Alan Franciscus, Editor-in-Chief - HCV Advocate.
The 2007 American Association for the Study of Liver Diseases (AASLD) conference included data on a variety of new medications to treat hepatitis C. This is a very exciting era in the understanding of the hepatitis C virus and in the discovery of new medications that will be used in combination with pegylated interferon plus ribavirin to increase the effectiveness of treatment. This year I am concentrating on the data from three drugs in development that I believe provided the most important news stories from this year’s conference.
The top news story is about telaprevir (VX-950) followed by Albuferon and R1626. I am also providing my own analyses based on what I have learned while attending the poster sessions, oral presentations and discussing the results with various HCV advocates and medical providers.
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 were 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).
PROVE 1:
A total of 250 patients in the United States were enrolled in this Phase 2 study. The study participants were non-cirrhotic, treatment naïve genotype 1. The patient characteristics were well matched across the treatment arms.
The study participants were randomized into 4 different groups:
• Arm A: 75 patients treated with Pegasys plus ribavirin for 48 weeks (control arm).
• Arm B: 79 patients treated with telaprevir plus Pegasys/ribavirin for 12 weeks, then treated for an additional 36 weeks with Pegasys plus ribavirin.
• Arm C: 79 patients treated with telaprevir plus Pegasys/ribavirin for 12 weeks followed by an additional 12 weeks of treatment with Pegasys/ribavirin.
• Arm D: 17 patients treated with telaprevir plus Pegasys/ribavirin for 12 weeks – no further treatment.
Medication doses:
• Telaprevir (750 mg (pill) taken every 8 hours (or placebo pill)), Pegasys (180 ug injected once weekly), and ribavirin (dosed by body weight at either 1000 or 1200 mg a day).
Patients were followed for a total of 48 weeks. Undetectable HCV RNA was defined as < 10 IU/mL (Roche TaqMan HCV RNA assay). This is an intent-to-treat analysis (all patients who received at least one dose of the study drug).
Results
The sustained virological response (SVR) results for arms C and D were released at AASLD. The SVR results from arm A and B will not be available until 2008. But since all the patients have completed therapy, the side effect profile information on the entire patient population in this trial was released.
The SVR (24 weeks post treatment) was 61% in arm C compared to 35% in the arm D group. In arm C, 8 patients (10%) were lost to follow-up compared to 1 patient (6%) in arm D. Seventy nine percent of those people who had a rapid virological response (RVR – HCV undetectable 4 weeks after starting treatment) in the telaprevir treated groups went on to achieve an SVR.
The most frequent side effects (of all study participants) were rash and pruritus (itching), which were more common and severe in the telaprevir groups. Another frequent side effect was gastrointestinal related and was more common in the telaprevir groups. Thirteen percent of the telaprevir arms discontinued treatment due to side effects during the first 12 weeks compared to 3% in the control arm (arm A). Overall, the incidence of severe side effects was 27% in the telaprevir arm(s) compared to 24% the control arm (arm A).
PROVE 2:
In this study 323 HCV genotype 1 treatment-naïve non-cirrhotic patients in Europe were enrolled. The patients’ characteristics were well matched across the treatment arms.
The study participants were randomized into 4 different groups:
• Arm A: 82 patients received Pegasys plus ribavirin for 48 weeks (control arm)
• Arm B: 81 patients received telaprevir plus Pegasys/ribavirin for 12 weeks followed by another 12 weeks of Pegasys/ribavirin (24 week arm)
• Arm C: 82 patients received telaprevir plus Pegasys/ribavirin for 12 weeks (12 week arm)
• Arm D: 78 patients received telaprevir plus Pegasys for 12 weeks (no ribavirin arm)
Medication doses:
• Telaprevir (750 mg (pill) taken every 8 hours (or placebo pill)), Pegasys (180 ug injected once weekly), and ribavirin (dosed by body weight at either 1000 or 1200 mg a day). In this study the first dose of telaprevir was 1250 mg followed by the regular dosing above.
