Hepatitis C Support Group

HCV Advocate

Focus on AASLD 2007:
Drugs in Development
By Alan Franciscus
Editor-in-Chief, HCV Advocate
Having just returned from the American Association for the Study of Liver Diseases (AASLD) conference I was struck by how much information was released about new drugs in development to treat hepatitis C. This is a very hopeful and exciting era in the HCV drug development process. This article is a brief overview of the data about experimental HCV therapies that was released at the recent AASLD conference. More detailed information about some of these drugs will be available in the December issue of the HCV Advocate newsletter.
Telaprevir
The HCV protease inhibitor that is furthest along in development is telaprevir (VX-950). At this year’s AASLD conference a couple of posters and presentations were released. The most exciting was the results from two Phase II studies (PROVE 1 and PROVE 2). The PROVE studies included HCV genotype 1 patients who had not been previously treated (treatment naïve). The results listed here are for HCV treatment naïve patients (people who have never been treated with HCV medicines) for the arm(s) that included treatment for 24 week with the combination of telaprevir, pegylated interferon and ribavirin.
? PROVE 1: Of 79 patients in one arm, 61% achieved a sustained virological response (SVR-24 week post treatment).
? PROVE 2: Of 81 patients in one arm, 65% achieved a response (interim results 12 weeks post treatment).
Side effects that required treatment discontinuation were higher in the telaprevir triple arms compared to the pegylated interferon plus ribavirin arm (control arm) in both PROVE 1 and PROVE 2 (10-13%, vs. 2% respectively).
Dose: Telaprevir (pill) taken every 8 hours, pegylated interferon (Pegays) injected once a week, and weight-based ribavirin (pill, 1000/1200 mg/day).
R1626
Below are the phase 2a study results of HCV polymerase inhibitor R1626 from the POLI 1 study, which included 104 patients randomized into 4 different treatment arms:
1. 21 patients received 1500 mg R1626 bid (twice daily) plus pegylated interferon*,

2. 32 patients received 3000 mg R1626 bid plus pegylated interferon*,
3. 31 patients received 1500 mg R1626 bid in combination with pegylated interferon plus ribavirin*, and

4. 20 patient in the control arm (pegylated interferon plus ribavirin*)
*Pegasys and/or Copegus
In the study it was found that up to 81% of the patients treated in arm 3 were HCV RNA negative by week 4. The mean viral load reduction was 5.2 log 10 IU/mL and 50% of the patients ALT levels normalized. The side effects were considered mild to moderate with the most serious adverse events being Grade 4 neutropenia (low white blood cells), which was the major reason for dose reductions and treatment discontinuations. The good news is that in studies to date, R1626 has a low drug resistance profile that coupled with its good antiviral properties makes it a good candidate for advancement into larger trials. However, there are concerns over incidents of neturopenia. Hopefully, future studies will find a dose that is as effective, but that has a lower side effect profile.
Bavituximab
Bavituximab is a new class of anti-phosphotidylserine monoclonal antibody immunotherapeutics that is being investigated as a treatment for hepatitis C. In the study results presented at AASLD 24 patients received buvituximab twice daily in escalating doses based on body weight for two weeks and the patients were followed another two weeks. It was found that the HCV RNA viral load reductions were in the moderate range of .5 log10 . Bavituximab was found to be generally safe and well-tolerated with no dose limiting toxicities or serious side effects reported. Peregrine recently announced that it will begin studies of buvituximab in people coninfected with HIV and hepatitis C. Given the modest HCV RNA (viral load) reductions it will be interesting to see how Peregrine proceeds with development of this drug for hepatitis C.
GS 9190
Results from two parts of a phase I study of GS 9190, a HCV polymerase inhibitor, were released. In the first part of the study 31 patients treated with single escalating doses (40 milligrams to 480 mg) of GS9190 and compared to placebo found that it showed antiviral activity against HCV. Part of the study group took 120 mg and 240 mg with and without food to test the effects of food on drug absorption. The second part of the study was with 23 patients who received various doses twice daily. In both studies GS 9190 was generally well-tolerated, but in the second part of the study there was some safety data about potential heart problems. Due to these concerns, Gilead has initiated a new study to look more closely at the possible cardiac problems found (irregular heart rhythms). All other side effects were mild. If the issues around the cardiac problem can be resolved Gilead is expected to advance GS 9190 into larger studies.
VCH-759
Below is the data from a 10 day phase I study of VCH-759, a HCV polymerase inhibitor, given as a monotherapy to 32 treatment naïve HCV patients (31 HCV genotype 1 a/b and 1 HCV genotype 6). Please note that the efficacy results of HCV genotype 6 patient were not included in the analyses, but were included in the safety data.
The study included three arms:
1. 11 patients: 8 patients received 400 mg tid (three times a day ) VCH-759, 3 patients received placebo

