathologists based upon the Metavir scoring
system. Patients with advanced liver disease, including bridging
fibrosis (F3) and cirrhosis (F4), were eligible for the study as
long as they had normal liver function as evidenced by serum albumin
>3.5 mg/dL, platelet count >75,000/mm3, and no prior episode of
hepatic decompensation (variceal hemorrhage, hepatic encephalopathy,
ascites, or hepatocellular carcinoma).
Prior nonresponse and adherence after initial therapy with PEG-IFN
alfa-2a (180 ug/week) or PEG-IFN alfa-2b (1.5 ug/kg/week) plus RBV
was determined via careful chart review completed by the study site
principal investigator and confirmed by an external study monitor.
Nonresponders had to have had a <2-log10 decrease in HCV RNA between
weeks 12 and 24 or detectable HCV RNA at weeks 24 or 48. Patients
were required to have had completed a minimum of 90 days between
discontinuation of their prior regimen and the start of the current
study medication. All patients had to have received at least 80% of
the cumulative standard dosages of PEG-IFN and RBV for at least 38
weeks (80% of the planned treatment duration). Patients were
excluded if this previous treatment was prematurely discontinued,
dosing was interrupted, or if the dose of PEG-IFN was reduced
because of noncompliance, safety, or tolerability issues (including
hematologic or psychiatric side effects).
Patients were also excluded if they were pregnant or lactating women
or male partners of pregnant women, or if they were not suitable
candidates for enrollment or unlikely to comply with the
requirements of the study in the opinion of the investigator or
sponsor.
Treatment and Assessments.
Screening took place between 8 weeks and 1 day before the first day
of treatment. After providing informed consent, patients were
screened for inclusion criteria, underwent a physical examination,
provided a baseline medical history, and had blood drawn for
laboratory testing. After screening, eligible patients were
randomized in a 1:1:1 ratio to receive CIFN 9 or 15 ug/day plus RBV
1,000 mg/day (body weight <75 kg) or 1,200 mg/day (body weight >75
kg) or no treatment (Fig. 1). RBV was provided as capsules
containing 200 mg of active drug. An independent data monitoring
committee conducted regular interim safety assessments throughout
the study.
Plasma HCV RNA levels were determined first using the bDNA
quantitative assay, which has a sensitivity of detection of 615 IU/mL
and a reportable range of 615 to 6,920,000 IU/mL. The Bayer TMA
assay, with a sensitivity of detection of 5 IU/mL, was used whenever
HCV RNA levels were undetectable via bDNA assay.
Patients developing anemia, defined as hemoglobin (Hb) <10 g/dL,
were managed by reducing the dose of RBV to 600 mg/day. The use of
growth factors was not permitted. If the Hb increased to >10 g/dL,
the RBV dose could be increased in 200-mg/day increments as
tolerated according to the discretion of the site principal
investigator. RBV dose was not increased after being reduced to 600
mg/day for patients with a history of cardiovascular disease whose
Hb decreased by 2 g/dL or more during any 4-week period. RBV was
permanently discontinued in patients whose Hb dropped below 8.5 g/dL.
In those patients with a history of cardiac or cerebrovascular
disease, Hb remaining below 12 g/dL after 4 weeks on a reduced dose
required permanent discontinuation of RBV. Neutropenia was managed
by CIFN dose reduction; in patients whose absolute neutrophil count
fell to <0.75 x 109/L, starting doses of 15 ug were lowered to 9 ug
and then to 6 ug, and starting doses of 9 ug were lowered to 6 ug.
Efficacy Variables.
The primary efficacy variable was the proportion of patients with
SVR, defined as undetectable plasma HCV RNA by both bDNA and TMA
assays at 24 weeks after the last dose of study drug. In addition,
SVR was further explored for the effect of race, genotype, sex, age,
baseline HCV RNA, presence/absence of cirrhosis, body weight, and
previous response to PEG-IFN/RBV.
Safety and Tolerability.
All adverse events (AEs) and serious AEs were recorded for patients
who received at least 1 dose of study medication (active-treatment
groups) or who completed baseline assessments (no-treatment group).
AEs were recorded until either 30 days after the last dose of study
medication (active-treatment groups) or until the last study visit
(no-treatment group). AEs were graded from 1 to 5 (1, mild; 2,
moderate; 3, severe; 4, life-threatening or disabling; 5, death)
based on the Common Toxicity Criteria for Adverse Events v3.0. An AE
was considered a serious AE if it resulted in death, was
life-threatening, required inpatient hospitalization, or resulted in
persistent or significant disability or incapacity.
Statistical Methods.
