丙肝用药单一，已经硬化的能否进来聊聊经验和症状。

powerliu

IFN+RBV本来就是最佳治疗方案

这病头疼

昨天是打干扰素第33针了，现在对利巴韦林的反映越来越大了，吃不到一星期黄疸就上来了，利巴韦林减少也不行了，现在基本上要停利巴韦林两个星期才能在用上了。血小板在喝红枣花生汤的情况下基本正常了，可白细胞还是很低，医生开了利生素，可我看对肝的副作用太大没敢用。其它指标还都可以，b超不敢经常做听说辐射很大，基本3个月做一次，就是最近老是感觉两肋不怎么舒服，有涨和重的感觉，胃也感觉不舒服，但不是太厉害。担心脾会不会在增大，现在已经是巨脾了，在大只有切了。现在母亲在书上查说是香菇煮猪肉可以增加白细胞，这星期正在吃看下星期化验是否有作用了。现在尽可能减少药物的摄入量，希望能让肝的负担不要在加重。这样的努力天知道会有什么结果，心好累，不过还是在坚持。

liver411

忘记了，你的HCV是第一型（Type I）？SAMe （S-腺苷-L-蛋白氨酸 - 在普通药房维生素柜台应该可以买到）可以帮助增加干扰素效益和肝脏答应。这样可以配合干扰素，减低利巴韦林。

SAMe Improves Early Response to Pegylated Interferon/ribavain in Small Study

By Liz Highleyman

About half of patients with genotype 1 chronic hepatitis C virus (HCV) infection do not achieve a sustained response to standard interferon-based therapy, and researchers have explored other types of treatment. In addition to directly-targeted "STAT-C" agents such as HCV protease and polymerase inhibitors, some have also studied various alternative or complementary therapies.

S-adenosyl methionine (SAMe) is a compound made from adenosine triphosphate and methionine. Sold as a dietary supplement, marketed brand names include Adomet, Admethionine, Heptral, and Samyr; it is available as a prescription drug in some countries. SAMe has been promoted for a variety of ailments, including depression, osteoarthritis, Alzheimer's disease, and liver disease, and several clinical trials have demonstrated some benefit.

In a small study presented at the recent 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) in San Francisco, researchers assessed the effect of SAMe on interferon signaling and early HCV viral kinetics, to see whether it might have promise as an adjunct therapy in combination with interferon-based therapy.

As background, the investigators noted that SAMe has been shown to enhance interferon signaling in cell culture and animal models by acting as a methyl donor to transcription factor STAT1, leading to improved STAT1-DNA binding.

The study included 9 chronic hepatitis C patients with HCV genotype 1 who were non-responders to prior therapy with pegylated interferon plus ribavirin. Participants were given pegylated interferon alfa-2a (Pegasys) plus ribavirin for 2 weeks to establish baseline responses (Course A). Treatment was stopped for a 1-month washout period, after which patients received 1600 mg SAMe daily for 2 weeks, at which point pegylated interferon/ribavirin was restarted along with SAMe for a planned duration of 48 weeks (Course B).

Early HCV viral kinetics and interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells (PBMCs) were compared during periods with and without SAMe. Interim results were presented after all 9 patients completed Course A, and a subset were partially through Course B.

Results

    • HCV RNA decline from time 0 to 48 hours after starting treatment (phase 1 kinetics) was similar during Course A and B.

    • There was a significant improvement in the second phase slope of viral decline in 8 of 9 patients and in the group taking SAMe (-0.11 vs -0.33 log/week for Courses A and B, respectively; P = 0.007).

    • 5 of 7 patients -- all previous non-responders -- achieved early virological response (EVR) at week 12 of Course B, including 3 with undetectable HCV RNA.

    • ISG-15 induction in PBMCs was significantly greater in 6 of 9 patients, and for the group as a whole, during treatment with SAMe (area under the curve 133 vs 187 RU for Course A and B, respectively; P = 0.001).

    • ISG-15 fold induction was greater at all time points, with the greatest difference seen at 24 hours (171 vs 350 RU respectively; P = 0.04).

    • A similar pattern was observed with gene MxA.

    • ISG15 and MxA expression were greater at time 0 in Course B than in Course A, after receiving 2 weeks of SAMe monotherapy.

    • During the 2 weeks of SAMe monotherapy, ALT values decreased significantly (mean change 37 U/ml; P = 0.004).

    • HCV RNA levels, however, increased slightly during SAMe monotherapy (mean change 0.22 log; P = 0.05).

Based on these findings, the researchers concluded, "SAMe appears to improve early viral kinetics in interferon non-responders and the observation that it leads to greater ISG induction suggests that the effect may be through improved interferon signaling."

12/12/08

Reference
JJ Feld, AA Modi, G Ahlenstiel, and others. SAMe Improves Early Viral Kinetics and Interferon Stimulated Gene Induction When Added to Peginterferon and Ribavirin Therapy for Previous Hepatitis C Non-Responders. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract LB5.

liver411

另外，最近也有人试验过用水飞蓟提取物水飞蓟宾(silibinin)作为HCV点滴抗病毒使用，试药是评估剂量和效果的...

Silibinin Milk Thistle Derivatives Demonstrates Antiviral Activity in Non-responders to Interferon-based Therapy for Chronic Hepatitis C Patients

By Liz Highleyman

Given that about half of patients with genotype 1 chronic hepatitis C virus (HCV) infection do not achieve a sustained response to standard pegylated interferon/ribavirin therapy, researchers have explored other types of treatment including various alternative or complementary therapies.

Milk thistle (Silybum marianum) has been used in several traditional medicine systems to treat liver disease, and its derivatives (silibinin, silymarin) have been tested in clinical trials. Substantially higher doses can be administered intravenously; the efficacy of oral preparations is unclear.

Peter Ferenci from the University of Vienna in Austria and colleagues reported results of a study of silibinin in chronic hepatitis C patients at the recent 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) and in the November 2008 issue of Gastroenterology.

Silibinin, the main flavonoid extracted from milk thistle, has previously been shown to inhibit HCV replication in laboratory studies. In the present study, the researchers initially investigated whether lowering oxidative stress can improve sensitivity to interferon by pre-treating 16 chronic hepatitis C patients with 10 mg/kg intravenous (IV) silibinin for 7 days.

Unexpectedly, they found that HCV RNA declined during silibinin monotherapy (from 6.59 log IU/mL at baseline to 5.26 log IU/mL at day 8; P < 0.001), but increased again in most patients after the infusion period, despite being on pegylated interferon/ribavirin.

The investigators then conducted a dose-finding study and safety assessment of IV silibinin in 20 patients who were non-responders to a previous course of full-dose pegylated interferon/ribavirin (defined as > 2 log decline in HCV RNA at week 12 or lack of end-of-treatment response). Most participants (85%) were men and the mean age was about 53 years. 17 patients had HCV genotype 1 and 7 had advanced liver fibrosis or cirrhosis (stage F3-F4).

Participants first received 5, 10, 15, or 20 mg/kg daily silibinin monotherapy infused over 4 hours for 14 consecutive days. On day 8, they started treatment with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day ribavirin. After day 14, they added 280 mg oral silymarin (another milk thistle product) 3 times daily.

Results

    • After 7 days of IV silibinin monotherapy, the 5 mg/kg dose was only marginally effective (HCV RNA log drop 0.5).

