Good News for Non-Responders to HCV Combination Therapy

HCV Drug Pipeline - Updated June 11, 2008

EASL 2008
Alan Franciscus, Editor-in-Chief

This year’s EASL (European Association for the Study of Liver Disease) conference was held in Milan, Italy.  EASL is becoming one of the premiere liver disease conferences and is comparable in its scope and importance to the AASLD (American Association for the Study of Liver Disease) Conference held in the United States.  This article will review the data presented on HCV drugs being developed to treat hepatitis C.  

Telaprevir is an HCV protease inhibitor that is being developed by Vertex. It is currently the furthest along in clinical development among the new antivirals.  Of note, it was recently announced that the phase 3 clinical trial had enrolled the first patients.  At EASL two key phase II study results were presented: final results from the PROVE1, and SVR12 data from the PROVE2 trials, as well as preliminary data from Study 107 – a study that is investigating the treatment of prior non-responders, null responders and relapsers from the PROVE1, 2 and 3 clinical trials.

PROVE1
The final results of the PROVE1 trial were presented at EASL.  In this trial there were 250 genotype 1 treatment-naïve patients.  The patients were divided into 4 treatment arms and the patient characteristics were fairly balanced between the arms.  A description of the treatment arms and the intent to treat (ITT) SVR rates are listed below.* 

Arm A:  75 patients treated with Pegasys plus ribavirin for 48 weeks (control arm).  SVR = 41%

Arm B:  79 patients treated with telaprevir plus Pegasys/ribavirin for 12 weeks, then treated for an additional 36 weeks with Pegasys plus ribavirin.  SVR = 67%

Arm C:  79 patients treated with telaprevir plus Pegasys/ribavirin for 12 weeks followed by an additional 12 weeks of treatment with Pegasys/ribavirin. SVR=61%

Arm D:  17 patients treated telaprevir plus Pegasys/ribavirin for 12 weeks – no further treatment. SVR=35%

*Medication doses: 
Telaprevir (750 mg or placebo) TID, Pegasys (180 ug injected once weekly), and ribavirin (dosed by body weight at either 1000 or 1200 mg a day).

Importantly, these results confirm early data that the optimal treatment duration is 24 weeks – the  relapse rate in the arms that included telaprevir was significantly lower (0-2%) in those who were HCV RNA negative at weeks 4 and 12.  

The most common types of serious side effects reported were skin rashes, gastrointestinal events, and anemia.  The incidents of overall serious side effects were higher in the telaprevir arms: 11% in the telaprevir groups compared to 5% in the group that received pegylated interferon and ribavirin only.  Treatment discontinuation rates through week 12 due to adverse events were higher in the telaprevir arms (18%) compared to those who did not receive telaprevir (4%).  The incidence of severe rash was 7% in the participants who received telaprevir. 

PROVE2
The PROVE2 study design is similar to that of PROVE1 and has enrolled 323 HCV genotype 1 treatment naïve patients.  The clinical trial is being conducted in Europe.  The trial also included an arm of telaprevir and Pegasys, but without ribavirin.  The interim results were similar to PROVE1 with 68% SVR12 in the arm that received 24 weeks of treatment.  Final results are expected later this year. 

Bottom Line

The final results from PROVE1 and the SVR12 results from PROVE2 have confirmed that 24 weeks of treatment produced comparable sustained virological response rates when the same treatment regime was given for 48 weeks. 

There have been some concerns raised about anemia, but the incidence of anemia was only slightly higher in the telaprevir arms and resolved after treatment was discontinued.  The severe rash is also another concern, but the rate of treatment discontinuation due to the rash was relatively low, and the rash also resolved after treatment was discontinued.

Study 107
The preliminary results from Study 107 on the retreatment of the people in the PROVE1, PROVE2, and PROVE3 control arms who did not receive telaprevir were included in this study.  Participants from the PROVE studies were eligible for Study 107 if they were either null responders, partial responders or relapsers.  Participants who discontinued treatment because of side effects were not eligible for Study 107.