2. 8 patients: 5 patients received 800 mg twice a day (bid) VCH-759, 3 received placebo

3. 12 patients: 9 received 800 mg tid VCH-759, 3 received placebo
The results found that all of the study participants who received VCH-759 achieved more than a 1 log10 decrease in HCV RNA. In the 800 mg tid group the highest log drop was 2.5 log10. The drug was generally well tolerated. The study is ongoing to determine if there are mutations once the drug was stopped.
TMC435350
Results from a phase I placebo-controlled study in healthy volunteers (without HCV) of the safety and tolerability of TMC434350 a HCV protease inhibitor was released. In this study 2 groups of study participants (6 receiving TMC435350, 3 receiving placebo) were given single doses up to 600 mg daily, and 5 days of oral doses up to 400 mg once-daily. The drug was found to be generally well-tolerated and safe. The good news is that the pharmacokinetic profile supports a once-day dosing.
R7128
A 14 day phase I monotherapy study of R7128, an HCV polymerase inhibitor, found that R7128 was generally well-tolerated with no safety concerns in the 4 groups ( in each group 8 patients received R7128; 2 patients recieved placebo). It was very encouraging that in this small study there was greater than a 99% mean decrease or reduction in HCV RNA and that the pharmacokinetic profile suggests that twice a day dosing was more effective than every 8 hours. Future studies will include R7128 in combination with pegylated interferon and ribavirin.
Albuferon
Final results from a phase 2b study of Albuferon in combination with ribavirin were released. In the trial 458 HCV treatment naïve patients were treated with Albuferon (900 mcg every two weks, 1200 mcg every two weeks, or 1200 mcg every 3 weeks) or pegylated interferon (Pegasys) once a week. All patients received weight-based ribavirin daily. The results by study are are below:
? 900 mcg Albuferon group: 58.5% in the Albuferon group achieved an SVR compared to 57.9% in the Pegasys group. The rate of discontinuation due to adverse events was 9.3% in the Albuferon group compared to 6.1% in the Pegasys group.

? 1200 mcg Albuferon group: 55.5% in the Albuferon group achieved an SVR compared to 57.9% in the Pegasys group. The rate of discontinuations due to adverse events was 18.2% in the Albuferon group compared to 6.1% in the Pegasys group.

? 1200 mcg Albuferon group: 50.9% achieved an SVR in the Albuferon group compared to 57.9% in the Pegasys group. The rate of discontinuation due to adverse events was 12.1% in the albuferon group compared to 6.1% in the Pegasys group.

Larger phase III studies of Albuferon/ribavirin have completed enrollment and Human Genome Sciences commented that they expect to file an application for FDA marketing approval by 2009.
Nitazoxanide
One of the most interesting studies released at AASLD was a small study that was conducted in Egypt using nitazoxanide (Alinia) to treat hepatitis C. Nitazoxanide is a medicine approved by the FDA for the treatment of diarrhea caused by Cryptosporidium and Giardia. In this study, 96 treatment naïve HCV genotype 4 patients were randomized into three groups:
1. 40 patients who received pegylated interferon plus ribavirin (control arm) for 48 weeks.

2. 28 patients who received nitazoxanide for 12 weeks followed by 36 weeks of nitazoxanide plus pegylated interferon (dual therapy),

3. 28 patients who received nitazoxanide followed by 36 weeks of nitazoxanide plus pegylated interferon plus ribavirin (triple therapy),
An additional 24 HCV patients who had previously received interferon treatment were randomized: 12 weeks of nitazoxanide followed by either the dual regimen (12 patients) or the triple therapy (12 patients).
Note: nitazoxanide was given as one 500 mg pill twice daily; pegylated interferon was given as an 180 mcg injection once a week, and ribavirin was weight based 1000/12000 mg daily.
At 12 weeks post treatment it was found that 79% of patients in the triple therapy group achieved an SVR compared to 43% who achieved an SVR in the group receiving the combination of pegylated interferon plus ribavirin. In the group of previously treated patients the SVR was 25% in the group who received the triple therapy compared to 8 percent in the group who received the dual therapy. The speaker commented that the mechanism of action is not really understood and that larger studies are needed to confirm these findings and to understand the mechanism of action. These results are almost too good to be true, but hopefully the results from this study can be replicated in a well designed study with a larger patient population of people with HCV genotype 1.


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Posted on 04/01/08, 03:04 pm