At least 170 patients were needed in each of the three study groups
(for a total of 510 patients) to provide an approximately 91% power
to detect a difference in SVR between each of the active treatment
groups and the no-treatment group. This analysis was performed using
a two-sided Fisher's exact test at alpha= 0.05 significance level,
with adjustment for multiple comparisons, and assumed an SVR rate of
10% for either of the active treatment groups and 1.2% for the
no-treatment group. The study was not powered to detect differences
between the 9 ug and the 15 ug arms.
Data were summarized and analyzed for two patient populations: the
intention-to-treat (ITT) population and patients who did not receive
any dose modifications. The ITT group consisted of all patients who
were randomized to receive CIFN in DIRECT-001, as well as all
patients from the no-treatment group in DIRECT-001 who went on to
receive at least 1 dose of CIFN in DIRECT-002. Data from the ITT
population were used in all efficacy and safety analyses.
Descriptive statistics were determined for continuous variables
(patient counts, mean, standard deviation, median, minimum, and
maximum) and categorical variables (number and percentage of
patients for each category). Percentages were calculated using the
number of patients without missing data as the denominator unless
otherwise indicated. Calculations of virologic response (both
sustained and at specific visits) used the number of ITT patients as
the denominator. All statistical testing was conducted at the 0.05
level of significance using SAS software, version 8.2.
Results
Patients and Disposition.
Five hundred fifteen patients were randomized at 44 sites in the
United States and Puerto Rico to receive CIFN 9 g/day plus RBV 1,000
or 1,200 mg/day (n = 171), CIFN 15 g/day plus RBV (n = 172), or no
treatment (n = 172). Of the 172 patients in the no-treatment group
in DIRECT-001, 144 continued on to DIRECT-002. Of these, 74 received
CIFN 9 ug/day plus RBV 1,000 or 1,200 mg/day, and 70 received CIFN
15 g/day plus RBV 1,000 or 1,200 mg/day. The final ITT population
included 487 patients (245 who received CIFN 9 ug/day and 242 who
received CIFN 15 ug/day).
Baseline demographic and clinical characteristics of the two CIFN
treatment groups are presented in Table 1. The majority of patients
were male (70%) and Caucasian (64%). Of the enrolled patients, 59.3%
had advanced liver disease on biopsy, including bridging fibrosis
(F3; 35%) or cirrhosis (F4; 25%). In addition, 52% of patients had
hepatic steatosis. The average time between biopsy sampling and
study day 1 was 1.6 years. Patients included in the DIRECT trial
were required to be off PEG-IFN/RBV therapy for at least 3 months
prior to starting CIFN therapy. The median washout period between
previous treatment and day 1 of CIFN therapy was 448 days (15
months) and 506 days (16.8 months) for the 9 ug and 15 ug groups,
respectively. Sixty-eight percent of the patients had high baseline
HCV RNA levels of >850,000 IU/mL. The majority of patients (79%)
failed to achieve an early virologic response (at least a 2-log10
drop in HCV RNA from the pretreatment baseline) to previous PEG-IFN
therapy.
Antiviral Efficacy.
By ITT analysis, pooled end-of-treatment response via TMA assay in
the pooled 9 ug arm was 14.7% (36/245), with a subsequent SVR of
6.9% (17/245). In the 15 ug arm, pooled end-of-treatment response
via TMA assay was 18.5% (45/242), with an SVR rate of 10.7%
(26/242). Relapse rates pooled for both arms were 52% (19/36) and
42% (19/45) for the 9 ug and 15 ug groups, respectively. Post hoc
analysis revealed steatosis and time to viral negativity had the
most impact on relapse rates.[13] As expected, in DIRECT 001,
patients in the no-treatment arm achieved a 0% SVR. In patients who
did not have dose modifications, overall SVR rates were 7% in the
CIFN 9 ug group and 17% in the 15 ug group (Fig. 2A,B). The SVR
rates were not significantly different between the 001 and 002 arms
(P = 0.818). Although the study was not powered to detect
differences between the 9 ug and 15 ug groups, a post hoc analysis
revealed no difference in SVR rates between the two (P = 0.141, 95%
CI -8.8%-1.2%).
Patients who achieved a complete early virologic response (defined
as viral negativity at week 12 via TMA assay) were more likely to
demonstrate an SVR than the general study population. In the 9 ug
group, 81.3% (13/16) of patients with complete early virologic
response achieved SVR, whereas in the 15 ug group, 63.6% (14/22) of
patients with complete early virologic response demonstrated SVR. In
patients deemed slow responders (>2-log drop at week 12,
viral-negative at week 24), SVR rates were 11.7% (2/17) and 35.4%
(11/31) in the 9 ug and 15 ug groups, respectively. Two patients in
the 9 ug arm and one patient in the 15 ug arm achieved SVR despite
being viral-positive at week 24.
