FDA Staff Sees Only Minor Issues for Telaprevir

FDA Staff Sees Only Minor Issues for Telaprevir

By John Gever, Senior Editor, MedPage Today
Published: April 26, 2011
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An FDA staff assessment gave high marks to the investigational hepatitis C drug telaprevir, suggesting that the agent will sail easily through an advisory committee review on Thursday.

However, a briefing document released in advance of the meeting did raise concerns about skin rashes and anemia seen in patients receiving telaprevir in clinical studies and the emergence of mutations in the drug's enzyme target that appear to render the virus drug-resistant.

Telaprevir, developed by Vertex Pharmaceuticals, is one of two hepatitis C virus (HCV) protease inhibitors to be reviewed this week by the FDA's Antiviral Drugs Advisory Committee. The other, boceprevir (Victrelis), will come before the panel Wednesday.
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Approval of both drugs has been widely expected. They would be the first drugs to target the virus directly; the current standard HCV treatment regimen of pegylated interferon and ribavirin works to boost patients' immune responses.

Clinical trials have indicated that these agents dramatically improve sustained virologic response rates when added to the standard therapy. Moreover, they are effective both as first-line therapy and in the large number of patients who have already received the standard treatment without sustained responses.

Fewer than half of patients treated with peginterferon and ribavirin achieve sustained responses. The telaprevir trials indicated that adding the drug to peginterferon and ribavirin could boost the sustained response rate above 70% in treatment-naive patients, to as much as 90% according to results from one study.
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Sustained response rates were lower in patients with previous inadequate responses to the standard treatment, but still much higher than in control groups receiving another round of conventional therapy:

• Prior null responders: 31% versus 3%
• Prior partial responders: 57% versus 15%
• Prior relapsers: 84% versus 24%

Relapse rates were slashed in patients receiving telaprevir relative to controls: 5% versus 26% in previously untreated patients and 10% versus 57% in treatment-experienced patients.
The core dosing recommendation proposed by Vertex for the drug's label is 750 mg of telaprevir three times daily for 12 weeks, combined with peginterferon and ribavirin at standard doses for 24 or 48 weeks, depending on virologic response.

For treatment-naive patients and prior relapsers whose viral loads are undetectable at weeks four and 12, the shorter regimen would be recommended, according to Vertex's application. Other patients would receive the full 48 weeks of therapy.

This type of "response-guided therapy" raised a concern for FDA staff reviewing the data for boceprevir, as some of the trials showed lower response rates for the alternative dosing scheme.
The FDA's briefing document for telaprevir, on the other hand, did not highlight any problems with the response-guided therapy, although the advisory committee will still be asked to consider its appropriateness.
A somewhat greater worry for FDA staff was a finding of mutations in the HCV protease enzyme that appeared to make the virus resistant to telaprevir. Data from the trials indicated that, in patients not maintaining good responses, certain point mutations in the protease had emerged during treatment.
In one of the studies, 90% of treatment failures had treatment-emergent amino acid substitutions in the protease sequence, according to the briefing document.

The significance of this treatment-emergent resistance also will be a topic of discussion for the panel.
Safety concerns center on two toxicities seen during the telaprevir studies -- skin rashes that, in some patients, were severe enough to warrant stopping the drug, and anemia that was substantially more common with telaprevir.

More than half of patients receiving the drug reported rash or pruritus, with 6% discontinuing treatment as a result. These rates were about double those in the control groups.
Similarly, hemoglobin reductions of grade 3 or more were seen in 55% of telaprevir patients versus 25% of control patients.

Anemia is also an issue for boceprevir, but the skin problems are unique to telaprevir.
Advisory committee members will be asked how these side effects affect their risk-benefit assessments.
They will also give a formal up-or-down vote on whether the drug should be approved.
Other discussion topics will include recommendations for telaprevir's use in specific populations such as blacks -- as with boceprevir, sustained response rates were about 20 percentage points lower in African Americans -- and recommendations for postmarketing studies on the drug's optimal use.

http://www.medpagetoday.com/InfectiousDisease/Hepatitis/26136