This Web Site is committed to the memory of Janis Morrow.

            

New Drugs In Devolvement

2009-2008

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Index of All New Drugs

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HCV Drugs/Achillion Positive Preliminary Results

Novel Hepatitis C InhibitorsDrug Discovery & Development -

Combination of IDX184, a Nucleotide Prodrug Polymerase Inhibitor, with Other Classes of HCV Inhibitors is Additive to Synergistic in the HCV Replicon in vitro  

Dec 21

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For anyone who is not privy to understanding all

the exciting news about HCV protease inhibitors,

we hope to guide you to a better
understanding.

 

Dec 20

 

Several therapeutic regimens have been developed in an attempt to treat hepatitis C virus (HCV)-related liver disease. The current Standard Of Care (SOC) for the treatment of hepatitis C is combination therapy with pegylated interferon alfa and ribavirin. This combination regimen can be very effective in patients infected with HCV genotype 2, with more than 80% of patients achieving a Sustained Virologic Response, (SVR). The response rate is lowest among patients with genotype 1 disease, with approximately 40% achieving a sustained virologic response

http://cme.medscape.com/viewarticle/556641?rss

SVR Sustained Virologic Response:  Means that there is no Hepatitis C virus detectable in the blood six months after a person completes HCV treatment

HCV therapy started with Interferon, but lets jump ahead to treating with either Pegasys or Pegintron in combination with Ribavirin .

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.

The study :

Preliminary, Top-line Results from Schering Plough's IDEAL Study: PegIntron versus Pegasys -

Some articles on new HCV therapies theorize that Pegylated interferon will be retired.

How close are we to that becoming a reality?

There are issues and problems with the new protease inhibitors, resistance, side effects, virological failure (breakthrough, relapse, and nonresponse) .  Sounds pretty familiar to us, right?

As we read through the studies/trials the stats on those issues are improving. 

There is new hope on the horizon.

Moving Ahead

The wait for Telaprevir and Boceprevir to be approved.

Protease and polymerase inhibitors block proteins the hepatitis C virus needs to replicate.

Telaprevir and Boceprevir are protease inhibitors.

This ever changing drug scene is an welcomed event for anyone with HCV. The choices for HCV therapy are looking better and better. The pharmaceutical companies are coming up with better SVR rates and shorter treatment duration. Yeah !

Even less side effects ? Well, that's to be decided.

For anyone who is just entering the world of Hepatitis C, and treatment, its easy to be overwhelmed, and confused.

Even with these wonderful new protease inhibitors we must not forget we will still be treating with pegylated interferon/Ribavirin.

So be it, roll out those new drugs.

In the world of HCV there are a lot of people who are null responders, and relapsers (is that even a word?).

People who are stage 3 (one stage away from cirrhosis) are waiting on the side lines for better treatment. Anyone in this position is ready to fight this disease head on, side effects and all.

For the most part being infected with HCV is reason enough to eradicate the virus.

 

Caution

 However, the agenda here is to kill the virus not the host

With that said this needs to be said.

The most important part of treatment is getting the right physician. Once this is in place treatment can be managed appropriately  and the individual treating has less anxiety. We all know there will be side effects, which can cause anyone to doubt their physician. ( we get confused on treatment, start to get a feeling that our doctor is letting us suffer? )  Even when we know this isn't the case, we need to feel that someone is in control, because in the middle of treatment we sure aren't.

 

During treatment we can feel hopeless, lost, and confused

Do we ask for rescue meds ? Why isn't my doctor ordering labs ? What's going on ?

HELP I want my money back.

 

You must be treated by a doctor you trust

We need to feel confident and know that treatment is individualized enough to give us the best advantage of reaching SVR.

This is better accomplished  in competent hands. Find a specialist,  if possible at a teaching hospital.

 

Side Effects

The down side of treatment has always been those side effects. Even with these new drugs there are additional side effects. Again, we will still have pegylated interferon/Ribavirin in the mix.

 

Fact : Boceprevir shows anemia/ Telaprevir had problems with skin rash -

Fact : Both can be treated.

Boceprevir

Phase III trials for Boceprevir began in 2008. Results available to date have demonstrated the compound to be well tolerated, with adverse events that were  fatigue, anemia, nausea and headache but within the range of current standard-of-care therapy. Thus, Boceprevir may have the potential to increase sustained virological response rates and possibly also to shorten duration of therapy; data from ongoing clinical trials are awaited.

Telaprevir

One side effect is the Telaprevir-associated rash. In some cases severe enough sending patients to the hospital or discontinuation of treatment. Lets assume that the drug companies will come up with some sort of rescue drugs to help. With the new studies showing possible shorter treatment duration hopefully we will have less side effects. Or treatment will be short enough to manage them.

Both

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

Telaprevir Shorter Treatment Duration

In Telaprevir patients who achieved rapid viral response, defined as undetectable levels of virus at week four, and who maintained undetectable levels through week 20, were able to stop all treatment after 24 weeks of therapy

When doctors are able to tailor treatment on an  individual basis according to early treatment response, we could then improve the chance of achieving SVR.

More good news for Telaprevir:

Difficult to treat patients

Telaprevir Patients who had had prior relapses did much better than those who had not responded at all to standard treatment,  With sustained response rates of up to 76% versus less than 40% for prior nonresponders.

Genotype 1 Patients and Telaprevir, amazing folks.

The studies on Telaprevir are promising

All previous Phase II studies of the highly promising experimental drug tested the medicine at three times a day dosing given at eight-hour intervals. This study hoped to show telaprevir could be administered twice a day 12 hours apart, which would be more convenient for patients. Patients who received telaprevir twice a day in combination with the standard treatments of pegylated-interferon and ribavirin had a sustained viral response (SVR) of 82 percent in one arm and 83 percent in another, depending on which brand of interferon they received. That compared with 81 percent and 85 percent of patients who were given telaprevir in the three times daily regimen, according to data to be presented at the American Association for the Study of Liver Diseases (AASLD) meeting in Boston. The percentage of patients in whom the virus is undetectable 24 weeks after completing treatment yields the critical measure known as sustained viral response, or SVR, which is considered tantamount to a cure. "SVR rates of 75 to 80 percent (in twice daily dosing) would be very well received by investors," Sanford Bernstein analyst Geoffrey Porges said prior to release of the data.

More Than 80 Percent of HCV Genotype 1 Treatment-Naive Patients Achieved Sustained Virologic Response With Twice-Daily Telaprevir-Based Regimen

 

Introducing Telaprevir and Boceprevir

The Studies

The introduction of Specifically Targeted Antiviral Therapy (STAT-C) added 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, and 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.

Thank you Jules and NATAP (favorite site of many in the HCV community, as is HCV Advocate and http://www.hivandhepatitis.com.

http://www.natap.org/2009/HCV/100809_01.htm

Boerhinger vs. Telaprevir

Boerhinger Ingelheim's BI-201335 (let's call it '335 for short) seems to be the telaprevir competitor

Boceprevir is an HCV NS3 (non-structural protein 3) serine protease inhibitor being developed by Schering-Plough Corp

- The hepatitis C drug telaprevir from Vertex Pharmaceuticals 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.

 

 

http://www.thestreet.com/story/10607120/1/investors-eye-vertex-hep-c-competitor-biobuzz.html?cm_ven=GOOGLEFI

 

BOCEPREVIR

"Boceprevir with standard of care for 48 weeks nearly doubles SVR."/Sprint-1-Study

The SPRINT-1 was a phase II study of HCV genotype 1 treatment-naïve patients. In the current retrospective study, data from patients from the original study who achieved less than a 1 log10 drop in HCV RNA viral load (called null-responders in this analysis) after 4 weeks of PegIntron plus ribavirin (lead-in phase) was analyzed.