Patients achieving the greatest log reduction in terms of viral
response to initial PEG-IFN/RBV therapy had the best likelihood of
responding to retreatment with CIFN and RBV (Fig. 3A,B). Among F0-F2
patients with >2-log10 decreases in HCV RNA during their prior PEG-IFN/RBV
therapy, SVR rates were 13.3% (2/15) and 30.0% (3/10) in the 9 ug
and 15 ug groups, respectively. A similar trend was seen in the 15
ug arm in patients with bridging fibrosis (F3). SVR for the F0-F2
group of patients was 8.7% (9/104) in the 9ug group and 14.9%
(14/94) in the 15 ug group. With patients displaying bridging
fibrosis only on biopsy, overall SVR was 6.8% (6/88) and 11.1%
(9/81) in the 9 and 15 ug groups, respectively. Complete SVR for
noncirrhotics (F0-F3) was 7.8% (15/192) in the 9 ug group versus
13.1% (23/175) in the 15 ug group, whereas cirrhotics achieved SVR
rates of 3.8% (2/53) and 4.5% (3/67) in the 9 ug and 15 ug groups,
respectively. In the cirrhotic cohort, patients required at least a
1-log drop on prior therapy to benefit from retreatment with CIFN
and RBV. African American patients achieved lower SVR rates than
Caucasians (4.2% versus 11%, respectively). In this population,
pooled analysis between the two dosage arms revealed that 35.4% of
the patients had failed at least two or more prior treatment
regimens, with 52.7% having obtained a <1-log drop on prior PEG-IFN/RBV
therapy. In addition to this, 60.2% had dose reductions while on
CIFN/RBV therapy. Finally, non-genotype 1 patients (genotype 2/3)
achieved an overall SVR rate of 23.1% (3/13) and 88.8% (8/9) in the
9 ug and 15 ug groups, respectively. Further univariate predictors
of response are discussed in Table 2.
Safety and Tolerability.
A total of 83.6% of patients in the 9 ug group and 71.7% of patients
in the 15 ug group received at least 80% of their cumulative CIFN
dose. The most common reason for early termination was treatment
failure. Discontinuation due to not achieving a >2-log drop at week
24 was similar between the pooled dosage arms of 001 and 002 (32.3%
versus 28.4%, P value not significant). Other reasons for treatment
discontinuation are listed in Table 3.
Table 4 summarizes the most common AEs experienced by patients in
the pooled 001 and 002 arms of the DIRECT trial. Most AEs were grade
2 or 3 and were more commonly related to administration of both CIFN
and RBV than either drug alone. Most patients experienced at least
one AE in the study. Individual AEs resulting from treatment with
CIFN were typical of those reported with IFN-based therapy. All AEs
were more common in the CIFN 9 and 15 ug groups than in the
no-treatment group. RBV-induced hemolytic anemia occurred in 6.4% of
patients. In general, most AEs were either not drug-related based on
the opinion of the study site principal investigator or were thought
to be related to the combination of study drugs rather than to
either CIFN or RBV alone. The most common AEs leading to dose
modifications in both CIFN treatment groups included neutropenia,
fatigue, leukopenia, depression, nausea, myalgia, lymphopenia, and
anemia. Overall, discontinuations for AEs occurred in 14% of the 9
ug group and 21% of the 15 ug group in the pooled ITT analysis.
from Jules: selected AEs in Table 4, (download pdf to see all
tables): neutropenia 36% and 44% in 9 and 15 ug/day; nausea 45% i 9
& 15 ug/day; fatigue 75% and 77% in 9 and 15 ug/day; flu-like
symptoms 40% & 42% in 9 and 15 ug/day;
Discussion
Retreatment of PEG-IFN/RBV nonresponders with daily CIFN/RBV
resulted in an SVR rate of 6.9% with 9 ug/day CIFN and 10.7% with 15
ug/day CIFN. Patients whose doses were not reduced achieved SVR
rates of 7% in the 9 ug group and 17% in the 15 ug group. These
findings are consistent with a previous clinical trial demonstrating
encouraging SVR rates with this higher dose of CIFN, 15 g/day.[14]
The best response rate, 31.6%, was observed in noncirrhotic patients
(F0-F3) who had a partial virologic response with a >2-log10 decline
in HCV RNA during their previous course of PEG-IFN treatment.
These results were achieved even though the patients in the DIRECT
trial had numerous poor prognostic factors for a successful
response. Approximately 95% had HCV genotype 1, about 20% were
African American, 68% had a high baseline HCV RNA level of >850,000
IU/mL, and almost 90% had a baseline HCV RNA level of >400,000 IU/mL.
Approximately 80% had a <2-log10 decline in HCV RNA during prior
treatment. Sixty percent of patients had advanced liver disease,
including cirrhosis (25%) and bridging fibrosis (35%), and 52% had
steatosis on biopsy. All of these factors have been shown to
significantly reduce rates of SVR.