The dosing of this study is as follows:

12 weeks of telaprevir (750 mg TID), Pegasys (180 ug-injected weekly) plus ribavirin (1000/1200 mg/day) followed by 12 weeks of  Pegasys plus ribavirin alone (24 week treatment duration)

Included in the study design was a stopping rule: if HCV RNA was higher than 25 IU/mL at weeks 4 and 12, the treatment was stopped.    

Interim Analysis

A total of 72 patients have received at least one dose of the study medicines.  Of these, 63 are currently on treatment – for this analysis there were 60 patients who completed 4 weeks of therapy, 36 patients who completed 8 weeks of therapy and 16 patients who completed 12 weeks of therapy.   The preliminary results found that at week 4, 83% achieved HCV RNA less than 25 IU/mL and that all the patients who continued treatment beyond week 4 maintained their viral responses by weeks 8 and 12.  The range of viral breakthrough was very low (3%), and those who developed viral breakthrough were identified early on.  Based on these positive treatment response rates, the protocol has been amended so that the relapsers and partial responders will receive 12 weeks of telaprevir in combination with 24 or 48 weeks of Pegasys plus ribavirin.  The patients who were previous non-responders will receive telaprevir, Pegasys and  ribavirin for 12 weeks followed by 48 weeks of Pegasys plus ribavirin therapy. 

The side effect profile was similar to what has been previously reported in telaprevir, Pegasys and ribavirin therapy.  Two patients discontinued treatment due to pleuritis/costochondritis (inflammation and pain in the lungs and chest), and a generalized rash.

Bottom Line

These results, although very preliminary, are encouraging because the early response rates are the highest yet seen in a population of HCV patients who are in the greatest need of treatment.  It is hoped that this positive trend of improved treatment outcomes will carry over to the PROVE3 study that is retreating HCV genotype 1 prior non-responders.  The PROVE3 study is a blinded study so no preliminary or interim results have been announced.  But stay tuned – the results from PROVE3 are expected mid-2008.  This study will give us a much better picture of the effectiveness of telaprevir, Pegasys, and ribavirin therapy in a non-responder group of genotype 1 patients.  It is definitely the ONE to watch.

Boceprevir

Boceprevir is an HCV protease inhibitor that is being developed by Schering Plough. Of note, on May 21, 2008 Schering announced the initiation of 2 phase III studies of boceprevir/PegIntron and ribavirin. Interim results from the SPRINT-1 study were released at EASL.  The study aim was to evaluate the most effective treatment strategy for HCV genotype 1 treatment-naïve patients.  The aims included determining the most optimal treatment duration (28 vs. 48 weeks), the dose of ribavirin (800-1300 mg/daily vs. 400-1000 mg/daily), whether treatment would benefit from a lead-in phase (PegIntron plus ribavirin) before beginning boceprevir (800 mg TID), or if the triple combination of boceprevir, PegIntron, and ribavirin from the beginning of therapy produced the best treatment results. The baseline characteristics were similar across the treatment arms except that more males were included in the PegIntron plus ribavirin control group than in the boceprevir arms. 

The SVR12 data from the two 28-week boceprevir arms was presented.  In the group that received the PegIntron plus ribavirin (lead-in phase), followed by the addition of boceprevir there was a 57% SVR12 compared to 55% of the group who received boceprevir, PegIntron and ribavirin (triple therapy) from the beginning of treatment.  In those patients who achieved a rapid virological response (HCV RNA negative after 4 weeks of treatment), the lead-in group, 86% achieved an SVR12 compared to 74% achieving an SVR12 in the group that received the triple therapy from the beginning. 

The side effect profile between the boceprevir and the PegIntron arms were similar except there was more anemia and dysgeusia (taste changes) in the boceprevir arm.  The discontinuation rates were higher in the boceprevir arms (11 and 15%) compared to the PegIntron plus ribavirin control arm (8%).   

The interim results suggest that a shorter duration of treatment (28 weeks total) that includes a lead-in phase with PegIntron plus ribavirin prior to the introduction of boceprevir produces higher treatment response rates and that a rapid virological response is a good predictor of treatment response.  