The patients were followed for 48 weeks. Undetectable HCV RNA was defined as < 10 IU/mL (Roche TaqMan HCV RNA assay). The analysis is intent to treat. The 36 week interim analysis of this trial was presented at AASLD. The results presented were response rates 12 weeks post treatment. The usual definition of SVR is when HCV RNA is undetectable 24 weeks post treatment. However, the definitions are changing with the newer therapies since it seems that the results seen at 12 weeks post treatment seem to be equal to the results seen week 24 post treatment. However, more data is needed to confirm this ‘newer’ definition.
Results
The SVR rates were 59% in arm C, and 29% in arm D. The SVR 12 week rates were 65% in arm B. There was also a low relapse rate in those who achieved RVR in the telaprevir groups.
The most common side effects were similar to the side effects reported in PROVE 1 – rash, pruritus (itching), gastrointestinal side effects and anemia. Discontinuation rates were 5% in the Control Arm compared to 10-15% in the telaprevir arms.
Probably the side effect that has received the most attention in both the PROVE 1 and 2 studies is the rash. In the presentation the rash was described as a maculopapular, which is a rash that is generally flat in appearance, reddish with papules (small raised bumps) and covers a large area of skin. The good news is that the rash resolved after treatment was stopped.
Bottom Line:
These results are very encouraging. The most important information that we have learned from these two studies (besides safety and tolerability) include:
• Duration of treatment with the triple combination therapy should be for 24 weeks. Unfortunately, the 12 week treatment group had a higher relapse rate.
• Ribavirin is a key to achieving an SVR in this and in every other study seen to date. It also confirms that ribavirin will be a part of the HCV drug cocktail until such time as there are multiple protease and polymerase medications available to replace it.
So what does all this mean? If these results can be confirmed in larger phase III studies (to begin in early 2008) the response rates will be increased by approximately ten percent from the current ~50% SVR rates to approximately 60%. At the same time treatment duration could be reduced from the current 48 weeks for genotype 1 to 24 weeks. This is really good news and the approval of triple therapy of telaprevir, pegylated interferon and ribavirin will be a major advancement in the treatment of hepatitis C. If there are no glitches or major problems in the phase III studies there is a very real possibility that the triple combination could be FDA approved by 2010-2011.
The results from another telaprevir study called the PROVE 3 study are eagerly awaited. In this study, prior HCV genotype 1 non-SVR responders to treatment with pegylated interferon plus ribavirin are being treated with a triple combination of telaprevir (or placebo), and Pegasys plus ribavirin. The study has completed enrollment and clinical trial results are expected in 2008. This is a really important study especially for those people who have not achieved an SVR and are waiting for new drugs that we all hope will increase the odds of successful treatment for this very large group of people who currently have limited treatment options.
Albuferon
The final phase II study results from two studies with albinterferon alfa-2b (Albuferon) were released at AASLD. In the first study presented, 458 HCV genotype 1 treatment-naive patients were randomized into 4 groups:
• Arm A: Albuferon 900 mcg injected every two weeks
• Arm B: Albuferon 1200 mcg every two weeks
• Arm C: Albuferon 1200 mcg every 4 weeks
• Arm D: Pegasys 180 mcg once a week (control arm)
All patients received weight based ribavirin daily. The treatment duration was 48 weeks and the primary end-point was sustained virological response defined as undetectable (<10 IU/mL) 24 weeks post treatment.
Results
In the intent-to-treat analysis the SVR rates reported were:
• Arm A – 58.5% SVR. The rate of discontinuations due to adverse events was 9.3%.
• Arm B – 55.5% SVR. The rate of treatment discontinuations due to adverse events was 18.2%.
• Arm C – 50.9% SVR. The rate of treatment discontinuations due to adverse events was 12.1%.
• Arm D – 57.9% SVR. The rate of treatment discontinuations due to adverse events was 6.1%
In the second study, 115 prior interferon treatment non-responders were treated with various doses of albuferon plus ribavirin for 48 or 72 weeks of treatment. Unfortunately, the SVR rates were not encouraging for any of the treatment arms (1200 mcg once every 4 weeks, 900 mcg once every 2 weeks, 1200 mcg once every 2 weeks, 1500 mcg once every 2 weeks and 1800 once every 2 weeks) plus weight based ribavirin – overall SVR was 17.4%. This is not surprising since this group of people typically have very low treatment response rates.