    • The 10, 15, and 20 mg/day doses led to a significant decrease in viral load (log drops of 1.4, 2.1, and 3.0, respectively; P < 0.001).

    • After 1 week of silibinin combined with pegylated interferon/ribavirin, HCV viral load decreased further (log drops of 1.6, 4.2, 3.7, and 4.8, respectively, with the 5, 10, 15, and 20 mg/day doses; all P < 0.0001 vs baseline).

    • 2 of the 5 (40%) and 4 of the 9 (44%) patients in the 15 and 20 mg/kg arms, respectively, had undetectable HCV RNA (< 15 IU/mL) at day 15.

    • 7 patients experienced rapid virological response (RVR, HCV < 15 IU/mL) at week 4 of combination therapy.

    • 8 patients (57%) demonstrated early virological response (HCV RNA < 15 IU/mL) at week 12 of combination therapy, but 1 relapsed at week 9.

    • HCV viral load increased in all patients with HCV RNA > 50 IU/mL at the end of the infusion period.

    • HCV RNA became undetectable in 3 patients after a second cycle of IV silibinin infusions given after week 12 (pegylated interferon/ribavirin is continuing).

    • Beside mild gastrointestinal symptoms, IV silibinin monotherapy was well tolerated.

"Intravenous silibinin is a potent antiviral agent and may be a treatment option for treatment of [pegylated interferon/ribavirin] non-responders," the researchers concluded.

12/12/08

References

P Ferenci, T Scherzer, H Kerschner, and others. Intravenous silibinin for treatment of nonresponders to peginterferon/ribavirin therapy in chronic hepatitis C. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1863.

P Ferenci, TM Scherzer, H Kerschner, and others. Silibinin Is a Potent Antiviral Agent in Patients With Chronic HCV not Responding to Pegylated Interferon/Ribavirin Therapy. Gastroenterology 135(5):1561-1567. November 2008. (Abstract). Silibinin Milk Thistle Derivatives Demonstrates Antiviral Activity in Non-responders to Interferon-based Therapy for Chronic Hepatitis C Patients

By Liz Highleyman

Given that about half of patients with genotype 1 chronic hepatitis C virus (HCV) infection do not achieve a sustained response to standard pegylated interferon/ribavirin therapy, researchers have explored other types of treatment including various alternative or complementary therapies.

Milk thistle (Silybum marianum) has been used in several traditional medicine systems to treat liver disease, and its derivatives (silibinin, silymarin) have been tested in clinical trials. Substantially higher doses can be administered intravenously; the efficacy of oral preparations is unclear.

Peter Ferenci from the University of Vienna in Austria and colleagues reported results of a study of silibinin in chronic hepatitis C patients at the recent 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) and in the November 2008 issue of Gastroenterology.

Silibinin, the main flavonoid extracted from milk thistle, has previously been shown to inhibit HCV replication in laboratory studies. In the present study, the researchers initially investigated whether lowering oxidative stress can improve sensitivity to interferon by pre-treating 16 chronic hepatitis C patients with 10 mg/kg intravenous (IV) silibinin for 7 days.

Unexpectedly, they found that HCV RNA declined during silibinin monotherapy (from 6.59 log IU/mL at baseline to 5.26 log IU/mL at day 8; P < 0.001), but increased again in most patients after the infusion period, despite being on pegylated interferon/ribavirin.

The investigators then conducted a dose-finding study and safety assessment of IV silibinin in 20 patients who were non-responders to a previous course of full-dose pegylated interferon/ribavirin (defined as > 2 log decline in HCV RNA at week 12 or lack of end-of-treatment response). Most participants (85%) were men and the mean age was about 53 years. 17 patients had HCV genotype 1 and 7 had advanced liver fibrosis or cirrhosis (stage F3-F4).

Participants first received 5, 10, 15, or 20 mg/kg daily silibinin monotherapy infused over 4 hours for 14 consecutive days. On day 8, they started treatment with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day ribavirin. After day 14, they added 280 mg oral silymarin (another milk thistle product) 3 times daily.

Results

    • After 7 days of IV silibinin monotherapy, the 5 mg/kg dose was only marginally effective (HCV RNA log drop 0.5).

    • The 10, 15, and 20 mg/day doses led to a significant decrease in viral load (log drops of 1.4, 2.1, and 3.0, respectively; P < 0.001).

    • After 1 week of silibinin combined with pegylated interferon/ribavirin, HCV viral load decreased further (log drops of 1.6, 4.2, 3.7, and 4.8, respectively, with the 5, 10, 15, and 20 mg/day doses; all P < 0.0001 vs baseline).

    • 2 of the 5 (40%) and 4 of the 9 (44%) patients in the 15 and 20 mg/kg arms, respectively, had undetectable HCV RNA (< 15 IU/mL) at day 15.

    • 7 patients experienced rapid virological response (RVR, HCV < 15 IU/mL) at week 4 of combination therapy.

    • 8 patients (57%) demonstrated early virological response (HCV RNA < 15 IU/mL) at week 12 of combination therapy, but 1 relapsed at week 9.

    • HCV viral load increased in all patients with HCV RNA > 50 IU/mL at the end of the infusion period.

    • HCV RNA became undetectable in 3 patients after a second cycle of IV silibinin infusions given after week 12 (pegylated interferon/ribavirin is continuing).

    • Beside mild gastrointestinal symptoms, IV silibinin monotherapy was well tolerated.

"Intravenous silibinin is a potent antiviral agent and may be a treatment option for treatment of [pegylated interferon/ribavirin] non-responders," the researchers concluded.

12/12/08

References

P Ferenci, T Scherzer, H Kerschner, and others. Intravenous silibinin for treatment of nonresponders to peginterferon/ribavirin therapy in chronic hepatitis C. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1863.

P Ferenci, TM Scherzer, H Kerschner, and others. Silibinin Is a Potent Antiviral Agent in Patients With Chronic HCV not Responding to Pegylated Interferon/Ribavirin Therapy. Gastroenterology 135(5):1561-1567. November 2008. (Abstract).

liver411

新的“白蛋白干扰素 - (Albuferon)” 在HCV抗病毒和治疗效益上不比长效干扰素（PEG INF）差可能效果更加，注射次数更少...

Albumin Interferon (Albuferon) Works as Well as Pegylated Interferon in ACHIEVE 2/3 Trial

Pegylated interferon alfa (Pegasys or PegIntron) plus ribavirin is the current standard of care for chronic hepatitis C. Pegylated interferon, which includes polyethylene glycol to make the interferon last longer in the body, is more effective than the older conventional form of interferon alfa and can be administered once rather than 3 times per week.

But researchers continue to explore other formulations of interferon that may work equally well or better, and may be administered even less often. Albumin interferon alfa 2b (Albuferon) is interferon alfa attached to the human blood protein albumin, which further extends its half-life in the body, potentially allowing for administration once every 2 weeks.

Albuferon is currently being tested in combination with ribavirin for the treatment of chronic hepatitis C in patients with hard-to-treat HCV genotype 1 and easier-to-treat genotypes 2 and 3.

Below is an edited excerpt from a Human Genome Sciences press release describing the latest results from the Phase 3 ACHIEVE 2/3 trial, which found that Albuferon administered biweekly works as well as pegylated interferon in treatment-naive genotype 2 or 3 patients.