All the patients received either 24 or 44 weeks of additional treatment with boceprevir, PegIntron and ribavirin. A total of 206 patient records were analyzed. In both groups of null-responders the SVR rate was 38% (16 out of 50 patients). In the group that was treated for 28 weeks the SVR rate was 25% (7 out of 28 patients) and 55% (12 out of 22 patients) in the group that received 48 weeks of therapy.

Another analysis of the SPRINT-1 clinical trial noted that people who achieved a rapid virological response after treatment with boceprevir, PegIntron and ribavirin were able to achieve an SVR rate of 82% (54 out of 66 patients) in the 28 week treatment arm. In the patients who did not achieve an RVR but who were HCV RNA negative by week 16 and were treated for 48 weeks there was a 79% (15 out of 19 patients) SVR. These results support the rationale for response-guided therapy.
Comments: While these results are impressive a couple of caveats need to be made: the findings are from an analysis of previous data which can prove to be a slippery slope, and there were small patient numbers as well. The phase III studies of boceprevir will yield much more accurate information about response-guided therapy.

So, which drug is better and which one will be FDA approved first?

Telaprevir seems to cure this disease in a larger amount of HCV infected persons who have previously failed treatment. Telaprevir is one of several HCV protease inhibitors making their way through the development pipeline. Along with Boceprevir, it is the most advanced, with Phase III studies now underway.

They're widely expected to be the first direct antiviral drugs made available for HCV, with FDA approval possible in 2011.

The Trials

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.

http://www.natap.org/2009/HCV/102609_01.htm


The Concerns

"Although the numbers are small, this analysis of the HCV SPRINT-1 study data showed that it was possible to achieve SVR in a proportion of null responders to peginterferon and ribavirin when boceprevir was added to their backbone regimen," said lead investigator Paul Kwo, MD, from Indiana University School of Medicine said in a press release issued by Schering-Plough.

"However, the risk of developing viral resistance to protease inhibitors in patients who do not achieve SVR must be carefully weighed against the potential benefits of treatment with this new class of direct antiviral agents.

With the lead-in strategy, initial peginterferon and ribavirin responsiveness is determined prior to the addition of a protease inhibitor, thus allowing the physician to take into account the potential for the development of resistance.

"Phase 3 studies in treatment-naive hepatitis C patients (SPRINT-2) and people with prior treatment failure (RESPOND-2) -- both of which include the lead-in period for all boceprevir recipients -- are currently underway.

Continue reading........

http://www.hivandhepatitis.com/2009icr/aasld/docs/110609_d.html
 

Other Protease Inhibitors.

The antiviral activity of ACH-806 (also known as GS-9132; Achillion Pharmaceuticals/Gilead Sciences), another HCV protease inhibitor, has been tested in a phase 1 clinical trial. In data presented at the recent EASL meeting in Barcelona, Spain, treatment with ACH-806 was associated with a 2.38-log drop in HCV RNA within 5 days of therapy.^[17] It is important to note that there has been concern about an increase in beta-2-microglobulin and serum creatinine that was observed during this study. Finally, ITMN B (Intermune, Brisbane, California) is another HCV protease inhibitor that has been tested in replication model(s).^[6] Although protease inhibitors represent an exciting class of compounds in development for the treatment of HCV infection, they have a short half-life and require dosing every 8 hours.

HCV RNA Polymerase Inhibitors

In addition to protease inhibitors, many other agents are being developed to target the HCV RNA-dependent RNA polymerase. One of these agents, NM283 (Valopicitabine, Idenix Pharmaceuticals, Cambridge, Massachusetts), is a ribonucleoside analog that targets the viral RNA polymerase and is a viral RNA chain terminator. Godofsky and colleagues^[18] presented the results of a phase 1/2 dose-escalation trial of NM283 in the range of 50 mg per day to 800 mg per day. Results showed that the best response to NM283 occurred at a dose titrated between 400 mg and 800 mg/day. However, higher doses were associated with significant side effects, specifically nausea and vomiting. In a study presented at the recent EASL meeting, NM283 was administered in combination with pegylated interferon alfa-2a to HCV genotype 1 patients who were nonresponders to previous pegylated interferon alfa and ribavirin-based therapy.^[19] Despite early enthusiasm, this trial failed to demonstrate an enhanced sustained virologic response in this difficult-to-treat group of patients with hepatitis C. A study assessing the safety and efficacy of this agent given in combination with pegylated interferon alfa and ribavirin is currently underway.

R1626 (Roche Pharmaceuticals, Basel, Switzerland), another nucleoside analog oral polymerase inhibitor, has been administered at doses ranging from 500 mg to 1500 mg twice daily for 14 days in treatment-naive HCV genotype 1 patients. The initial clinical trial involving this agent demonstrated a clinically significant approximately 1.2-log reduction in HCV RNA associated with the 1500-mg twice-daily dosing regimen.^[20] A subsequent multiple ascending dose study of R1626 (500 mg, 1500 mg, 3000 mg, and 4500 mg twice daily for 14 days) was conducted in previously untreated patients with HCV genotype 1 infection.^[21] Mean (median) HCV viral reductions of 0.3 (0.2), 1.2 (0.8), 2.6 (2.7), and 3.7 (4.1) log10 were observed for doses of 500 mg, 1500 mg, 3000 mg, and 4500 mg, twice daily, respectively.

The nonnucleoside polymerase inhibitor HCV-796 (ViroPharma, Exton, Pennsylvania and Wyeth Research, Philadelphia, Pennsylvania) has been studied in a phase 1 clinical trial at doses ranging from 50 mg per day to 1500 mg per day. Approximately a 1.2-log drop in the HCV RNA viral load was observed among patients receiving the higher doses (500-1500 mg/day). However, this drug seems to be associated with an increase in HCV RNA levels, which may be the result of the emergence of HCV variants.^[22] A phase 2 clinical trial of this agent given in combination with pegylated interferon alfa-2a with or without ribavirin in both treatment-naive and nonresponder patients is currently underway. In addition to these agents, several other polymerase inhibitors, including MK-0608, A-837093, and AG-021541, are also under development in the preclinical setting

http://cme.medscape.com/viewarticle/556641_3

*** HCV Drug Pipeline Updated December 18, 2009

PHASE I TRIALS 2009

HCV protease inhibitors Telaprevir and Boceprevir

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CORRECT: Anadys Pharma Declines As ANA598 Data Doesn't Wow

Dec 17

 

ACH-1625 to Treat Hepatitis C - Achieves 3.94 log10 Reduction in HCV RNA

 

Therapeutic HCV Vaccines May Lower Viral Load and Improve Response to Interferon-based Therapy

 

Dec 16

 

Albinterferon alfa-2b vs. peginterferon alfa-2a, in combination with ribavirin

 

Waiting For Telaprevir/ Triple-Drug Cocktail in the Works for Hepatitis C Therapy

 

Dec 15

Effect of HCV RNA Suppression During Peginterferon Alfa-2a Maintenance Therapy on Clinical Outcomes in the HALT-C Trial -- Consider maintenance  or wait for Oral Protease in 2011 ? Must read from Jules Levin

Dec 14

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Sustained Response to Interferon-based Therapy Leads to Improved Quality of Life in Chronic Hepatitis C Patients

		SUMMARY: Chronic hepatitis C patients who achieve sustained virological response (SVR) to interferon-based treatment have a better of quality of life than non-responders, and these benefits last long-term after completion of therapy, according to a Canadian study reported in the October 2009 American Journal of Gastroenterology.

By Liz Highleyman

Ava John-Baptiste from the University of Toronto and colleagues compared the health status of hepatitis C patients with sustained response to interferon-based antiviral therapy -- defined as continued undetectable HCV viral load 6 months after completion of therapy -- versus that of individuals who "failed" treatment.

After finishing therapy, a total of 235 patients -- 133 sustained responders and 102 non-responders -- completed either written surveys by mail or in-person interviews. Questionnaires were completed an average of 3.7 years after the end of treatment.

