Boceprevir Wins Favorable FDA Staff Review

MedPage Today covers FDA review of Boceprevir. Aside from the issues regarding Merck's definition of 'null responder', the predictive value of viral kinetics and the hemotologic issues with the drug, the only formal voting issue, however, is whether "the available data support approval" of boceprevir for treating HCV genotype 1 in combination with peginterferon and ribavirin.

Boceprevir Wins Favorable FDA Staff Review
By John Gever, Senior Editor, MedPage Today
Published: April 25, 2011

WASHINGTON -- The FDA's professional staff believes the investigational hepatitis C drug boceprevir (Victrelis) is effective and reasonably safe, according to a briefing document made public in advance of a Wednesday advisory committee meeting.

But before the agency approves the drug, it wants the panel's views on certain marketing claims that the drug's manufacturer, Merck, is proposing to make. These include the drug's efficacy in patients with "null" responses to the standard regimen of pegylated interferon and ribavirin as well as the benefits of so-called response-guided therapy.

The Antiviral Drugs Advisory Committee will also be asked to review risks of anemia and other hematologic abnormalities associated with boceprevir.

The drug is one of two hepatitis C virus (HCV) protease inhibitors that will be reviewed during a two-day meeting this week. The other is telaprevir -- no brand name has been proposed as yet -- which will have its day on Thursday.

The two drugs would be the first HCV protease inhibitors to reach the market. They have attracted major buzz among physicians and patients on the basis of excellent-looking clinical trial results, most recently from two of boceprevir's pivotal studies published in the New England Journal of Medicine last month.

These data suggest that adding one of the drugs to the standard peginterferon-ribavirin combination doubles or triples the sustained viral response rates.

For example, among treatment-naive patients in one of the boceprevir trials, 40% of a control group receiving the conventional regimen had a sustained response versus about 70% of patients with the protease inhibitor added.

A separate trial in patients with previous partial or unsustained responses to the standard regimen showed that 21% achieved a sustained response with a second round, whereas approximately 60% did with the addition of boceprevir.

In the briefing paper prepared for Wednesday's panel meeting, the FDA staff reviewers could find little to fault in these data.

But they did question Merck's arguments in favor of "response-guided therapy," particularly in African-American patients and raised concerns about the drug's hematologic side effects.

The core treatment regimen with boceprevir tested in the trials included a four-week lead-in period with peginterferon and ribavirin with boceprevir then added for 44 weeks. But some of the trials also included a regimen in which the duration of boceprevir treatment could be extended based on viral responses after eight and 24 weeks.

In particular, Merck would like the drug's label to allow longer treatment for patients with detectable HCV RNA at eight weeks but who achieve a full virologic response at 24 weeks, as some data suggested that such a regimen improves the sustained response rate.

But the FDA staff reviewers pointed to data in one of the trials indicating a slightly lower sustained-response rate in previous treatment failures receiving the response-guided therapy compared with fixed-duration treatment (59% versus 66%).

They also noted that black participants in a study of treatment-naive patients also had a lower sustained-response rate with response-guided therapy (42% versus 53%).

"The 11% numerical difference ... is of some concern and will be an issue for discussion," the briefing paper said.

Another issue is whether a proposed indication for patients who completely failed previous peginterferon-ribavirin therapy is justified, considering that such patients were excluded from trials of previously treated patients.

Merck is arguing that its major trial in treatment-naive patients included null responders, identified as those with negligible responses during the lead-in with standard therapy, and the drug's efficacy in this population can be gauged from those results.

However, the FDA reviewers indicated that responses at week four do not perfectly predict who will ultimately respond. The lack of a trial designed expressly to test the drug in null responders "raises questions about using [standard therapy] lead-in responses as a surrogate," they wrote in the briefing document.

About a quarter of the briefing document was devoted to boceprevir's adverse hematologic effects, primarily anemia but also including neutropenia and thrombocytopenia.

In the drug's two main phase III trials, half the patients taking the drug had nadir hemoglobin values of 10 g/dL or below and more than 40% required erythropoietin therapy -- with both rates about twice those seen in the control groups.

The other hematologic effects were far less common, but still a potential concern, according the briefing document.

Counting all cases, the incidence of neutropenia was about the same with or without boceprevir, but the drug was associated with a greater rate of serious cases. Eight of 1,057 patients taking the drug discontinued the study because of neutropenia compared with none in the control groups.

Similarly, severe thrombocytopenia was seen in 15 boceprevir-treated patients compared with three control patients.

The FDA plans to ask the advisory panel to comment on these adverse events, as well as to discuss postmarketing studies that Merck should conduct if the product is approved.

The only formal voting issue, however, is whether "the available data support approval" of boceprevir for treating HCV genotype 1 in combination with peginterferon and ribavirin.