Bottom Line

These are also very encouraging early results.  The final results of all of the treatment arms will give us a much better idea of the effectiveness of boceprevir compared to PegIntron plus ribavirin therapy.  The good news about this study is that the design of the phase III study will include a lead-in phase and a shorter duration of treatment.

Boceprevir in Null Responders

The results from another study using boceprevir in combination with PegIntron plus ribavirin yielded less promising outcomes.  However, this trial was more about establishing the most effective dose of boceprevir, treatment duration, safety issues and if ribavirin was needed to maximize treatment response rates. 

In the study there were 357 genotype 1 patients enrolled who were deemed prior null responders – defined as either less than a 2 log10 drop in HCV RNA after 12 weeks of therapy with pegylated interferon/ribavirin therapy or who did not achieve undetectable HCV RNA if treated longer than 12 weeks.  There were 7 arms in this study – with or without different doses of boceprevir (100, 200, 400, 800 mg), and with and without ribavirin. This study had a lead-in phase using PegIntron alone.    

The authors found that boceprevir is safe and well-tolerated.  The overall intent-to-treat sustained virological response rates were 2% in the group that only received PegIntron plus ribavirin and up to 14% in the groups that received triple combination of PegIntron, ribavirin and boceprevir.  It was found that the most effective dose of boceprevir was 800 mg TID and that the use of ribavirin would be required to optimize treatment outcome.  The treatment duration would include an additional 24 weeks after HCV RNA became undetectable. 

Bottom Line

It is hard to draw any concrete conclusions because of the small patient population and the many different treatment arms.  The group of patients in this study are some of the most difficult to treat and most did not receive the most effective dose of boceprevir.  The newly announced phase 3 studies will hopefully answer the question of the role of boceprevir in the retreatment of prior non-responders. 

R1626

R1626 is a polymerase inhibitor that is being developed by Roche, and in previous studies it has been shown to have potent antiviral activity against hepatitis C.  Prior treatment data has suggested that there was a lack of viral resistance to R1626.  At the AASLD 2007 Conference 4-week data that was presented was very encouraging.  At EASL 2008 more information was released that included the end-of-treatment response rates (total treatment duration = 48 weeks) of the entire Phase 2 clinical trial. 

All study participants were HCV genotype 1 treatment-naïve.  A total of 104 patients were randomized into 4 treatment arms:

Arm A:  R1626 (1500 mg bid-twice a day) plus Pegasys for 4 weeks followed by Pegasys plus ribavirin for an additional 44 weeks. (21 patients)

Arm B:  R1626 (3000 mg bid) plus Pegasys for 4 weeks followed by Pegasys and ribavirin for an additional 44 weeks.  (32 patients)

Arm C:  R1626 (1500 mg bid) plus Pegasys and ribavirin for 4 weeks followed by Pegasys plus ribavirin for an additional 44 weeks. (31 patients)

Arm D:  Pegasys plus ribavirin for 48 weeks (control arm) (20 patients)

The patient characteristics were fairly well-matched except that arm A had a higher percentage of males (81%) compared to the other arms (41%, 39% and 40% respectively).  The fibrosis scores were fairly well-matched and all fell within the F0-F2 range. 

The highest end-of-treatment response rates were in Arm C – 84% which is slightly higher than the treatment response rates reported after 4 weeks of treatment.  There were 7 patients who initially were HCV RNA negative after the 4-week lead-in, but became HCV RNA positive (rebounded) during therapy.  In all of the patients who rebounded, they rebounded after R1626 was discontinued.  As reported with the 4-week data at AASLD 2007, there was no drug resistance to R1626 found in this study.  The safety profile was similar between the arms with the exception of grade 4 neutropenia and other lab abnormalities in the R1626 arms.  After treatment was discontinued all lab values returned to normal.  

Bottom LIne

Even though this is a small patient population, the lack of drug resistance and very high end-of-treatment response rates are very encouraging.  Due to the high incidence of grade 4 neutropenia during the period that R1626 was taken, Roche has launched a phase 2b dose ranging study to determine the most optimal dose of R1626 that has lower rates of lab abnormalities.         