The investigators used standardized health-related quality of life and preference (utility) measures:

	Hepatitis-specific Medical Outcomes Study;
	Short-Form 36-Item Health Survey (SF-36);
	Health Utilities Index Mark 2/3 (HUI-2/3);
	Time trade-off (TTO) for current health.

Respondents also provided information about demographic characteristics, history of substance abuse, co-existing conditions, and other aspects of health history. Finally, they indicated whether they missed work, volunteer activities, or household activities during the prior 3 months due to hepatitis C or its treatment. Detailed clinical information was obtained from medical chart reviews.

Results

	Relatively to sustained responders, participants who did not achieve SVR after treatment had:
	Significantly lower scores on the 8 SF-36 domains (P < 0.01); Lower scores on hepatitis-specific domains (P < 0.0001); Lower physical (42.5 vs 49.2) and mental (40.5 vs 46.1) component summary scores (P < 0.01).
	Non-responders also had significantly lower scores than sustained responders using other measures (all P < 0.05):
	HUI-2: 0.74 vs 0.80; HUI-3: 0.57 vs 0.70; SF-6D: 0.65 vs 0.71; TTO: 0.84 vs 0.89.
	However, differences in HUI-2 and TTO scores were no longer significant after adjusting for demographic and clinical variables.
	44% of participants who experienced treatment failure missed work, volunteer opportunities, or household activities due to hepatitis C or its treatment, compared with 9% of sustained responders (P < 0.001).

Based on these findings, the study authors concluded, "Patients with a sustained response to antiviral therapy for chronic HCV infection have better quality of life than treatment failures do."

"Our study validates the benefits associated with the sustained response to antiviral therapy in a real-world clinic population and shows that these benefits are maintained over the long term," they added.

Department of Health Policy, Management and Evaluation and Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; University Health Network, Toronto, Ontario, Canada; Toronto Health Economics and Technology Assessment (THETA) Collaborative, Toronto, Ontario, Canada.

12/11/09

Reference
AA John-Baptiste, G Tomlinson, PC Hsu, and others. Sustained Responders Have Better Quality of Life and Productivity Compared With Treatment Failures Long After Antiviral Therapy for Hepatitis C. American Journal of Gastroenterology. 104(10): 2439-2448 (Abstract). October 2009.

http://www.hivandhepatitis.com/hep_c/news/2009/121109_a.html

Dec 11

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Toll-like Receptor Antagonist IMO-2125 Stimulates Production of Natural Interferons with Activity against Hepatitis C Virus

		SUMMARY: The investigational toll-like receptor 9 (TLR9) antagonist IMO-2125 induced production of high levels of endogenous (natural) interferon alpha and other interferons that exhibited potent activity against hepatitis C virus (HCV), according to 2 presentations at the 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009) last month in Boston. Idera Pharmaceuticals recently announced the start of a Phase 1 clinical trial of IMO-2125 plus ribavirin in treatment-naive chronic hepatitis C patients.

Current standard treatment for hepatitis C involves administration of recombinant (genetically engineered) pegylated interferon alpha plus ribavirin. The directly targeted oral anti-HCV agents now in development work by interfering with various steps of the viral lifecycle.

IMO-2125 and related agents work a third way, by stimulating production of the body's own interferons, which play a key role in immune response against the virus.

At AASLD, Idera researchers presented data from 2 laboratory studies of IMO-2125. As with recombinant conventional and pegylated interferon, IMO-2125 is injected subcutaneously.

In the first study, they found that IMO-2125 induced high levels of endogenous interferon alpha, interferon beta, interferon lambda, and other cytokines (chemical messengers) in human peripheral blood mononuclear cells and dendritic cells; the cytokines demonstrated potent antiviral activity in HCV replicons. Adding antibodies against interferon alpha reduced this antiviral activity, but not completely, suggesting that other substances induced by IMO-2125 also play a role.

The second study, looking at gene expression profiles, offered more details about IMO-2125's mechanism of immune activation. The results showed that IMO-2125 mediated immune responses through TLR9 and associated interferon signaling pathways involving MyD88 and interferon regulatory factor 7 (IRF7). Several type 1 interferon-response genes, interferon-inducible proteins, antiviral proteins, TLR9 signaling molecules, and transcription factors were also up-regulated.

In early October, Idera announced the start of a Phase 1 clinical trial evaluating once-weekly IMO-2125 for 4 weeks in combination with oral ribavirin in treatment-naive chronic hepatitis C patients. Since ribavirin helps prevent relapse in people treated with recombinant interferon alpha, the same might be true for naturally produced interferon.

Another ongoing trial is looking at IMO-2125 as monotherapy in treatment-experienced hepatitis C patients who did not achieve a sustained response with standard-of-care pegylated interferon plus ribavirin.

12/11/09

References

L Bhagat D Yu, AF Trombino, and others. IMO-2125, a TLR9 agonist, induces Th1-type cytokines and interferons with potent anti-HCV activity in human peripheral blood mononuclear cells and plasmacytoid dendritic cells. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 1593.

W Jian, L Bhagat, D Yu, and others. Gene expression profiles induced by IMO-2125, an agonist of Toll-like receptor 9, in human peripheral blood mononuclear cells. 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2009). Boston. October 30-November 1, 2009. Abstract 1597.

Other sources

Idera Pharmaceuticals. Idera Pharmaceuticals Initiates Phase 1 Clinical Trial of IMO-2125, a TLR9 Agonist, in Combination with Ribavirin for Chronic Hepatitis C Virus Infection. Press release. October 7 2009.

Idera Pharmaceuticals. Idera Pharmaceuticals Presents Preclinical Data on IMO-2125, its Lead Drug Candidate for Chronic Hepatitis C Virus Infection, at Liver Meeting 2009. Press release. November 3, 2009.

http://www.hivandhepatitis.com/2009icr/aasld/docs/121109_a.html

Dec 11

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Hep Dart 2009: Hep Dart 2009

 Frontiers in Drug Development for Viral Hepatitis, Kohala Coast, HI, US.

 

: Analysis of antiviral resistance to MK-7009 in protocol 004, a phase 1b monotherapy study -

Safety and Tolerability of Filibuvir, a Non nucleoside Inhibitor of HCV Polymerase
 

Dec 11

Analysis of antiviral resistance to MK-7009 in protocol 004, a phase 1b monotherapy study

Pharmacokinetics of a Polymerase Inhibitor, ABT-333, in Treatment-naïve HCV Genotype 1-Infected Subjects Following Treatment with 2 days of ABT-333 Followed by 26 Days of ABT-333 Plus Pegylated Interferon and Ribavirin

Pharmacokinetics and Tolerability of the HCV Protease Inhibitor ABT-450 Following Single Ascending Doses in Healthy Adult Volunteers with and Without Ritonavir

Pharmacokinetics, Safety and Tolerability of the HCV Protease Inhibitor ABT-450 with Ritonavir Following Multiple Ascending Doses in Healthy Adult Volunteers

Safety, Tolerability, Pharmacokinetics and Antiviral Activity of the HCV Polymerase Inhibitor ABT-072 Following Single and Multiple Dosing in Healthy Adult Volunteers and Two Days of Dosing in Treatment-Naïve HCV Genotype 1-Infected Subjects

Dec 9

 

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Update From Novembers Liver Meeting

Asian and White Patients With Chronic Hepatitis C (CHC) Achieve Similar Response Rates With Peginterferon (PEG-IFN) Alfa-2b Plus Ribavirin (RBV) in Genotypes (G) 2 and 3: Subanalysis of the REDD 2/3 Study -

Identifying HCV genotype 2/3 patients who could receive a 16-week abbreviated course of peginterferon alfa-2a (40KD) plus ribavirin

Ribavirin priming enhances efficacy of chronic hepatitis C re-treatment in patients who had not responded to previous combination therapy -

PREDICT Study Final Results: Efficacy and Safety of 24-Wk Regimen of Peginterferon alfa-2b Plus Weight-based Ribavirin in Patients With Chronic Hepatitis C Virus (HCV) Genotype 1 (G1) With Low Viral Load Who Achieve Rapid Viral Response -

In Case You Missed It

Dec1-09/New HCV Drugs Summary

Dec 8

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Pharmasset Announces Continuation of Phase 2b Trial of HCV Polymerase Inhibitor RG7128

Dec 4

		SUMMARY: Pharmasset, Inc. last week announced that its development partner Roche will continue enrolling participants in a Phase 2b study of the experimental nucleoside analog hepatitis C virus (HCV) polymerase inhibitor RG7128 (formerly R7128) plus pegylated interferon/ribavirin, following a favorable review of safety data. RG7128 is also being studied in conjunction with the HCV protease inhibitor RG7227 (also known as ITMN-191) in the INFORM trials -- the first experimental combination regimen without interferon.