Human Genome Sciences Announces Albuferon Meets Primary Endpoint in Phase 3 Trial in Chronic Hepatitis C
Albuferon (albinterferon alfa-2b) met its primary endpoint of non-inferiority to Pegasys (peginterferon alfa-2a) in the ACHIEVE 2/3 trial in patients with genotypes 2 and 3 chronic hepatitis C
Patients receiving 900 mcg Albuferon had comparable rates of serious adverse events, severe adverse events, and discontinuations due to adverse events vs. peginterferon alfa-2a

Rockville, MD, December 8, 2008 -- Human Genome Sciences, Inc. (Nasdaq: HGSI) today announced that Albuferon (albinterferon alfa-2b) met its primary endpoint of non-inferiority to peginterferon alfa-2a (Pegasys) in ACHIEVE 2/3, a Phase 3 clinical trial of Albuferon in combination with ribavirin in treatment-naive patients with genotypes 2 and 3 chronic hepatitis C (p=0.0086). Albinterferon alfa-2b is being developed by HGS and Novartis under an exclusive worldwide co-development and commercialization agreement entered into in June 2006.

"We are pleased that Albuferon met its primary endpoint in the ACHIEVE 2/3 trial. These Phase 3 data show that the efficacy of Albuferon was comparable to Pegasys, with half the injections," said H. Thomas Watkins, President and Chief Executive Officer, HGS. "We look forward to having the results of ACHIEVE 1, our other Phase 3 trial of Albuferon, in March 2009. If ACHIEVE 1 is successful, we believe Albuferon could become the market-leading interferon for the treatment of chronic hepatitis C, and we expect that global marketing applications will be filed by fall 2009."

David Nelson, MD, Professor of Medicine, Medical Director of Liver Transplantation, and Chief of the Hepatobiliary Disease Section, University of Florida, said, "Chronic hepatitis C represents a significant unmet medical need. These Phase 3 results suggest that albinterferon alfa-2b has the potential to become an important new treatment option for patients with chronic hepatitis C. Albuferon requires half as many injections as the pegylated interferons, and clinical results to date suggest that it may offer comparable efficacy, with no difference in clinically significant adverse events. The observed variation in response by geography is an unexpected finding and requires further analysis. We look forward to results from the ACHIEVE 1 trial, which is evaluating albinterferon alfa-2b in the treatment of patients with genotype 1 hepatitis C."

In the randomized, multi-center, active-controlled non-inferiority Phase 3 trial, 933 treatment-naive patients with genotypes 2 and 3 chronic hepatitis C were initially assigned to one of three treatment groups, including two groups that received albinterferon alfa-2b once every two weeks at doses of 900 mcg or 1200 mcg, and an active control group that received peginterferon alfa-2a once weekly at a dose of 180 mcg -- with all patients receiving oral ribavirin daily at 800 mg in two divided doses.

In January 2008, a dose modification was made and patients originally assigned to receive the 1200 mcg dose of albinterferon alfa-2b had their dose reduced to 900 mcg albinterferon alfa-2b every two weeks. The dose modification was recommended by the independent Data Monitoring Committee (DMC) for the Albuferon Phase 3 trials, following their observation during a routine review of unblinded data from both trials that serious pulmonary adverse events were higher in the 1200 mcg Albuferon treatment group.

Following the dose modification, the study continued to follow all patients randomized into the trial on an intention-to-treat (ITT) basis according to their original dose assignment. The primary data analysis compares the 900 mcg albinterferon alfa-2b treatment group to the peginterferon alfa-2a treatment group. The trial included 24 weeks of treatment, and the primary efficacy endpoint was non-inferiority to peginterferon alfa-2a, based on a comparison of the rate of SVR, defined as undetectable viral load (HCV RNA < 10 IU/mL) at Week 48 (24 weeks following completion of treatment).

"We are encouraged that albinterferon alfa-2b met the primary efficacy endpoint of non-inferiority to peginterferon alfa-2a in the ACHIEVE 2/3 study," said David C. Stump, MD, Executive Vice President, Research and Development, HGS. "These data show that the rate of sustained virologic response was comparable for the treatment group receiving the 900 mcg dose of albinterferon alfa-2b every two weeks, versus the treatment group receiving the standard dose of peginterferon alfa-2a once weekly. Importantly, the number of serious and severe adverse events, including pulmonary adverse events, was also comparable. When we have ACHIEVE 1 results in March, we will be in a position to assess the full therapeutic potential of albinterferon alfa-2b."

Key Findings from ACHIEVE 2/3

The topline ACHIEVE 2/3 results include the following key findings:

Treatment Group Receiving Albinterferon Alfa-2b 900 mcg Every Two Weeks, vs. Treatment Group Receiving Peginterferon Alfa-2a 180 mcg Every Week

    • Based on an ITT analysis of the treatment group assigned to receive 900 mcg albinterferon alfa-2b every two weeks, the topline results demonstrate that albinterferon alfa-2b met its primary efficacy endpoint of non-inferiority to peginterferon alfa-2a, with 79.8% (249/312) of patients achieving SVR in the 900 mcg albinterferon alfa-2b treatment group, vs. 84.8% (263/310) in the peginterferon alfa-2a treatment group (p=0.0086 for non-inferiority).

    • By region, SVR rates were

        • North America: 82.5% (85/103) for 900 mcg albinterferon alfa-2b, vs. 81.5% (88/108) for peginterferon alfa-2a;

        • Asia: 79.8% (75/94) for 900 mcg albinterferon alfa-2b, vs. 95.5% (85/89) for peginterferon alfa-2a;

        • Europe: 78.1% (64/82) for 900 mcg albinterferon alfa-2b, vs. 81.7% (67/82) for peginterferon alfa-2a;

        • Other regions: 75.8% (25/33) for 900 mcg albinterferon alfa-2b, vs. 74.2% (23/31) for peginterferon alfa-2a.

    • Patients receiving 900 mcg albinterferon alfa-2b had comparable rates of serious adverse events, severe adverse events, and discontinuations due to adverse events, vs. peginterferon alfa-2a.

    • The incidence of severe and/or serious adverse events was comparable between the two groups, with 17.3% (54/313) in the albinterferon alfa-2b 900 mcg treatment group, vs. 17.5% (54/309) in the peginterferon alfa-2a treatment group.

    • The incidence of severe and/or serious pulmonary adverse events was also comparable between these groups: severe and/or serious pulmonary infections were 0.6% (2/313) for 900 mcg albinterferon alfa-2b, vs. 0.6% (2/309) for peginterferon alfa-2a; and severe and/or serious respiratory, thoracic, or mediastinal disorders were 1.0% (3/313) for 900 mcg albinterferon alfa-2b, vs. 1.3% (4/309) for peginterferon alfa-2a.

    • Overall, adverse events observed were those typically associated with interferon therapy, and the rate of discontinuations due to adverse events was comparable: 4.8% (15/313) for 900 mcg albinterferon alfa-2b, vs. 3.6% (11/309) for peginterferon alfa-2a.

Treatment Group Originally Randomized to Receive Albinterferon Alfa-2b 1200 mcg Every Two Weeks and Reduced to 900 mcg Following January 2008 Dose Modification, vs. Treatment Group Receiving Peginterferon Alfa-2a 180 mcg Every Week

Due to the dose modification announced in January 2008, patients in the treatment group originally randomized to receive albinterferon alfa-2b 1200 mcg every two weeks had their dose modified to 900 mcg albinterferon alfa-2b every two weeks. All patients had completed at least 12 weeks of treatment at the time of the dose modification. Data from all three treatment groups in the ACHIEVE 2/3 study were analyzed according to the original dose assignment. The following topline results for the treatment group originally randomized to receive 1200 mcg albinterferon alfa-2b every two weeks did not impact the primary analysis comparing the 900 mcg albinterferon alfa-2b treatment group to the peginterferon alfa-2a treatment group.

