Lots of headlines are coming through the newswires now about last week's unanimous decisions by the FDA's advisory panel to approve two new HCV candidates, telaprevir (Vertex/Janssen) and boceprevir (Merck).
On the surface things look pretty good for both compounds, however look below the surface a bit and you will see that telaprevir has come out of last week better off.
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Both protease inhibitors are clearly able to increase cure rate in HCV patients dramatically. Adverse effects don't even look too bad now and physicians should be able to manage them. Two issues are however worth mentioning about the adverse events.
For telaprevir, the main problem has been known for quite a while now - rash. Vertex/Jannsen designed a rash management program for the Phase 3 trials and it has succeeded, at least in part. The incidence of discontinuation of treatment due to rash has progressively fallen - this is due in part to the use of topical agents to reduce rash but also an understanding that discontinuing telaprevir while continuing with background PEG-INF and ribavirin (HCV standard of care) allows rash to resolve while continuing to eradicate the virus.
The current issue about rash is translating the Phase 3 program to a program that is easy to use in the real world. The real challenge is perhaps to enable non-specialist physicians to be able to distinguish minor rash from severe rash and severe rash from a group of very serious skin conditions known as SCAR.
The safety problems faced by boceprevir are however more serious. The major problem is the anaemia that frequently develops in patients. Anaemia is already a problem in HCV treatment due to ribavirin affects - boceprevir makes the problem worse. The problem faced by the regulators is that it is difficult to asses just how bad the problem is; moreover it is difficult to determine the effects of anaemia in patients treated with boceprevir.
Assessing the degree of anaemia is difficult for two reasons. Firstly baseline haemoglobin levels varied in the Phase 3 trials - secondly physicians were able to use erythropoitin (EPO) in the boceprevir studies (this was not allowed in the telaprevir studies). On a related matter, use of EPO creates its own problems - firstly it is associated with adverse events of its own; secondly it has not been approved for use in HCV; and thirdly it is expensive. Alternatives to EPO are ribavirin dose reduction and this is the approach preferred by Merck. However, there is no comparison of ribavirin dose reduction and EPO use. The study looking at this, PROVIDE, is coming and it may be that the FDA will wait until they see the data before approving boceprevir.
PROVIDE is important for a second reason. Pivotal telaprevir studies allowed the enrollment prior null responders; this was not the case for boceprevir studies. Merck has however now tried to get an indication for null responders. As one of the advisory committee members put it, Merck has "tortured the data to death". In effect it has said patients with a <1 log drop in the lead-in phase used in its pivotal studies are the same as those with a<2 log drop at week 12 - the definition of null responders. Patients with a <1 log drop in the lead in phase are able to show pretty good SVR rates (about 40%) if boceprevir is added to the treatment regimen. The advisory panel did not buy this entirely last week and instead Merck may have to rely on PROVIDE. The study included patients who were characterized as "real null patients". Boceprevir was able to eliminate virus in an appreciable number of these patients at the end of treatment in PROVIDE. However we are still at least 12 weeks off of SVR data from the study and again the FDA may wait until it sees this data prior to approval.
So that is the second reason why Merck may have problems. The third reason is that Merck was highly criticized last week for a lack of drug interaction studies. We don't know yet how boceprevir interacts with antidepressant or methadone. It is quite possible that if used in the real world, patients on antidepressants (of which there are many with HCV - PEG-INF actually produces depression as an adverse event) may be at increased risk of suicide if boceprevir is co-administered. In fact the FDA concluded in its review that rates of depression were higher in boceprevir treated arms. Perhaps drug interaction is the reason why. Equally it is possible that ex-drug users will relapse if boceprevir alters the behavior of methadone. Just as serious drug interactions could diminish the concentration of boceprevir increasing the risk of resistance.
A final reason why Merck may have problems is that it the boceprevir treatment regimens are complex. Depending on the patient's characteristics there are about 5 different treatment schedules. As another panel member put it last week - you have to be a Talmudic scholar to use boceprevir.
So all in all, although both agents received unanimous recommendations for approval last week, we would not be surprised if final approval of boceprevir by the FDA is delayed giving telaprevir first to market advantage. Even if both are approved we believe that, at least until Merck releases more data to allay those concerns described above, physicians will prefer telaprevir as the more simple option for treating HCV.
LeadDiscovery has no relationships with any of the companies discussed in this blog
Labels: boceprevir, hcv, hepatitis, telaprevir