Below is a press release from Pharmasset describing the ongoing Phase 2b trial as well as other studies of RG7128.

 

Pharmasset Announces the Continued Enrollment of the Phase 2b Trial of RG7128 for the Treatment of Hepatitis C Data Monitoring Committee (DMC) determines RG7128, a first-in-class nucleoside analog polymerase inhibitor continues to have acceptable safety profile An additional ~300 HCV positive genotype1 and 4 patients to be randomized equally across five treatment arms Additional RG7128 phase 2 studies to be initiated in first half 2010 Princeton, JN -- November 23, 2009 -- Pharmasset, Inc. (Nasdaq: VRUS) announced today that the enrollment of Cohort 2, led by its partner Roche (SWX: ROG.VX; RO.S, OTCQX: RHHBY), will continue for the remaining 300 genotype 1 and 4 patients in the ongoing phase 2b trial of RG7128, a first-in-class nucleoside analog polymerase inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. The decision was reached after a scheduled review by an independent Data Monitoring Committee (DMC) of all available safety data from the first cohort of approximately 100 patients completing 8 or 12 weeks of RG7128 or matching placebo in combination with pegylated interferon and ribavirin. The DMC reviewed any potential drug discontinuations, incidence and details of adverse events, and selected laboratory assessments. No safety events in the DMC review were considered significantly different from those expected from HCV patients taking pegylated interferon and ribavirin treatment. The committee expressed no safety concerns that would preclude enrollment of the remaining 300 patients in the ongoing phase 2b study in the HCV positive genotype 1 and 4 population, and have not recommended modification of dose or duration of any RG7128 dosing regimens. Enrollment of these patients pre-screened for this Cohort in the fourth quarter 2009 has begun and is expected to be complete by the end of the first quarter of 2010. "We welcome Roche's decision to open enrollment of Cohort 2 for the remaining 300 patients in the phase 2b trial," stated Michelle Berrey, MD, MPH, Pharmasset's Chief Medical Officer. "We are encouraged by the safety profile of RG7128 to date, which, when coupled with the higher barrier to resistance offered by nucleoside and nucleotide analog inhibitors has the potential to improve SVR rates over the current standard of care." Additional RG7128 Studies Pharmasset's development partner, Roche, plans to initiate a number of additional, longer duration phase 2b trials with RG7128 in the first half of 2010. An additional study in patients infected with HCV genotypes 2 and 3 is being planned to initiate later in 2010. About the RG7128 Phase 2b Trial The Phase 2b trial is anticipated to enroll a total of about 400 HCV-infected patients with genotypes 1 or 4 who have never received HCV treatment. The trial is evaluating the dose and duration of treatment with RG7128 in combination with Pegasys [pegylated interferon alfa-2a] plus Copegus (ribavirin). The primary efficacy endpoint of the trial is the proportion of patients achieving an SVR, defined as serum HCV RNA below the limit of detection as measured by the Roche TaqMan assay 24 weeks after completion of treatment. Patients are equally randomized into one of 5 arms: 24 weeks of total treatment, with RG7128 500 mg BID [twice daily] in combination with Pegasys and ribavirin for 12 weeks, followed by 12 weeks of Pegasys and ribavirin ("12+12") 24 weeks of total treatment, with RG7128 1000 mg BID in combination with Pegasys and ribavirin for 12 weeks, followed by 12 weeks of Pegasys and ribavirin ("12+12") 24 weeks of total treatment, with RG7128 1000 mg BID in combination with Pegasys and ribavirin for 8 weeks, followed by a further 16 weeks of Pegasys and ribavirin ("8+16") 48 weeks of total treatment, with RG7128 1000 mg BID in combination with Pegasys and ribavirin for 12 weeks, followed by a further 36 weeks of Pegasys and ribavirin ("12+36") A control arm with Pegasys and ribavirin for 48 weeks. Patients randomized to the 24-week regimen will discontinue all treatment at week 24 if they have achieved a rapid virological response, defined as serum HCV RNA below the limit of detection at week 4, a strategy known as "RVR-guided" treatment. Patients who do not achieve an RVR will continue on the standard of care therapy (Pegasys and ribavirin) until week 48. About Pharmasset Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV) and, secondarily, on the development of Racivir(TM) for the treatment of human immunodeficiency virus (HIV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase thus inhibiting viral replication. We currently have three clinical-stage product candidates. RG7128, a nucleoside analog for chronic HCV infections, is in a Phase 2b clinical trial in combination with Pegasys plus Copegus and is also in INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys and Copegus to treat chronic HCV. These clinical studies are being conducted through a strategic collaboration with Roche. Our other clinical stage candidates include PSI-7851, an unpartnered, next generation HCV nucleotide analog, has completed initial Phase 1 clinical studies which provided supportive safety and efficacy data to initiate a Phase 2a trial in 1Q 2010 and Racivir, for the treatment of HIV, which has completed a Phase 2 clinical trial. We have also recently announced the nomination of two purine nucleotide analogs, PSI-938 and PSI-879, for preclinical development.

12/4/09

Source
Pharmasset, Inc. Pharmasset Announces the Continued Enrollment of the Phase 2b Trial of RG7128 for the Treatment of Hepatitis C. Press release. November 23, 2009.

http://www.hivandhepatitis.com/hep_c/news/2009/120409_b.html

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The news about all of the new therapies to treat hepatitis C is very exciting and inspiring

AASLD 2009 - Part 1
Alan Franciscus, Editor-in-Chief

http://www.hcvadvocate.org/news/newsLetter/2009/advocate1209.html

Dec 1

The American Association for the Study of Liver Diseases (ASSLD) conference was recently held in Boston, MA.  As expected the majority of information about HCV was from studies on the new drugs being developed to treat hepatitis C.  That’s the good news about the conference.  The not so good news about the conference is that the information about HCV epidemiology, disease progression and disease management was minimal, which is unfortunate (to say the least) because of all the unanswered questions about these important issues.  Having said this, the news about all of the new therapies to treat hepatitis C is very exciting and inspiring especially since we are moving closer to the eventual approval of drugs that will improve the treatment response rates.  It is, however, important to keep in mind that most of the studies reviewed in this report include only a small number of participants and the period of time the drugs are being taken by people is short.  Larger clinical trials with a diverse HCV population using a new drug over a longer period of time will give a much better picture of the safety, tolerability and efficacy of a study drug. 

INFORM-1

This is the first clinical trial of the combination of an HCV polymerase inhibitor, RG7128, and an HCV protease inhibitor, RG7227.  What is noteworthy is the absence of interferon and ribavirin.  The theory behind this clinical trial is that by combining two different types of direct HCV antiviral medications there is a different mechanism of action to attack the virus at different parts of the replication process to help to prevent the virus from becoming resistant to either medication.  Also of note is that the drugs are eliminated differently from the body—one from the kidneys and one from the liver.  Another compelling reason for hoping this combination will work is that both are oral medications that only have to be taken twice a day—which will make adherence much easier compared to taking a shot of interferon, multiple doses of ribavirin and possibly 3 daily doses of an HCV direct antiviral a day. 