    • Based on an ITT analysis of results for the treatment group originally randomized to receive 1200 mcg albinterferon alfa-2b every two weeks, 80.0% (248/310) of patients in this treatment group achieved SVR, vs. 84.8% (263/310) in the peginterferon alfa-2a treatment group, which statistically demonstrated non-inferiority (p=0.0059).

    • The incidence of severe and/or serious adverse events was comparable between the two groups, with 16.8% (52/310) in the treatment group originally randomized to receive 1200 mcg albinterferon alfa-2b every two weeks, vs. 17.5% (54/309) in the peginterferon alfa-2a treatment group.

    • The incidence of severe and/or serious pulmonary adverse events was also comparable between these groups: severe and/or serious pulmonary infections were 1.3% (4/310) in the treatment group originally randomized to receive 1200 mcg albinterferon alfa-2b, vs. 0.6% (2/309) in the peginterferon alfa-2a treatment group; severe and/or serious respiratory, thoracic or mediastinal disorders were 1.6% (5/310) in the treatment group originally randomized to receive 1200 mcg albinterferon alfa-2b, vs. 1.3% (4/309) in the peginterferon alfa-2a treatment group.

    • Overall, adverse events observed were those typically expected with interferon therapy. The incidence of discontinuations due to adverse events was 5.5% (17/310) in the treatment group originally randomized to receive 1200 mcg albinterferon alfa-2b every two weeks, vs. 3.6% (11/309) in the peginterferon alfa-2a treatment group.


About Albinterferon Alfa-2b (Albuferon)

Albinterferon alfa-2b is a novel, longer-acting form of interferon alfa that was created using the proprietary HGS albumin-fusion technology. Human albumin is the most prevalent naturally occurring blood protein in the human circulatory system, persisting in circulation in the body for approximately 19 days. Research has shown that genetic fusion of therapeutic proteins to human albumin decreases clearance and prolongs the half-life of the therapeutic proteins. Albuferon results from the genetic fusion of human albumin and interferon alfa.

Albuferon is being developed by HGS and Novartis for the treatment of chronic hepatitis C under an exclusive worldwide co-development and commercialization agreement entered into in June 2006. HGS and Novartis will co-commercialize Albuferon in the United States and will share clinical development costs, U.S. commercialization costs and U.S. profits equally. Novartis will be responsible for commercialization in the rest of the world and will pay HGS a royalty on those sales. Clinical development, commercial milestone and other payments to HGS could total as much as $507.5 million, including $132.5 million received to date.

1/13/09

Source
Human Genome Sciences, Inc. Human Genome Sciences Announces Albuferon Meets Primary Endpoint in Phase 3 Trial in Chronic Hepatitis C. Press release. December 8, 2008.

liver411

HCV Polymerase Inhibitor R7128 Demonstrates Good Antiviral Activity in Genotype 2 or 3 Prior Non-responders and Relapsers

By Liz Highleyman

Given the suboptimal efficacy, side effects, and cost of interferon-based therapy for chronic hepatitis C virus (HCV) infection, investigators have explored several novel drugs that directly target various stages of the viral lifecycle -- an approach called "STAT-C."

In a late-breaker presentation at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) last week in San Francisco, researchers reported the data on one such agent, Roche and Pharmasset's HCV polymerase inhibitor R7128, in prior non-responders with HCV genotypes 2 or 3. This represents one cohort in a larger study that also included genotype 1 patients.

While individuals with genotype 2 or 3 respond more favorably to therapy than those with genotype 1, patients who fail to respond to a prior course of interferon-based therapy have poor response rates when re-treated with the current standard of care, pegylated interferon plus ribavirin. Investigational STAT-C agents have often been tested in non-responders, but usually those with genotype 1.

Preclinical studies showed that R7128 (a prodrug of PSI-6130) demonstrated activity against genotype 2/3 HCV in vitro, the investigators noted as background. When administered at doses of 1000 to 1500 mg twice-daily in combination with standard of care for 28 days in treatment-naive genotype 1 patients, 85%-88% achieved rapid virological response (RVR), or undetectable HCV RNA at week 4 of therapy.

The present study included 25 non-cirrhotic patients with HCV genotype 2 (n = 10) or 3 (n = 15) who failed to achieve sustained virological response (SVR) after previous interferon-based therapy lasting at least 12 weeks; half were primary non-responders and half were relapsers. Most (60%) were men, 40% were white, 40% were Hispanic, and the mean age was 53 years. The median baseline HCV RNA level was about 6 log10 IU/mL.

Participants were randomly assigned to receive 1500 mg twice-daily R7128 (n = 20) or placebo (n = 5), administered with 180 mcg/week pegylated interferon + 1000-1200 mg/day weight-adjusted ribavirin for 28 days, followed by pegylated interferon + ribavirin alone for a minimum of 20 weeks.

Results

    • At week 4, 90% of patients receiving R7128 achieved RVR (HCV RNA < 15 IU/mL), compared with 60% of those receiving placebo.

    • The mean decrease in HCV RNA was 5.0 log10 IU/mL in the R7128 arm compared with 3.7 log10 IU/mL in the placebo arm.

    • Responses were similar for patients with genotype 2 and genotype 3.

    • R7128 was well tolerated overall.

    • No serious adverse events (AEs) were reported and there were no discontinuations due to AEs.

    • AEs were similar in prevalence and severity to those previously reported with pegylated interferon + ribavirin alone.

    • Laboratory safety assessments revealed no grade 3-4 changes in hematocrit, hemoglobin, absolute neutrophil count, or platelets, nor clinically significant changes in other laboratory parameters, vital signs, or ECGs.

Based on these preliminary results, the investigators suggested that "R7128 1500 mg [twice-daily] combined with [pegylated interferon/ribavirin] in prior HCV genotype 2/3 non-responders provides a high rate of RVR (> 86%), similar to R7128 + [standard of care] in genotype 1 non-responders, with an acceptable side-effect profile."

"These high response rates in a difficult-to-treat patient population suggest that combination therapy featuring R7128 deserves further exploration in both treatment-naive and non-responsive genotype 2/3 patients with HCV," they concluded.

Race/ethnicity and Weight

In a related study, investigators performed a sub-analysis of 2 cohorts (n = 25 each) of genotype 1 patients in the same study, looking at differences in response according to race/ethnicity and weight. Cohort 1 received 500 mg twice-daily R7128 or placebo while Cohort 2 received 1500 mg twice-daily R7128 or placebo, all with plus pegylated interferon/ribavirin.

Among the 50 subjects randomized into these 2 cohorts, 48% were white, 24% were Latino, 16% were African-American, and 8% were classified as "other." 54% of whites, 33% of Latinos, 38% of African-Americans, and 75% of "other" patients weighed > 85 kg. Proportions with body mass index (BMI) > 30 were 15%, 42%, 25%, and 25%, respectively.

Results

    • Among participants receiving placebo + standard of care, only 1 white patient (10%) achieved RVR.