Bottom line:
The larger phase III studies will give a better picture of the effectiveness and side effect profile of Albuferon. However, it seems that Albuferon’s effectiveness is comparable to pegylated interferon, at least in this study. A couple of big questions remain to be answered – is the convenience of dosing every two weeks vs. once a week dosing enough of an improvement over current therapy? And is the side effect profile of Albuferon better than pegylated interferon? In a company press release a sub-analysis of the data was done that found that there may be a lower side effect profile with Albuferon and that heavier patients may respond better to Albuferon than to pegylated interferon. But there are a couple of problems with coming to these conclusions. The first problem is that reporting side effects is subjective – one person’s idea or experience of a lower quality of life or side effects differs from what another person’s experience especially if you consider the small population of 115 patients. The second problem is that it is difficult to come to a conclusion that Albuferon works better in heavier patients because again the number of study participants was relatively small. To help answer the question of the effectiveness of Albuferon in heavier patients, Novartis (Human Genome Science’s drug development partner) announced that they are planning a phase 2b study that will hopefully shed more light on this issue. Novartis expects to begin enrollment by the end of 2007.
According to Human Genome Science (HGS) the enrollment in their phase III studies has been completed and results are expected by spring 2009. In the same press release HGS stated that they expect to file for FDA marketing approval in 2010. If there are no glitches in the clinical trials or application process Albuferon could be available to patients by 2011.
R1626
Another new HCV medication that has generated a lot of excitement is R1626. R1626 is an HCV polymerase inhibitor. The results from the POLI.1 study were released at AASLD. In this study 100 HCV genotype 1 treatment-naïve (non-cirrhotic) patients were randomized into 4 different treatment arms:
• Arm A: 20 patients received 1500 mg R1626 bid (twice daily) plus Pegasys,
• Arm B: 30 patients received 3000 mg R1626 bid plus Pegasys,
• Arm C: 30 patients received 1500 mg R1626 bid in combination with Pegasys/ribavirin (triple combination),
• Arm D: 20 patients were treated with Pegasys/ribavirin (control arm)
Ribavirin was weight based (1000/1200 mg/day) and Pegasys by injection once a week.
In arms A, B, and C study participants received R1626 for 4 weeks followed by Pegasys/ ribavirin for an additional 42 weeks. The participants in the control arm were treated for 48 weeks. HCV RNA undetectable was defined as <15 IU/mL with Roche COBAS TaqMan HCV Test.
After 4 weeks of treatment the percentage of people who were undetectable was 33% (arm A), 69% (arm B), and 81% (arm C) compared to 5% in the control group (arm D). Fifty percent of the patients in the R1626 arms achieved normalization of ALT levels.
There were 8 patients who had viral rebound (viral load went from undetectable to detectable), but these were only in people who had stopped taking R1626. In all of the people who took R1626 none developed drug resistant mutations.
The side effects were considered mild to moderate with the most serious adverse event being Grade 4 neutropenia (low white blood cells), which was the major reason for dose reductions and treatment discontinuations. The degree of neutropenia was not associated with infection and the neutrophil counts rebounded significantly after stopping R1626.
Bottom line:
R1626 does not appear to produce drug resistance and when used in combination with Pegasys and ribavirin the viral load reductions are very impressive. The combination of these factors makes it a very good candidate for advancement into larger clinical trials. However, the side effect profile is a cause for concern, especially the incidence of neutropenia. In response to these concerns, Roche announced that it is conducting another phase 2b study of R1626 in 490 patients to test different doses of R1626 (500, 1000 and 1500 mg bid), and Pegasys (90 ug and 180 ug) plus standard ribavirin dosing to find the best dose(s) that will produce the highest response rates, but that will also minimize the side effect profile.
In next month’s HCV Advocate I will continue this report on the data on new drugs that was presented at AASLD 2007.
