Hepatitis C for Fools II: The Other Protease Inhibitors
Last week, to the great ennui of the CAPS community, I began a new blog series to address the underlying science behind baby biotech. I kicked things off with the fascinating subject of hepatitis C and the protease inhibitor telaprevir, being developed by Vertex. To develop the subject of protease inhibitors further I'll discuss the laggards in the field, Merck’s boceprevir and Intermune’s ITMN-191.
As I described previously, the current standard of care in hepatitis C is PEGylated interferon alpha + ribavirin. This combination treatment yields SVR of 40% for genotype 1 and 82% for genotype 2/3. Phase II data indicates that adding telaprevir to the regimen increases SVR to as much as 70% for genotype 1, and phase III data will be released in a few months.
Merck inherited boceprevir via their merger with Schering-Plough which closed in 11/09. Since the Schering-Plough website is no more and Merck doesn't provide much in the way of clinical trial data on theirs, collecting data on boceprevir is quite work-intensive.
SPRINT-1 - final results 4/09. Phase II boceprevir in 595 treatment-naive genotype 1. Groups received 28 or 44 weeks of boceprevir after 4 weeks of PR (lead-in) or at the beginning of treatment, and a control group received 48 weeks of PR. SVR's were 75% for 44 weeks with lead-in, 56% for 28 weeks with lead-in, 67% for 44weeks without lead-in, 54% for 28 weeks without lead-in, and 38% for PR control. Another treatment arm with low dose ribavirin had poor results. In the lead-in groups, null responders after 4 weeks had a 55% SVR with 44 weeks boceprevir and a 25% SVR after 28 weeks boceprevir. Treatment discontinuation due to side effects was 9-19% in boceprevir arms vs 8% in PR arm.
TRIALS IN PROGRESS
SPRINT-2 - phase III boceprevir in 1099 treament-naive genotype 1. All three groups receive 48 weeks PR (PEG-Intron +ribavirin). One group also receives 28 weeks boceprevir and one group also receives 48 weeks boceprevir. Boceprevir is begun 4 weeks after initiation of PR. Boceprevir patients with RVR by week eight of treatment stop all treatment after 28 weeks. Enrollment completed 1/09. Study completion 6/10 per clinicaltrials.gov.
RESPOND-2 - phase III trial boceprevir in 404 treatment-failure genotype 1. All three groups receive 48 weeks PR. One group also receives 36 weeks boceprevir and one group receives 48 weeks boceprevir. Boceprevir patients with RVR by week eight of treatment stop all treatment after 28 weeks. Enrollment completed 11/08. Study completion 4/10 per clinicaltrials.gov.
While the conventional wisdom is that boceprevir is not as promising as telaprevir, the 75% best SVR for boceprevir compares favorably to the 67-69% SVR seen for telaprevir in the PROVE trials. However, telaprevir definitely has the advantage with respect to data in treatment-failure patients. Only limited data is available for boceprevir, from the null responders in the 4 week lead-in periods in SPRINT-1. But data from the PROVE-3 and ongoing Study 107 trials of telaprevir indicate it has substantial efficacy in patients who have already failed other regimens. Given the potential variability between phase II and phase III data however, boceprevir definitely has the potential to be a significant fly in Vertex's ointment come summer.
And now on to Intermune. The protease inhibitor ITMN-191 has been renamed RG7227 due to a partnership with Roche. The main twist here is that Intermune has been using ritonavir to boost RG7227 levels in trials. Ritonavir is an inhibitor of cytochrome P450-3A4, which degrades protease inhibitors such as the ones being developed for hepatitis C.
Several short phase I trials
INFORM-1 - combination of RG7227 + Pharmasset's polymerase inhibitor RG7128. Highest RG7227 dose cohort had 63% undetectable viral RNA after 2 weeks in treatment-naive and 25% undetectable viral RNA in prior null responders.
TRIALS IN PROGRESS
Phase Ib multiple ascending dose study of RG7227 + ritonavir + PR for 15 days in treatment-naive patients. Initiated in 9/09. Two lowest dose cohorts have been reported, with RVR seen in more than 50%. Trial will continue with higher dose cohorts and likely expansion of treatment to 12 weeks.
Phase IIb study of RG7227 + PR (no ritonavir) for 12 weeks. Initiated in 9/09. Preliminary data is expected in late Q1 or early Q2.
Phase IIb of RG7227 + ritonavir + PR for 12 weeks. Expected to begin in Q3 2010.
INFORM-2: RG7227 + ritonavir + RG7128 for 12 weeks. Expected to begin in H2 2010.
Intermune's data is mostly viral kinetics rather than the SVR variety, as they seem to have elected to go with shorter studies to accelerate development. This makes comparisons with telaprevir and boceprevir rather difficult in these early stages. Given that they are far behind in the race, Intermune and Roche are intelligently breaking new ground by combining RG7227 with ritonavir and a polymerase inhibitor, as well as with the standard of care.
If I decide to continue on with this series the next installment will explore the Hepatitis C polymerase inhibitors, such as Pharmasset's RG7128 and Anadys' ANA598.