    • Among patients in Cohort 1 receiving 500 mg R7128, RVR rates were 45% for whites, 25% for Latinos, 0% (0 of 3) for African-Americans, and 0% for "other."

    • Among patients in Cohort 2 receiving 1500 mg R7128, the corresponding RVR rates were 90%, 86%, 50% (1 of 2), and 100% (1 or 1), respectively.

    • Patient sex, weight, and BMI were not significant predictors of antiviral response.

    • No serious adverse events (AEs) were reported, and no differences in AEs were noted according to race/ethnicity.

Based on these findings, the investigators concluded, "R7128 administered in combination with [pegylated interferon + ribavirin] for 28 days demonstrated clinically significant antiviral potency regardless of race/ethnicity, with a numerical improvement in RVR rates in Latino patients who received R7128 1500 mg [twice-daily]."

Auckland Clinical Studies Limited, Auckland, New Zealand; Fundacion de Investigacion d Diego, Santurce, Puerto Rico; University of Florida, Gainesville, FL; Weill Cornell Medical College, New York, NY; Duke Clinical Research Institute, Durham, NC; University of Miami, Miami, FL; Quest Clinical Research, San Francisco, CA; Orlando Immunology Center, Orlando, FL; University of Colorado, , Aurora, CO; University of Pennsylvania, Philadelphia, PA; Pharmasset, Inc., Princeton, NJ; Roche, Palo Alto, CA.

11/14/08

References

EJ Gane, M Rodriguez-Torres, DR Nelson, and others. Antiviral Activity of the HCV Nucleoside Polymerase Inhibitor R7128 In HCV Genotype 2 and 3 Prior Non-Responders: Interim Results of R7128 1500mg BID with PEG-IFN and Ribavirin For 28 Days. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract LB10.

M Rodriguez-Torres; J Lalezari, EJ Gane, and others. Potent Antiviral Response to the HCV Nucleoside Polymerase Inhibitor R7128 for 28 Days With Peg-IFN and Ribavirin: Subanalysis by Race/Ethnicity, Weight and HCV Genotype. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1899.

liver411

HCV Protease Inhibitor ITMN-191 (R7227) Demonstrates Antiviral Potency in Genotype 1 Patients; New ITMN-5489 Also Under Study

The limited efficacy and side effects of interferon-based therapy for chronic hepatitis C virus (HCV) infection have spurred investigators to study several novel drugs that directly target various stages of the viral lifecycle -- an approach known as "STAT-C."

In a set of presentations at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) last week in San Francisco, researchers reported data on one such agent, InterMune and Roche's investigational HCV NS3/4A serine protease inhibitor ITMN-191 (also known by its Roche designation, R7227).

Healthy Volunteers

A Phase 1a single-ascending-dose (SAD) study in healthy volunteers demonstrated that ITMN-191 was safe and well-tolerated when given to 64 HCV negative adults at single doses ranging from 2 to 1600 mg (poster 871).

The pharmacokinetics of ITMN-191 were linear over a dose range of 100 to 800 mg, and administration with food increased the expected trough and overall concentrations by 40%-50% compared with an empty stomach. This food effect has led InterMune and Roche to explore lower doses in subsequent clinical trials.

Adverse events (AEs) were generally mild and transient, and were similar between treatment groups -- with the exception of a higher frequency of mild diarrhea and abdominal pain in the highest-dose (1600 mg) ITMN-191 group. No serious AEs or clinically significant laboratory or ECG abnormalities were reported.

Intermune, Inc, Brisbane, CA; ICPD/Ordway Research Institute, Inc., Albany, NY; Biotrial, Rennes, France.

Monotherapy in Genotype 1 Patients

A randomized Phase 1b multiple ascending dose (MAD) study assessed ITMN-191 in 4 cohorts of treatment-naive patients with HCV genotype 1, plus 1 cohort of genotype 1 prior non-responders (poster 1847). A total of 50 participants received ITMN-191 as monotherapy at doses of up to 600 mg, or else placebo, for 14 days.

ITMN-191 reduced HCV RNA in a dose-dependent manner when administered every 8 or every 12 hours. Viral load reductions occurred rapidly and were typically sustained through day 14. The greatest median decrease in HCV RNA -- 3.8 log10 -- was seen in patients receiving 200 mg every 8 hours.

In the exploratory non-responder cohort, participants who failed to achieve at least a 2.0 log10 reduction in HCV RNA with prior standard-of-care therapy, or who still had detectable HCV RNA after 24 weeks of treatment, received ITMN-191 at a dose of 300 mg every 12 hours (twice-daily). By day 14, viral load fell by a median 2.5 log10.

ITMN-191 appeared safe and well-tolerated. AEs were generally mild and transient and did not correlate with dose level. A single serious AE (benign paroxysmal positional vertigo) was observed, but was deemed unrelated to the study drug. Resistance mutations were detected in patients who experienced virological rebound, but not those with a continued decline in HCV RNA.

JW Goethe Universität, Frankfurt, Germany; CHU, Montpellier, France; Pontchaillou Hospital, Rennes, France; Hôpital Beaujon, Clichy, France; Centre CAP, Montpellier, France; Biotrial, Rennes, France; Intermune, Inc, Brisbane, CA.

ITMN-5489

Intermune also presented very early data on a new agent, ITMN-5489, another NS3/4A protease inhibitor (poster 1909). The performance characteristics of this non-macrocyclic compound compared favorably with those of ITMN-191.

In laboratory studies, ITMN-5489 had a 50% effective concentration (EC50) of approximately 1 nM against a genotype 1b HCV replicon model, and 81 nM produced replicon clearance in 14 days. ITMN-5489 exhibited significant stability in liver cells derived from rats, monkeys, and humans. The drug's plasma concentration 24 hours after dosing was higher than the concentration of ITMN-191 after 12 hours, and the overall area under the curve was 5- to 10-fold higher, suggesting that once-daily dosing of ITMN-5489 may be feasible.

Intermune, Inc, Brisbane, CA.

11/14/08

References

N Forestier, DG Larrey, D Guyader, and others. Treatment of Chronic Hepatitis C Virus (HCV) Genotype 1 Patients with the NS3/4A Protease Inhibitor ITMN-191 Leads to Rapid Reductions in Plasma HCV RNA: Results of a Phase 1b Multiple Ascending Dose (MAD) Study. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1847.

WZ Bradford, C Rubino, S Porter, and others. A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics (PK) of Single Ascending Oral Doses of the NS3/4A Protease Inhibitor ITMN 191 in Healthy Subjects. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1871.

BO Buckman, L Pan, L Huang, and others. Identification of Novel Non-Macrocyclic Inhibitors of HCV NS3/4A Serine Protease Activity. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1909.

Other source
InterMune, Inc. InterMune to Present Four Abstracts on HCV Protease Inhibitor ITMN-191 at the AASLD Meeting. Press release. September 24, 2008.

liver411

HCV Protease Inhibitor Telaprevir (VX-950) Continues to Perform Well in PROVE Trials

By Liz Highleyman

Given the suboptimal efficacy, side effects, and cost of interferon-based therapy for chronic hepatitis C virus (HCV) infection, investigators have explored several novel drugs that directly target various steps of the viral lifecycle -- an approach dubbed "STAT-C."

At the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) last week in San Francisco, researchers presented the latest data on the STAT-C agent furthest along in the development pipeline: telaprevir (VX-950), an HCV protease inhibitor being developed by Vertex Pharmaceuticals and Tibotec.