R7128

R7128 is an HCV polymerase inhibitor that is being developed by Pharmasset and Roche.  At AASLD 2007 it was reported that R7128 alone for treatment of HCV genotype 1 treatment-naïve patients for 4 weeks achieved an average of 2.7 log10 decline in HCV RNA with a maximum decline of 4.2 log10.  It was also found that twice a day dosing was the most effective.

At EASL 2008, Pharmasset presented results from another trial of R7128 in combination with Pegasys and ribavirin for 4 weeks.  In this trial, 50 HCV genotype 1, treatment-naïve patients were enrolled.  The treatment arms* and the results after 4 weeks of treatment are listed below.   

Group A:  R7128 500 mg BID plus Pegasys and ribavirin (20 patients).  30% were HCV RNA negative; mean HCV RNA reduction was -3.82 log10.

Group B:  R7128 1500 mg BID plus Pegasys and ribavirin (20 patients).  85% HCV RNA negative; mean HCV RNA reduction was -5.12 log10

Group C:  Placebo plus Pegasys and ribavirin (10 patients) – control arm.  10% were HCV RNA negative; mean HCV RNA reduction was -2.95 log10

*After initial treatment of R7128 (at various doses) combined with Pegasys and  ribavirin for 4 weeks, trial participants were then treated for another 4 weeks with Pegasys plus ribavirin – then all the study participants were rolled over to receive an additional 40 weeks with Pegasys plus ribavirin (total duration of treatment was 48 weeks). 

The safety and tolerability was similar between the 3 arms including the arm that did not include R7128. 

Bottom Line

The data is very impressive, but more long-term data is needed before any conclusions can be drawn.  It was announced at EASL that Pharmasset will conduct new studies to evaluate R7128 at 1500 mg BID in HCV genotype 2 & 3 patients who did not achieve a sustained virological response to a previous course of interferon based therapy, as well as testing R7128 at 1000 mg BID.   

In a related development, on May 19, 2008 Pharmasset announced that a new compound designated as PSI-7851 will be advanced into animal toxicity studies and that Pharmasset will apply to the Food and Drug Administration for an Investigational New Drug (IND) designation.  PSI-7851 is an HCV polymerase inhibitor that has demonstrated in vitro (test tube) a potency that is about 15- to 20 fold greater than R7128.  

More New Drugs in Development

There was more news from EASL on drugs in early development including the following studies:

• VCH-916 is a HCV polymerase inhibitor being developed by ViroChem.  In a study of healthy volunteers who received up to a single dose of 600 mg, VCH-916 was found to be generally safe and well-tolerated and achieved plasma concentrations proportional to the dose given.  Based on these results a 14-day study of HCV genotype 1 treatment-naïve subjects is being planned. 

• TMC435350 is an HCV protease inhibitor being developed by Medivir and Tibotec. In the study there were 52 healthy volunteers and 6 patients with HCV.  Once a day dosing with TMC435350 at 200 mg was given to all study participants.  The drug was found to be safe and well-tolerated in both the healthy and the HCV-positive participants.  In the 6 patients with HCV genotype 1, TMC435350 was found to have strong and rapid antiviral activity with a median viral load reduction of -3.9 log10.  Further studies are being planned.

• Nitazoxanide is a broad spectrum antiviral that is being tested for the treatment of hepatitis C by Romark Laboratories.  In a previous study released at AASLD 2007, nitazoxanide used in combination with pegylated interferon and ribavirin for the treatment of HCV genotype 4 patients produced an SVR12 of 79% compared to 43% in the group that received pegylated interferon plus ribavirin but without nitazoxanide.  The prior study had a 12 week lead-in of nitazoxanide.  In this study a 4 week lead-in phase using nitazoxanide alone was studied.  The authors found that the SVR12 rates were similar between the different lead-in phases (80% for the 4-week lead-in vs. 79% for the 12-week).  This is one to keep track of since the potential for increased response rates by adding nitazoxanide to the current standard of care of pegylated interferon plus ribavirin is encouraging. 
http://www.hcvadvocate.org/news/newsLetter/2008/advocate0608.html#1