Overall, the alternative strategies for improving SVR in PEG-IFN/RBV
nonresponders have not met with success. Two trials of maintenance
IFN therapy were evaluated in PEG-IFN/RBV nonresponders with
advanced fibrosis or cirrhosis to determine if this strategy can
reduce progression to cirrhosis, complications of cirrhosis,
hepatocellular carcinoma, the need for liver transplantation, and
death.[8][15] The Hepatitis C Antiviral Long-Term Treatment Against
Cirrhosis trial demonstrated that maintenance PEG-IFN alfa-2a
therapy at a dose of 90 g/week over 3.5 years provided no overall
benefit compared with no treatment.[8] Similar results were observed
in the Colchicine versus PEG-Intron Long Term study, which compared
PEG-IFN alfa-2b 0.5 g/kg/week to colchicine over 3.5 years.[15]
In the recently completed REtreatment with PEgasys in PATients Not
Responding to Peg-Intron Therapy (REPEAT) trial, nonresponders and
relapsers to previous PEG-IFN alfa-2b and RBV were retreated with
either a standard dose of PEG-IFN alfa-2a 180 g/week or a higher
dose of 360 g/week for 12 weeks, after which the dose was reduced to
the standard dose.[16] Patients who became HCV RNA undetectable by
week 24 were treated for either 48 or 72 weeks. In a
protocol-defined primary analysis, SVR rates after retreatment with
PEG-IFN alfa-2a and RBV were only 7% to 9% with 48 weeks of
treatment but increased to 14% to 16% in those patients treated for
72 weeks. This increase in SVR resulted from a decline in relapse
with the prolonged course of treatment. The use of the higher
induction dose of PEG-IFN alfa-2a, 360 g/week, did not impact SVR
rates. The SVR results of this study, using 72 weeks of PEG-IFN
alfa-2a are comparable with those achieved with 48 weeks of
treatment with CIFN/RBV in the DIRECT trial. Several differences
exist between the REPEAT and DIRECT trials that confound direct
comparison of the results. It is not known what proportion of
patients in the REPEAT trial were treatment-compliant, and the
number of relapse patients included in the trial is not clear.[17]
Furthermore, the patients enrolled in the DIRECT trial had more
advanced liver disease than those in REPEAT (60% versus 27% with
stage F3-F4) and contained a higher percentage of African American
patients (20% versus 10%).
Recent studies of CIFN and RBV have demonstrated a favorable
response in the retreatment of PEG-IFN/RBV nonresponders.[14][18][19]
Two open-label trials demonstrated SVR rates ranging from 10% to
37%, with varying CIFN regimens.[17][19] In a third study, 137
consecutive patients who did not become HCV RNA-undetectable during
treatment with PEG-IFN alfa-2b with RBV were switched to CIFN 15 ug/day
for 12 weeks, followed by CIFN three times weekly for an additional
36 weeks with weight-based doses of RBV.[14] SVR rates were noted in
37% of patients who remained on their full doses of therapy. The SVR
rate was 27% in African Americans and 41% in Caucasian patients.
Several other new and promising therapies are under development for
the treatment of chronic hepatitis C. These include RBV-like
molecules, polymerase and protease inhibitors, and novel IFN
formulations.[7][20] Two protease inhibitors, Boceprevir and
Telaprevir, are the furthest along in development. Phase III studies
are in the midst of enrollment, and these agents may gain U.S. Food
and Drug Administration approval in 2 to 3 years. In addition, it
has already been demonstrated that both protease and polymerase
inhibitors will require the use of both IFN and RBV to achieve an
SVR in treatment-naÏve or treatment-experienced patients.
In conclusion, the current study shows the benefit CIFN holds for
difficult-to-treat patients with chronic hepatitis C who have failed
to respond to previous treatment with PEG-IFN and RBV. The present
study demonstrated that some patients with chronic hepatitis C who
have failed to respond to treatment with PEG-IFN and RBV can be
successfully retreated with daily CIFN and RBV. The greatest SVR
rate during retreatment in the present study was observed in F0-F3
patients who had a partial virologic response during their prior
course of treatment. Therefore, once-daily CIFN in combination with
RBV can be considered for select patients with chronic HCV who have
failed to respond to prior treatment with PEG-IFN and RBV.
Valeant Sells European Ops to Meda for $392M in Cash - Aug 4, 2008
To that end, the company in May sold US and Canadian rights to hepatitis C
drug Infergen (interferon alfacon-1) to Three Rivers Pharmaceuticals LLC,
BioWorld Online,
Overall, about 7% of
patients in the 9 mcg consensus interferon group and 11% in the 15 mcg
group achieved SVR.