PROVE 2 Final Results

Telaprevir has been studied in a series of related Phase 2b trials. Data from the PROVE 1 and PROVE 2 studies were presented earlier this year at the annual meeting of the European Association for the Study of the Liver (EASL). Final results from PROVE 2 were presented at AASLD.

In PROVE 2, a total of 323 treatment-naive patients with genotype 1 chronic hepatitis C were randomized to receive 1 of the following regimens:

    • 750 mg telaprevir every 8 hours + 180 mcg/week pegylated interferon alfa-2a (Pegasys) for 12 weeks (T12/P12);

    • Telaprevir + Pegasys at the same doses + 1000-1200 mg/day weight-adjusted ribavirin for 12 weeks (T12/PR12);

    • Telaprevir + Pegasys + ribavirin for 12 weeks, followed by Pegasys + ribavirin without telaprevir for 12 additional weeks (T12/PR24).

    • Standard therapy with Pegasys + ribavirin (+ telaprevir placebo) for 48 weeks (PR48).

A majority of participants (about 60%) were men, 94% were white, and the median age was 45 years. Most (nearly 90%) had HCV RNA > 600,000 IU/mL at baseline and about 7% had advanced liver fibrosis.

Results

    • In the final intent-to-treat analysis, proportions of patients who achieved sustained virological response (SVR) 24 weeks after completion of therapy were as follows:

        • 69% of patients in the T12/PR24 arm;
        • 60% in the T12/PR12 arm;
        • 46% in the standard therapy PR48 arm;
        • 30% in the T12/P12 (no ribavirin) arm.

    • 14% of patients receiving a 24-week telaprevir regimen discontinued therapy due to adverse events, compared with 7% in the 48-week standard therapy arm.

    • 7% of patients across all telaprevir arms discontinuation due to skin rash.

Based on these findings, the researches concluded that, "Telaprevir in combination with [pegylated interferon/ribavirin] demonstrated significantly higher SVR rates compared with the control group in patients infected with HCV genotype 1, with the potential to shorten the overall treatment duration by half in most patients."

While telaprevir improved response, however, it still appears that ribavirin is needed to reduce the risk of relapse and increase the likelihood of sustained response.

Dept of Internal Medicine I, JW Goethe University Hospital, Frankfurt a.M., Germany; AP-HP Henri-Mondor Hospital & University of Paris 12, Créteil, France; Medical University of Vienna, Vienna, Austria; Royal Free Hospital, London, UK; Medicines Development Group, Vertex Pharmaceuticals, Inc., Cambridge, MA.

PROVE 3

John McHutchison and colleagues presented results from a 36-week planned interim analysis of PROVE 3, which included 453 genotype 1 chronic hepatitis C patients who were null responders, partial responders, or relapsers following a previous course of treatment with interferon plus ribavirin.

Two-thirds of study participants were men, about 90% were white, and the median age was about 50 years. About 60% had HCV genotype 1a, 30% had 1b, and the rest were undetermined. About 25% had bridging fibrosis and about 15% had compensated cirrhosis. About 60% were prior non-responders (never achieved undetectable HCV RNA), about 30% were relapsers (undetectable HCV RNA at the end of treatment but relapsed during follow-up and did not achieve SVR), and the remainder experienced virological breakthrough while still on therapy.

Participants were randomly assigned to receive 1 of the following regimens:

    • 750 mg telaprevir every 8 hours + 180 mcg/week Pegasys + 1000-1200 mg/day ribavirin for 12 weeks, followed by Pegasys + ribavirin without telaprevir for 12 additional weeks (T12/PR24);

    • All 3 drugs at the same doses for 24 weeks, followed by Pegasys + ribavirin alone for 24 additional weeks (T24/PR48).

    • Telaprevir + Pegasys without ribavirin for 24 weeks (T24/P24);

    • Standard therapy with Pegasys + ribavirin for 48 weeks (+ telaprevir placebo for the first 24 weeks) (PR48).

HCV RNA was measured at week 4 (rapid virological response, or RVR), week 12 (early virological response, or EVR), end of treatment (EOT), and 12 months after completion of therapy for the 2 groups treated for 24 weeks (SVR12; standard sustained virological response is ascertained 24 weeks after competing treatment.) Stopping rules required patients to discontinue treatment if they did not achieve a response by week 4 or 12, or if they experienced viral breakthrough.

Results

    • In an intent-to-treat analysis at week 4, no patients in the PR48 arm, 61% in the T12/PR24 arm, 47% in the T24/P24 (no ribavirin) arm, and 50% in the T24/PR48 arm achieved undetectable HCV RNA.

    • At week 12, the corresponding percentages were 8%, 75%, 53%, and 66%.

    • At week 24, the percentages were 33%, 70%, 48%, and 56%, respectively.

    • In the 2 groups whose treatment ended at 24 weeks, SVR12 rates were 52% in the T12/PR24 arm and 21% in the T24/P24 arm:

        • 41% vs 11% for prior non-responders;
        • 73% vs 46% for prior relapsers;
        • 44% vs 20% for those with prior viral breakthrough.

    • In the longer treatment groups, 30% in the PR48 arm and 46% in the T24/PR48 arm achieved undetectable HCV RNA at 36 weeks, but they were still receiving therapy.

    • In the telaprevir arms, viral breakthrough occurred more often in patients with genotype 1a compared with 1b.

    • A total of 224 patients discontinued therapy prior to week 24:

        • Due to stopping rules: 72% in the PR48 arm, 28% in the T12/PR24 arm, 50% in the T24/P24 arm, and 49% in the T24/PR48 arm;

        • Due to adverse events (AEs): 4%, 7%, 8%, and 22%, respectively.

    • Gastrointestinal symptoms were significantly more frequent in the telaprevir arms.

Based on these findings, the investigators stated, "In a population of patients who have failed previous [pegylated interferon/ribavirin] treatment, response rates 12 weeks after end of treatment were 52% overall in the T12/PR 24 arm: 73% in prior relapsers, 41% in prior non-responders."

AEs reported more frequently in the tipranavir arms compared with the standard therapy arm were gastrointestinal symptoms, headache, anemia, and skin symptoms (rash and pruritis, or itching).

"Other AEs were similar in type and frequency to those seen with [pegylated interferon/ribavirin]," they noted. Treatment discontinuation rates at week 36 were 16% in the telaprevir arms and 4% in the standard therapy arm.

"Data from Phase 2 telaprevir clinical studies in genotype 1 HCV patients are encouraging as responses were seen in treatment-naive patients, as well as in those who had previously failed treatment with the current standard of care regimen," McHutchison stated in a press release issued by Vertex. "PROVE 3 data showed that a telaprevir regimen produced a 52% SVR12 in treatment-failure subjects, which is noteworthy as patients who have failed therapy are very difficult to manage due to limited available treatment options and are at greater risk for developing progressive liver disease."

PROVE 3 is ongoing, and will report SVR outcomes for patients in the 48-week treatment arms at a later date.

Duke Clinical Research Institute, Durham, NC; McGuire DVAMC, Fairfax, VA; University of California, San Francisco, CA; Medizinische Hochschule Hannover, Hannover, Germany; St Louis University, St Louis, MO; Weill Medical College of Cornell University, New York, NY; Beth Israel Deaconess Medical Center, Boston, MA; University of Toronto, Toronto, Ontario, Canada; Saarland University Hospital, Homburg/Saar, Germany; University of Amsterdam, Amsterdam, Netherlands; Vertex Pharmaceuticals, Inc., Cambridge, MA.