All patients in this study were HCV genotype 1 patients who did not have cirrhosis.  Treatment relapsers, partial responders and null responders as well as treatment-naïve patients were included in the trial. 

Part 1
In April 2009 the results from part 1 of the phase I study were released.  In part 1 the combination dosing for 14 days produced a median reduction of HCV RNA of -4.8 to -5.2 log₁₀ IU/ml in the highest doses; all doses of the combination produced HCV RNA reductions (less than 40 IU/mL) in 63% of the trial participants  The drugs were well-tolerated over the 14-day dosing period with no serious treatment-related adverse events, dose reductions or discontinuations

Part 2
The objective of the second part of the study was to assess the safety and tolerability of a combination of the two drugs for up to 13 days.

All of the study medications were dosed at BID (twice a day) and in each group two patients received a placebo (sugar pill).  A total of 24 patients were randomized to one of three treatment arms; the RNA decline is listed after the dosing regimen below:  

• 8 patients who were treatment failure but NOT null-responders received 1000 mg RG7128 plus 600 mg RG7227

  • -4.0 log₁₀ IU/ml (range -6.0 to -2.5); HCV RNA < 15 IU/mL = 1 patient

• 8 patients who were null-responders received 1000 mg RG7128 and 900 mg RG7227. 

  • -4.9 log₁₀ IU/mL (range -5.3 to -3.5);  HCV RNA <15 IU/mL = 2 patients

• 8 patients who were treatment-naïve received 1000 mg RG7128 and 900 mg RG7227. 

  • -5.1 log₁₀ IU/mL (range -5.9 to -3.0);  HCV RNA <15 IU/mL – 5 patients

Safety:
Similar to part 1 of the study results released earlier this year, headache was the most common side effect followed by nausea, diarrhea, and rash that were possibly related to the study drugs.  There were no treatment discontinuations due to side effects.  One person dropped out of the study due to personal reasons. 

Resistance:
There was no treatment-emergent resistance identified.  One patient in the low dose group had a rebound of HCV RNA viral load, but it was suppressed with treatment of pegylated interferon plus ribavirin. 

The authors noted that this is the first interferon-free study to demonstrate that HCV RNA could be suppressed to the same extent as that shown with the use of the combination of HCV protease inhibitors, pegylated interferon and ribavirin over a two week period. 

Comments:
The results from this study are remarkable although it is important to remember that the number of people who actually took the drugs was very small and the people were only given the study drugs for a short period of time.  The next steps (INFORM-2) are to study the combination of RG7128 and RG7227 with and without pegylated interferon and ribavirin for a longer period of time.  The companies expect to start the studies in the first half of 2010.

TELAPREVIR

Telaprevir is currently in phase III studies, but other on-going studies are being conducted and data is being released.  Included in this report are results from three different telaprevir studies. 

PROVE3 Final
Final SVR results from PROVE3 were released that confirmed that SVR12 data is the same as SVR data—at least in this study.  PROVE3 was a study conducted in people who did not achieve an SVR with a previous course of pegylated interferon and ribavirin.  The study was composed of 4 treatment arms, but the arm that resulted in the highest response rate and lowest relapse rate was the 48-week treatment arm that included 24 weeks of telaprevir, pegylated interferon, and ribavirin followed by 24 weeks of pegylated interferon plus ribavirin.  In this arm the SVR12 results ranged from 53 to 76% depending on the type of prior non-response.  This group also had the lowest relapse rate (4%), which is pretty remarkable.  The results comparing the SVR12 results to standard SVR (HCV RNA negative 24 weeks after the end of treatment) were the same except that one person was lost to follow-up. 

Comments:
This is an important finding since the shorter period of SVR will, hopefully, speed up the future development. 

Study C208
Study C208 is an important study because it compared a telaprevir dose taken every 8 hours (current phase III study) to a dose taken every 12 hours. 

In the current study there were a total of 161 HCV genotype 1 treatment-naïve patients divided into 4 treatment arms.  All patients received the triple combination listed below for 12 weeks followed by an additional 12 weeks with pegylated interferon (Pegasys, PegIntron) plus ribavirin.  Listed below are the dosing arms as well as the SVR rates:

Arm A:  40 patients received telaprevir 750 mg every 8 hours plus Pegasys and ribavirin.
      SVR=85%

Arm B:  42 patients received telaprevir 750 mg every 8 hours plus PegIntron plus ribavirin.
      SVR=81%

Arm C:  40 patients received telaprevir 1125 mg every 12 hours with Pegasys and ribavirin. 
      SVR= 82.5%

Arm D:  39 patients received telaprevir 1125 mg every 12 hours with PegIntron plus ribavirin. 
      SVR=82.1% 

*Note:  The daily dose or exposure of telaprevir was the same across all treatment arms = 2250 mg  

The percentage of people who achieved a rapid virological response (undetectable viral load after 4 weeks) and went on to achieve an SVR was similar across all treatment arms—91 to 93%. 

There were 14 people who discontinued treatment due to side effects—7 people due to rash; 2 people due to pruritus (itching).  Of note, unlike in previous studies there was a rash management plan that included provider education and recommendations for over-the-counter medications to control the rash; this is believed to have contributed to the lower incidence of rashes in this study.   

Comments:
This study is important because it shows that the drug efficacy of the every 12 hours dosing schedule is the same as the every 8 hours dosing schedule.  The two drugs that are furthest along in development are telaprevir and boceprevir—both dosing schedules are for taking the protease inhibitor every 8 hours, ribavirin twice a day and pegylated interferon one time a week.  Maintaining 100% adherence for many patients will be a struggle with the new triple therapy.  Failure to follow a dosing schedule or missing doses of the new direct antivirals will lead to drug resistance and, of course, lower treatment response rates.  A regime with drugs taken every day from every 8 to every 12 hours will be a huge step forward in improving adherence and treatment outcomes.  But since the phase III studies are using the 3 times a day dose, the immediate implications are unclear.

Study 107 
Results from Study 107, an on-going study of people who failed to achieve an SVR with a previous course of pegylated interferon plus ribavirin therapy in prior telaprevir studies (SOC or standard of care arms), were released at AASLD.  The interim results were from 94 patients who were rolled over to treatment with telaprevir, pegylated interferon plus ribavirin for 12 weeks followed by either an additional 12 or 36 weeks of pegylated interferon plus ribavirin. 

The sustained virological response rates between the two groups (total treatment duration) was not broken down so the results below are listed by type of response:

1. Prior null responders (patients who had a viral load reduction < 1 log₁₀ at week 4 or < 2 log₁₀ at week 12).  A total of 28 of whom 16 (57%) achieved an SVR.

2. Prior partial responders (patients who had a viral load reduction > 2 log₁₀ at week 12, but who had detectable HCV RNA at week 24.  A total of 29 patients of whom 16 (55%) achieved an SVR.

3. Prior relapsers (patients who had an undetectable viral load during treatment, but had detectable viral load after treatment ended.  A total of 29 patients of whom 26 (90%) achieved an SVR.

4. Prior viral breakthrough (patients who had undetectable viral load during treatment, but detectable viral load before the end of treatment.  A total of 8 patients of whom 6 (75%) achieved an SVR.

*The SVR rates are combined for both treatment durations by type of non-response, but it was noted that the optimal treatment duration is 48 weeks.

According to a company press release the side effect profile was similar to what has been seen in previous telaprevir studies. 

Comments:
This important but small study is encouraging for improving the SVR rates in people who have been previously treated with pegylated interferon plus ribavirin therapy.  The larger phase III studies of people who did not achieve an SVR with a previous course of pegylated interferon plus ribavirin will give us a much better picture of the future of retreatment in the HCV population that is in the most need of treatment options. 