Telaprevir in Black and Latino Patients

Numerous studies have shown that African-American and Latino patients have lower SVR rates than white when using interferon-based therapy, but it remains to be determined whether this is also the case with STAT-C agents.

In the PROVE 1 trial, treatment-naive genotype 1 patients were randomized to receive telaprevir for 12 weeks + Pegasys for either 12, 24, or 48 weeks, or else standard therapy with Pegasys + ribavirin for 48 weeks. Out of 250 total participants, nearly 75% were white and about 10% each were black and Latino.

Viral decline at 1 week was significantly different in the white and African-American subgroups receiving Pegasys/ribavirin standard therapy, but not in the groups that added telaprevir. SVR rates in patients receiving telaprevir appeared higher compared with standard therapy across all racial/ethnic groups:

    • 62% vs 41% for whites;

    • 44% vs 11% for African-Americans;

    • 65% vs 33% for Latinos.

"This sub-analysis suggests that telaprevir-based regimens enhance early viral responses and subsequently lead to improved viral responses in African-Americans, Latinos, and Caucasians," the researchers concluded. "Given the burden of disease among African-Americans and Latinos, it is imperative these results be confirmed in larger phase 3 clinical trials."

Duke Clinical Research Institute, Duke University, Durham, NC; Alamo Medical Research, San Antonio, TX; Henry Ford Hospital, Detroit, MI; Weill Medical College of Cornell University, New York, NY; Vertex Pharmaceuticals, Boston, MA; Fundacion de Investigacion de Diego, Ponce School of Medicine, San Juan, Puerto Rico.

Twice-daily Dosing

Finally, the open-label Study C208 is assessing the efficacy and safety of telaprevir at a dose of 1125 twice-daily (every 12 hours) versus the three-times-daily (every 8 hours) dose used in the PROVE trials. Telaprevir at each dose level was combined with either Pegasys or pegylated interferon alfa-2b (Pegintron) + ribavirin

    • In an interim analysis of data from 161 treatment-naive genotype 1 chronic hepatitis C patients, the following percentages achieved undetectable HCV RNA:

        • Telaprevir every 8 hours + Pegasys/ribavirin: 80% at week 4, 93% at week 12;

        Telaprevir every 8 hours + PegIntron/ribavirin: 69% and 93%, respectively;

        Telaprevir every 12 hours + Pegasys/ribavirin: 83% and 83%, respectively;

        Telaprevir every 12 hours + PegIntron/ribavirin: 67% and 85%, respectively.

    • Treatment discontinuation rates were 10%, 5%, 10%, and 8%, respectively, in the 4 study arms.

    • 3%, 7%, 5%, and 8%, respectively, experienced virologic breakthrough.

In the context of the two currently available standard-of-care regimens," the researchers concluded, "telaprevir 750 mg [every 8 hours] or 1125 mg [every 12 hours] in combination with [pegylated interferon/ribavirin] yielded high rates of virological response and low viral breakthrough at week 4."

Liver Unit, University of Barcelona, Barcelona, Spain; Hôpital Beaujon, Clichy, France; Klinikum der Universität zu Köln, Köln, Germany; Medical University of Vienna, Vienna, Austria; University Hospital Gasthuisberg, Leuven, Belgium; Clinic of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy; Radboud University Nijmegen Medical Center, Nijmegen, Netherlands; Tibotec BVBA, Mechelen, Belgium; Tibotec Inc., Yardley, PA.

11/11/08

References

S.. Zeuzem, C Hezode, P Ferenci, and others. Telaprevir in Combination with Peginterferon-Alfa-2a with or without Ribavirin in the Treatment of Chronic Hepatitis C: Final Results of the PROVE2 Study. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 243.

JG McHutchison, ML Shiffman, N Terrault, and others. A Phase 2b Study of Telaprevir with Peginterferon-Alfa-2a and Ribavirin in Hepatitis C Genotype 1 Null and Partial Responders and Relapsers Following a Prior Course of Peginterferon-Alfa-2a/b and Ribavirin Therapy: PROVE3 Interim Results. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 269.

AJ Muir, EJ Lawitz, JG McHutchison, and others. 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-Naïve Genotype 1-infected Subjects with Hepatitis C. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1846.

X Forns, P Marcellin, T Goeser, and others. Phase 2 Study of Telaprevir Administered q8h or q12h with Peginterferon-Alfa-2a or -Alfa-2b and Ribavirin in Treatment-Naïve Subjects with Genotype 1 Hepatitis C: Week 4 Interim Results. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1854.

Other source
Vertex Pharmaceuticals. New Clinical Data Support Broad Profile for Telaprevir in Patients with Genotype 1 Hepatitis C Virus (HCV) Infection. Press release. November 2, 2008.

liver411

Experimental HCV Protease Inhibitor TMC435350 Demonstrates Favorable Safety and Efficacy in Phase 2a Trial

By Liz Highleyman

Given the suboptimal efficacy and side effects of interferon-based therapy for chronic hepatitis C virus (HCV) infection, investigators have explored several small molecule agents -- collectively designated "STAT-C" -- that directly target various steps of the viral lifecycle.

One such candidate is TMC435350 (or simply TMC435), an HCV NS3/4A protease inhibitor being developed by Tibotec and Medivir. Data from a Phase 2a clinical trial of TMC435 were presented last week at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) in San Francisco.

In the ongoing double-blind, proof-of-concept OPERA-1 trial, investigators from 5 European countries are assessing the pharmacokinetics (PK), antiviral activity, and safety of TMC435 in genotype 1 treatment-naive chronic hepatitis C patients.

Study participants were randomly assigned to receive either:

    • TMC435 or placebo once-daily for 7 days, followed by TMC435 or placebo + standard of care treatment with 180 mcg/week pegylated interferon alpha-2a (Pegasys) + 1000-12000 mg/day ribavirin for 21 days;

    • TMC435 or placebo + Pegasys + ribavirin for 28 days.

Thereafter, all participants continued on Pegasys + ribavirin for an additional 20 or 44 weeks (24 or 48 weeks total). Results from 50 patients in Cohort 1, who received 25 or 75 mg TMC435 versus placebo, were reported at AASLD. About two-thirds were men and almost all were white.

Results

    • At doses of 25 mg and 75 mg once-daily, TMC435 demonstrated dose-dependent antiviral activity, both alone and in combination with Pegasys/ribavirin.

    • Using the 25 mg dose, mean reductions in HCV RNA at day 7 were 2.63 log10 IU/mL with TMC435 monotherapy and 3.47 log10 IU/mL with triple therapy.

    • Using the 75 mg dose, the corresponding reductions were 3.43 and 4.55 log10 IU/mL, respectively.

    • In the 25 mg 4-week triple therapy arm, 3 of 9 patients achieved undetectable HCV RNA (< 10 IU/mL) at day 28 -- for a rapid virological response (RVR) rate of 33% -- while 3 more achieved HCV RNA < 25 IU/mL.

    • In the 75 mg 4-week triple therapy arm, 8 of 9 participants achieved HCV RNA < 10 IU/mL at day 28 -- for a RVR rate of 89% -- while the remaining patient achieved HCV RNA < 25 IU/mL.