BOCEPREVIR

The SPRINT-1 was a phase II study of HCV genotype 1 treatment-naïve patients.  In the current retrospective study, data from patients from the original study who achieved less than a 1 log₁₀ drop in HCV RNA viral load (called null-responders in this analysis) after 4 weeks of PegIntron plus ribavirin (lead-in phase) was analyzed.  All the patients received either 24 or 44 weeks of additional treatment with boceprevir, PegIntron and ribavirin.  A total of 206 patient records were analyzed.  In both groups of null-responders the SVR rate was 38% (16 out of 50 patients).  In the group that was treated for 28 weeks the SVR rate was 25% (7 out of 28 patients) and 55% (12 out of 22 patients) in the group that received 48 weeks of therapy.

Another analysis of the SPRINT-1 clinical trial noted that people who achieved a rapid virological response after treatment with boceprevir, PegIntron and ribavirin were able to achieve an SVR rate of 82% (54 out of 66 patients) in the 28 week treatment arm.  In the patients who did not achieve an RVR but who were HCV RNA negative by week 16 and were treated for 48 weeks there was a 79% (15 out of 19 patients) SVR.  These results support the rationale for response-guided therapy. 

Comments:
While these results are impressive a couple of caveats need to be made: the findings are from an analysis of previous data which can prove to be a slippery slope, and there were small patient numbers as well.  The phase III studies of boceprevir will yield much more accurate information about response-guided therapy.

In part 2 of AASLD conference coverage I will discuss the results from more than a dozen studies of the new agents that are being developed to treat hepatitis C.

                       http://www.hcvadvocate.org/news/newsLetter/2009/advocate1209.html

 

How Do Targeted Anti-HCV Drugs Work?
 

Liz Highleyman

Drugs that attack the hepatitis C virus (HCV) directly—dubbed specifically-targeted antiviral therapy for hepatitis C, or “STAT-C”—represent a paradigm shift in the management of the disease.

The current standard of care for chronic hepatitis C treatment, pegylated interferon plus ribavirin, works by stimulating the body’s immune response against the virus. Interferons are natural chemical messengers (cytokines) that regulate immune function. Ribavirin, an IMPDH inhibitor (Inosine monophosphate dehydrogenase), has the ability to inhibit viral replication by interfering with ribonucleic acid (RNA) production, but in practice appears to work primarily as an immune modulator.

Several new anti-HCV drugs now in development work another way—by blocking or interfering with specific steps in viral replication. In order to understand the potential of these novel agents, it is useful to look at the HCV life cycle and various ways it can be disrupted.

THE HCV LIFE CYCLE

HCV is a small virus consisting of a genome encased in a capsid shell and surrounded by an outer envelope.

 

HCV life cycle:

a) Virus binding and internalization, b) cytoplasmic release and uncoating, c) IRES-mediated translation and polyprotein processing, d) RNA replication, e) packaging and assembly, f) virion maturation and release. The topology of HCV structural and nonstructural proteins at the endoplasmic reticulum membrane is shown schematically. HCV RNA replication occurs in a specific membrane alteration, the membranous web. Note that IRES-mediated translation and polyprotein processing as well as membranous web formation and RNA replication, illustrated here as separate steps for simplicity, may occur in a tightly coupled fashion (from Moradpour D. et al. Nat. Rev. Microbiol. 2007;5:453-463.) http://www.chuv.ch/imul/imu_recherche
_moradpour.htm

Click Here to view an animation of the HCV Life Cycle

 

The HCV genome, or genetic material, takes the form of positive single-strand RNA, which serves as a “blueprint” for the production of proteins and enzymes that make up the virus.

In order to replicate, or reproduce, HCV must enter a host cell and take over its machinery. The virus first attaches itself to receptors on the host cell’s surface, penetrates the cell membrane, and uncoats itself by shedding its outer layers.

Using the cell’s ribosomes tiny protein-production factories the RNA is translated, or used to create new viral proteins. The viral genome copies itself using genetic building blocks present in the host cell. Finally, these newly produced proteins and RNA are assembled to form complete virus particles that bud out of the host cell and go on to infect additional cells.

HCV PROTEASE

Specific viral enzymes are required to carry out certain steps in the replication process. Compounds that interfere with the action of these enzymes can therefore slow or halt viral reproduction. The STAT-C drugs furthest along in development target the HCV protease and polymerase enzymes.

When viral RNA is translated, it initially produces a single large polyprotein containing about 3,000 amino acids. This polyprotein must then be cleaved, or cut up into smaller pieces that can be used to assemble new viral particles. This is the job of protease enzymes, which act as “molecular scissors.”

The hepatitis C drug candidates expected to emerge first from the development pipeline, Vertex’s telaprevir and Schering-Plough’s boceprevir, are both covalent NS3/4A serine protease inhibitors. These compounds interfere with the HCV non-structural NS3 serine protease and the NS4A cofactor that facilitates protease function. The “next-generation” protease inhibitor narlaprevir belongs to the same class. These agents bind covalently to an active site on the protease enzyme, preventing it from carrying out its normal activity.

Other promising agents, including RG7227 (also known as ITMN-191) and MK-7009, work similarly, but with non-covalent binding to the HCV protease. Many other protease inhibitor candidates are in earlier stages of development.

HCV POLYMERASE

Different enzymes are needed to copy viral RNA, the other crucial component of new virus particles. Genetic material is composed of a chain of building blocks known as nucleotides. HCV’s positive RNA strand is used as a template to produce a complementary negative (antisense) strand, which in turn is used to make more positive strands. HCV accomplishes this using an enzyme called RNA-dependent RNA polymerase, meaning it uses RNA to produce RNA (human cells, in contrast, use DNA to produce DNA, while retroviruses like HIV use RNA to produce DNA).

The HCV NS5B RNA-dependent RNA polymerase produces new RNA by adding successive nucleotides in a chain. Nucleoside or nucleotide analog drugs act as defective building blocks, or chain terminators. When added to a growing RNA chain, they prevent the addition of further nucleotides, thereby bringing production to a halt.

Some promising experimental agents, including RG7128, are nucleoside analog HCV polymerase inhibitors, as was the now-discontinued valopicitabine. (Ribavirin and successors like taribavirin are also nucleoside analogs but, as noted, seem to work by other mechanisms in anti-HCV therapy). The experimental agents PSI-7851 and IDX184 are examples of nucleotide analogs, which require less processing in the body than nucleoside analogs before they can be used.

Drugs may also interfere with polymerase activity in a different way, by binding to the enzyme and preventing it from working properly. Several non-nucleoside HCV polymerase inhibitors are in earlier stages of development, including Abbott’s ABT-072, Anadys Pharmaceuticals’ ANA598, Japan Tobacco’s JTK-003, and Vertex’s VCH-916.

OTHER DRUG TARGETS

While protease and polymerase inhibitors are furthest along in development, agents targeting other steps in the HCV life cycle are also being studied.

Compared with other viruses, researchers know relatively little about how HCV enters host cells. Nevertheless, drug developers are working on agents that interfere with viral attachment to cells by blocking either cell receptors or viral envelope proteins.

Once inside a host cell, HCV sheds its outer layers to release its genetic material. Agents that interfere with this uncoating process are also potential drug candidates. Unlike some other viruses, HCV does not integrate its genetic material into the host cell’s genome, so integrase inhibition is not a potential drug target.

In order to produce new proteins, HCV uses the host cell’s ribosomes and a replication complex where gene translation takes place. The viral genome contains an internal ribosomal entry site (IRES) at one end to enable this process. Companies are working on early development of various agents that interfere with IRES and HCV messenger RNA, including antisense oligonucleotides, ribozymes, and short interfering RNA sequences (siRNA).

After the HCV polyprotein is cleaved by a protease, some of the component pieces must be further processed before they can be used to assemble new virus particles. Various compounds such as castanospermine and its derivative celgosivir disrupt these processes. Helicase enzymes are “motor” proteins that separate strands of genetic material. The function of the HCV helicase is not fully understood, but it represents another potential drug target. Finally, anti-HCV agents could interfere with the final step of replication, inhibiting viral assembly or budding from host cells.

STAT-C TOXICITY

Drugs that specifically target HCV are less likely to cause systemic or whole body side effects such as those seen with interferon, which affects immune response rather than the virus itself. However, experience with antiretroviral therapies for HIV which work by some of the same mechanisms as anti-HCV agents indicates a need for caution.

HCV protease inhibitors, for example, have the potential to mimic the activity of human protease inhibitors. Nucleoside or nucleotide analogs could potentially interfere with copying of human as well as viral genetic material. Though the underlying mechanisms are not fully understood, drugs targeting HIV protease and reverse transcriptase (a form of polymerase) have been linked to a variety of metabolic and mitochondrial toxicities, so researchers should be on the lookout for similar side effects with anti-HCV agents.

PREVENTING DRUG RESISTANCE

Compared with DNA viruses, RNA viruses like HCV mutate frequently as they replicate, and lack a “proofreading” mechanism to eliminate such errors. Many viral mutations are either irrelevant or detrimental, but others can enable the virus to overcome the action of drugs. For example, a small change in the structure of the HCV protease binding pocket can mean protease inhibitors no longer fit into the pocket to disrupt protease function.

For all protease and polymerase inhibitors in development, single amino acid changes have been identified that reduce viral sensitivity to the drug. But combining agents that work by different mechanisms can slow or prevent such resistance. To overcome the effects of multiple drugs, HCV would have to produce multiple mutations, which tends to reduce viral fitness.

Pharmaceutical companies are testing several STAT-C combinations to determine whether the drugs have synergistic activity. Furthest along is a combination of the HCV protease inhibitor RG7227 plus the polymerase inhibitor RG7128. In the Phase 1 INFORM-1 trial, the two drugs demonstrated potent antiviral activity over 14 days in both treatment-naïve and interferon-experienced genotype 1 chronic hepatitis C patients.

In the future, it is likely that hepatitis C treatment will come to increasingly resemble therapy for HIV or hepatitis B virus, using combinations of small oral agents that attack the virus from multiple angles simultaneously, thereby improving the chances of disrupting viral replication over the long term.



Jamalot

C.D.Mazoff, PhD, Managing Editor/Webmaster

It may be just a coincidence, or maybe the timing was just right, but this week the Journal of the American Medical Association (JAMA) published an interesting article on viral hepatitis.  The article, “The Silent Epidemic of Viral Hepatitis May Lead to Boom in Serious Liver Disease,” ¹ doesn’t really say much that we didn’t know before, especially after the release of the Milliman Report, officially known as Consequences of Hepatitis C Virus (HCV): Costs of a Baby Boomer Epidemic of Liver Disease in May of this year.

But now there is a Bill before Congress, the Viral Hepatitis and Liver Cancer Control and Prevention Act of 2009 (H.R. 3974), introduced by Mike Honda and others in October, and of course there is the also the newer H.R. 3962, The Affordable Health Care for America Act, revealed at just about the same time.  Looks like a triple whammy to me.  But it’s anyone’s guess.

The JAMA article basically summarizes the state of hepatic epidemiology in the US:

• More than 5 million US residents have viral hepatitis

• Prevention efforts have drastically reduced the incidence

• HCV down to 19,000 in 2006 from 180,000 in1982

• HBV down to 60,00 in 2004 from 200,000 in 1980

There is no doubt that this is quite impressive, and many health and medical organizations deserve congratulations—even the CDC.  But, now there is another problem looming on the horizon: baby boomers and immigrants.

Although the rate of new infections of hepatitis C has dropped drastically in the general population, thanks to more screening of the blood supply and better practices, many of those who do have hepatitis C have had it for just long enough for it to become nasty.  Most people with hepatitis C are asymptomatic, and few will progress to serious liver disease; but those who will (the 20% of the 180,000 in 1982 etc.) are beginning to knock on the doctor’s door.  Furthermore, the statistics used to calculate the amount of people infected were seriously flawed because they didn’t take into account the homeless, the poor, the incarcerated and the mentally ill and others who slip through the cracks in the healthcare system because they don’t have medical insurance.

As far as hepatitis B goes, infant and adolescent vaccination programs have really helped.  Not to mention other programs such as screening of pregnant women and educational campaigns.  But the problem with HBV is that there are over 400 million people worldwide with HBV and many of them are knocking at the door as well.  According to Dr. Hu, “50% to 70% of US residents with chronic HBV infections were born in another country, and more than half of new cases identified are in Asians or Pacific Islanders.”  The majority of these persons are asymptomatic, and without screening and education, they are at risk of spreading the disease.

So, even though we are stopping many new infections, the problem is that 15-40% of people with chronic HBV develop cirrhosis or liver cancer, while the figures for those with HCV are slightly less.

And there are other complications: those with liver disease often have other illnesses—heart disease, kidney disease, autoimmune disorders, and depression particularly with hepatitis C.  Lifestyle also plays a very important part: some with HCV are on the street and use drugs and share needles.  Many use alternative forms of medication including alcohol which are bad for the liver; many cannot afford a low fat diet, and are reduced to eating junk and fast foods.  

Of interest in the JAMA article is evidence of an apparent argument or kerfuffle between the US Preventive Services Task Force (USPSTF) and members of the AGA (American Gastroenterology Association), CDC and others because the USPSTF has recommended not only against increased screening in the asymptomatic but also in at risk populations.  In my opinion the decision of the USPSTF is patently absurd if not criminally negligent considering that 80 percent of people who are infected with HCV do not know it because they have no symptoms and have never been tested!

It is encouraging to know that many doctors and institutions are actually on the patient’s side and trying very hard to change the state of the health of the nation, in more ways than one.  Only time will tell; but for many, time is running out.

A report from the Institute of Medicine of the National Academies on ways to reduce the incidence of viral hepatitis is due out in 2010.

¹“Silent Epidemic of Viral Hepatitis May Lead to Boom in Serious Liver Disease,” by Bridget M. Kuehn. JAMA. 2009;302(18):1949-1954 (doi:10.1001/jama.2009.1588)

 

HEALTWISE: Hepatitis C Update
Lucinda K. Porter, RN

It’s a tradition. Every November, I scan the HCV Advocate website for the latest news from the American Association for the Study of Liver Diseases (AASLD) meeting. This year there were some juicy morsels, six of which I will review.

In the first study, Hepatitis C and Menopause: Interplay of Age, Gender, HCV Replication and Activity in Progression and Consequence for Therapy, Trépo, Bailly, Moreno, Lemmers, Adler, and Pradat investigate the differences in fibrosis progression among HCV patients. Previous studies revealed the possibility that estrogen may have anti-fibrogenic effects, so researchers specifically looked at fibrosis development in the light of gender, age, and menopause.

They looked at 163 enrollees, ages 23 to 84 years with a mean age of 55; 56% were male. Slightly more than half (55%) had progression of fibrosis, measured by a METAVIR fibrosis score of at least F3. Overall, males had higher progression rates at 66% versus 41% for women. However, for those under the age of 50, fibrosis progression was 51% for males versus 11% for females. Over age 50, the rate jumps to 77% for males versus 61% for females.

These data show a strong relationship between gender and fibrosis progression. The researchers surmise that estrogen may have a protective benefit for younger women with HCV. They recommend the use of estrogen replacement therapy for menopausal women.

Another interesting discovery appeared in this study. In general, viral loads dropped with age except in the group of post-menopausal women. There was no explanation for this.

The second study examined similar issues. Early Loss of Exposure to Estrogens is Critical in Determining Entity of Fibrosis and Response to IFN in Women with Hepatitis C is the title of a poster presented by Karampatou, Pazienza, Lei, Di Leo, Francavilla, and Villa. After observing that post-menopausal women with HCV had increased progression of fibrosis, these researchers wondered whether the correlation was due to aging and/or longer durations of infection or to menopause.

They analyzed data from 945 HCV-treatment patients of evenly-distributed genotype—541 men and 404 women. In the female group, 252 were menopausal. Most of these were spontaneously menopausal although 50 were surgical. Body weight was lower in pre-menopausal women; however histological steatosis (fatty liver) was not significantly different between the two groups.