    • No serious or severe adverse events related to TMC435 were observed.

    • No patients discontinued treatment for safety-related reasons, and there were no dose-related adverse safety findings.

    • The most common adverse events considered to be associated with TMC435 were nausea, diarrhea, and headache.

    • There were no clinically relevant mean changes in laboratory parameters, ECGs, or vital signs.

Based on these findings, the researchers concluded that "In Cohort 1 of the OPERA-1 study, 25 mg and 75 mg TMC435 administered once-daily in combination with standard of care ([Pegasys/ribavirin]) demonstrated dose-dependent potent antiviral activity and a favorable safety and tolerability profile up to 28 days of dosing in treatment-naive, chronic hepatitis C patients with genotype 1."

"These data demonstrate the potent antiviral activity of TMC435350 against genotype-1 HCV," stated Medivir CEO and President Lars Adlersson in a press release issued by the company. "Based on these clinical and non-clinical studies, we are confident that TMC435350 has the potential to become a valuable addition to available therapy, providing an efficacious treatment with once-daily dosing."

In related presentations, investigators reported that TMC435 had favorable pharmacokinetic parameters (abstract 1895) and was a potent inhibitor of NS3/4A proteins from HCV genotypes 1 through 6 (abstract 1912).

The OPERA-1 study is ongoing, and is currently assessing a higher dose of TMC435 (200 mg once-daily) in Cohort 2. The trial is also recruiting treatment-experienced patients who have not responded to or have relapsed after a previous course of pegylated interferon + ribavirin.

Medizinische Hochschule , Hannover, Germany; Amsterdam Medical Center, Amsterdam, Netherlands; Erasme Hospital, Université Libre de Bruxelles, Bruxelles, Belgium; Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany; Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France; Saint-Luc Université Catholique de Louvain, Leuven, Belgium; Royal Free Hospital, London, UK; Medical University of Bialystok, Bialystok, Poland; Tibotec BVBA, Mechelen, Belgium.

11/11/08

References

MP Manns, HW Reesink, C Moreno, and others. Safety and antiviral activity of TMC435350 in treatment-naïve genotype 1 HCV-infected patients. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract LB8.

GA van 't Klooster, I Vanwelkenhuysen, R Verloes, and others. Pharmacokinetics of once-daily regimens of the novel HCV NS3/4A-protease inhibitor TMC435350, with and without pegIFN and ribavirin, in HCV-infected individuals. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1895.

T Lin, B Devogelaere, O Lenz, and others. Inhibitory activity of TMC435350 on HCV NS3/4A proteases from genotypes 1 to 6. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1912.

Other source
Tibotec. Tibotec Presents Interim Findings for TMC435, an Investigational Genotype 1 Hepatitis C Treatment, at the AASLD Liver Meeting 2008. Press release. November 3, 2008.

liver411

HCV Polymerase Inhibitor PF-00868554 Inhibits Viral Replication in Treatment-naive Patients

By Liz Highleyman

Given the limitations of interferon-based therapy for chronic hepatitis C virus (HCV) infection -- especially in patients with hard-to-treat HCV genotype 1 -- investigators have explored several small molecule agents, collectively called "STAT-C," that directly target various steps of the viral lifecycle.

Two posters at the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) last week in San Francisco presented data from a study of PF-00868554, a novel non-nucleoside HCV polymerase inhibitor being developed by Pfizer.

Preclinical studies showed that PF-00868554 inhibits genotype 1a and 1b HCV replicons in vitro, and its safety and tolerability were demonstrated in healthy volunteers receiving up to 300 mg 3-times-daily for 14 days (abstract 1898).

In a double-blind study, investigators then evaluated the safety, tolerability, pharmacokinetics, and antiviral activity of PF-00868554 in 32 treatment-naive patients with genotype 1 chronic hepatitis C (abstract LB11). Most participants (84%) were men, almost all (97%) were white, and the mean age was about 45 years.

Four cohorts of 8 patients each were randomly assigned to receive oral PF-00868554 at doses of 100, 300, or 450 mg twice-daily or 300 mg 3-times-daily, or else placebo, for 8 days.

Results

    • All 32 randomized participants completed the study.

    • The half life of PF-00868554 ranged from 10 to 12 hours for all dose arms.

    • All doses resulted in plasma concentrations that exceeded the median protein binding adjusted in vitro 50% effective concentration (EC50) for genotype 1 HCV.

    • HCV RNA decreased rapidly during the first 48 hours of PF-00868554 administration.

    • Mean maximum reductions in HCV RNA were 0.97 log10 in the PF-00868554 100 mg twice-daily arm, 1.84 log10 in the 300 mg twice-daily arm, 1.73 log10 in the 450 mg twice-daily arm, and 2.13 log10 in the 300 mg 3-times-daily arm, compared with 0.27 log10 in the placebo group.

    • 4 of 6 patients (66%) in the 300 mg 3-times-daily group achieved > 2.0 log10 maximum reduction in HCV RNA, compared with 33% in the 450 mg twice-daily arm, 17% in the 300 mg twice-daily arm, and none in the 100 mg twice-daily or placebo arms.

    • Following the first phase of viral suppression, most patients experienced a plateau or rebound in HCV RNA.

    • However, 1 patient in the 300 mg twice-daily group and 3 in the 300 mg 3-times-daily arm maintained viral suppression through the completion of dosing on day 8.

    • Mean reductions in HCV viral load at the end of PF-00868554 treatment on day 8 were 0.68, 1.26, 1.21, and 1.95 log10, respectively, in the 4 dose groups, versus 0.08 in the placebo group.

    • One subject in the 450 mg twice-daily cohort experienced < 0.5 log10 reduction in HCV RNA; sequence analysis of the HCV NS5B gene at baseline identified an R422K mutation, which could potentially reduce susceptibility to PF-00868554.

    • All doses of PF-00868554 were well-tolerated.

    • The most frequently reported adverse events (AEs) -- all mild or moderate in severity -- were headache, flatulence, and fatigue.

    • No dose-limiting AEs, serious AEs, grade 3 or 4 laboratory abnormalities, withdrawals due to AEs, or deaths were reported.

"Results from this study indicate that PF-00868554 was safe and well tolerated at all dose levels," the investigators concluded. "PF-00868554 potently inhibited viral replication in HCV-infected, treatment naive subjects, with mean maximum reductions in HCV RNA ranging from -0.97 to -2.13."

"Results from the present study support the further evaluation of PF-00868554," they added, noting that a study investigating PF-00868554 in combination with pegylated interferon alpha-2a (Pegasys) and ribavirin in treatment naive subjects is currently underway.

Infectious Diseases, Pfizer Global Research and Development, New London, CT; Charité Research Organisation, Berlin, Germany; Clinical Pharmacology, Parexel International, Berlin, Germany; Pfizer Clinical Research Unit, Pfizer Global Research and Development, Erasme, Belgium. Pfizer Global Research and Development, New London, CT.

11/11/08

References

JL Hammond, VS Purohit, J Fang, and others. Safety, Tolerability and Pharmacokinetics of the HCV Polymerase Inhibitor PF-00868554 Following Multiple Dose Administration in Healthy Volunteers. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1898.

JL Hammond, MC Rosario, F Wagner, and others. Antiviral Activity of the HCV Polymerase Inhibitor PF-00868554 Administered as Monotherapy in HCV Genotype 1 Infected Subjects. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract LB11.