Pre-menopausal women had the highest response to HCV-therapy. The sustained virologic response (SVR) was 63% versus 51% of males and post-menopausal women. In short, post-menopausal women responded similarly to treatment as men did. 

The researchers concluded that menopause plays a significant role in determining the progression of fibrosis along with response to treatment. Estrogens have a powerful role in the regulation of inflammation and immunity. They recommended that interferon-based therapy be initiated at the youngest possible age, preferably prior to menopause.

The third item to catch my attention appeared in a 2009 supplement published by Hepatology and is also pertinent to women with HCV. Hepatitis C Virus (HCV) Infected Females Are at Higher Risk of Graft Loss after Liver Transplantation was presented by Jennifer Lai, MD and team of the University of California San Francisco. Data showed that women who had HCV-related liver transplantation have poorer long-term survival rates than men do. Women are also more likely to reject the donor liver. Lai also reported that women had a greater risk of advanced recurrent HCV after liver transplantation.

More research is needed to understand the reasons for the differences. Although she confirmed the need for further studies, Lai speculated that the differences may be due to:

• Aging differences between genders

• Gender mismatching of organs between donors and recipients

• Higher risk of kidney impairment in women prior to liver transplantation

Aging and HCV is the fourth item I will cover. In a poster titled, Aging of Hepatitis C Infected Persons in the United States: A Multiple Cohort Model of HCV Prevalence and Disease Progression, Davis, Alter, El-Serag, Poynard, and Jennings examine the aging HCV population.

The number of new HCV infections has been dropping, but those who acquired HCV during its peak years, are aging. The questions are these: 1) Will there be a rise in cirrhosis and other HCV-related problems, or 2) Has the burden of HCV reached a plateau?

Analyzing existing data from National Health and Nutrition Examination Survey (NHANES), Davis and team showed that the prevalence of HCV peaked in 2001 at 3.6 million.  They project the number to be about half of this by 2030. They calculated that the likelihood of cirrhosis occurs between ages 60 to 80, regardless of the age of initial infection.  Davis et al., project that of those with HCV, cirrhosis will reach 25% in 2010 and 45% in 2030, peaking at 1 million in 2020 (30.5%). They estimate that those with the severest form of cirrhosis (decompensation) will rise until 2022. HCV-related liver cancer will peak in 2019 at 14,000 annual cases.

A note about NHANES: Many HCV statistics are gleaned from this survey. Some experts believe that the NHANES estimates are low because certain populations with a high incidence of HCV were not counted, such as prisoners, homeless, military and those in institutions. Therefore, the number of those projected to experience HCV-related complications is likely to be significantly higher. 

 Davis and colleagues conclude that there will be a decline in chronic HCV as patients die of other non-HCV causes. The next two decades will experience a burden of HCV-related complications due to the long durations patients have had HCV. The researchers suggest that this impact could be reduced if more people are successfully treated for HCV.

The fifth study examined risk factors for HCV-associated fibrosis progression.  The title of the poster was: Age, Insulin Resistance and Steatosis are Independent Risk Factors for Fibrosis Progression in Untreated Patients with Mild Chronic Hepatitis C: A Prospective Study with Repeat Biopsies and was conducted by Stern, Cardoso, Moucari, Martinot-Peignoux, Ripault, Boyer, Bedossa, and Marcellin. 

Stern and colleagues looked at 265 patients with mild HCV who had never been treated and saw that the rate of fibrosis progression is low (27% in 6 years). However, factors that are associated with an increased rate of fibrosis are: older age, insulin resistance and the presence of fat in the liver (steatosis).

The final study I will discuss is my favorite. Titled, Resilience Affects the Quality of Life in Patients with Chronic Hepatitis C; it was conducted by Selmi, Giorgini, Cocchi, Meda, Marta, Monticelli, Magrin, Podda, and Zuin. They looked at the resilience of patients with HCV, meaning the ability to recover from or adjust easily to the diagnosis.   

This study enrolled 149 HCV patients, none with cirrhosis or mood or anxiety disorders: 55% were female, 42% had previously undergone HCV treatment and were either non-responders or relapsers. They used multiple questionnaires, surveying psychological well-being, health, quality of life, family and social relationships, job satisfaction, and other factors.

Selmi and colleagues found that HCV patients are quite resilient. Our social relationships and psychological well-being are generally strong and we maintain a good quality of life. However, quality of life is affected by individual factors, particularly by the length of time one is infected.  Selmi, et al. conclude, “informing patients regarding the disease natural history is critical to patient quality of life and should not be overlooked when new treatments are proposed.”

Summarizing these studies, I learned this:

• To avoid later complications, HCV treatment may help

• Treatment done early may have a better chance of success, particularly for pre-menopausal women

• Those with HCV should consider reducing the chances of acquiring fat around the liver by adopting a healthy lifestyle

Finally, I learned that as a group, HCV patients are quite resilient. However, that I already knew. You’ve been proving this for decades.

Check out the updated AASLD Practice Guidelines: Diagnosis, Management and Treatment of Hepatitis C – An Update, by Marc G. Ghany, Doris B. Strader, David L. Thomas, and Leonard B. Seeff.

 

From HCV Advocate Newsletter

AASLD 2009 - Part 1

HEALTHWISE: Hepatitis C Update

How Do Targeted Anti-HCV Drugs Work?

Silent Epidemic of Viral Hepatitis May Lead to Boom in Serious Liver Disease

HCV Among Truck Drivers

 

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November

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November/Continually Updated News From The Liver Meeting

Click Here For : November News / New Drugs Presented At The AASLD

Nov 16

Clinical Trials:  Experimental treatments; for hepatitis C that have been conducted in humans (phase I, II, III, IV) development to treat hepatitis C

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InterMune ITMN and Roches RHHBY HCV Drug Hit With Side Effects

InterMune Announces Modification To On-Going Phase 2b Study Of ITMN-191 In Patients With Chronic HCV Infection

Nov 18

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 October

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Treatment of insulin resistance with metformin in naïve genotype 1 chronic hepatitis C patients receiving peginterferon alfa-2a plus ribavirin

"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."

 

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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,
patients, customers and other stakeholders served by its colleagues around the
world. The company is based in Kenilworth, N.J., and its Web site is
www.schering-plough.com.


SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this news release
includes certain "forward-looking statements" within the meaning of the
Securities Litigation Reform Act of 1995, including statements relating to the
Company's marketed products and investigational agents for hepatitis C.
Forward-looking statements relate to expectations or forecasts of future
events. Schering-Plough does not assume the obligation to update any
forward-looking statement. Many factors could cause actual results to differ
materially from Schering-Plough's forward-looking statements, including market
forces, economic factors, product availability, patent and other intellectual
property protection, current and future branded, generic or over-the-counter
competition, the regulatory process, and any developments following regulatory
approval, among other uncertainties. For further details about these and
other factors that may impact the forward-looking statements, see
Schering-Plough's Securities and Exchange Commission filings, including Part
II, Item 1A. "Risk Factors" in the Company's second quarter 2009 10-Q, filed
July 24, 2009.




SOURCE Schering-Plough

Media, Robert Consalvo, +1-908-298-7409, or Investors, Janet Barth,
+1-908-298-7436, or Joe Romanelli, +1-908-298-7436, all for Schering-Plough

 

 

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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.

Source:  Hepatology 2009

http://www.hcvadvocate.org/news/Boceprevir_Resistance.html

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AASLD: Viral Responses in African Americans, Latinos, and Caucasians in the US Phase 2 Study (PROVE1) of Telaprevir with Peginterferon Alfa-2a and Ribavirin in Treatment-Naive, Genotype 1-Infected Patients with Hepatitis C -

Oct 01 09

 

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Hope for Hepatitis C patients: Two new drugs

"Telaprevir and Boceprevir"

 

 

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September

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