The FDA advisory panel unanimously backed the approval of Vertex Pharmaceuticals proposed hepatitis C-drug telaprevir.
Hepatitis C News; European Gastroenterologists Will Prescribe Telaprevir and Boceprevir to Nonresponder and Treatment-Naive Patients Following Launch
FDA May See Advantages for Telaprevir Over Boceprevir
By: JOSEPH HAAS, The Pink Sheet
04/27/11
For hepatitis C treatment, telaprevir may be suited for response-guided therapy in a larger population than boceprevir and may show greater efficacy in null responders, according to briefing materials for a Food and Drug Administration advisory committee.
Telaprevir goes before the Antiviral Products Advisory Committee on April 28; boceprevir is to be reviewed April 27.
Both of the protease inhibitors look to be headed for fairly easy reviews, with little concern raised in the FDA’s briefing documents on the efficacy.
Telaprevir and boceprevir are intended to improve therapy for chronic hepatitis C virus (HCV), adding a direct-acting antiviral to the current standard of care, a weekly injection of pegylated interferon and ribavirin, a daily tablet.
The course of therapy currently takes 48 weeks and is efficacious in fewer than half of all patients. With significant side effect profiles, including flulike symptoms and anemia, many patients discontinue therapy before completion. Both Vertex Pharmaceuticals (telaprevir) and Merck (boceprevir) hope to position their oral protease inhibitors as increasing the rate of sustained virologic response (viral cure) and reducing the duration of treatment for many patients.
Like Merck, Vertex is seeking a label that would authorize response-guided therapy (RGT) for patients who demonstrate initial improvement after receiving its drug. Vertex proposes RGT for patients who achieve extended virologic response, defined as undetectable levels of HCV RNA at weeks 4 and 12 of treatment. For telaprevir, RGT would consist of 12 weeks of combination treatment with standard of care followed by another 12 weeks on just peginterferon and ribavirin.
Vertex is asking the FDA to approve RGT in the treatment-naive population and in prior relapsers – patients who achieved cure previously on standard of care but then relapsed following treatment.
The briefing documents indicate support for Vertex’s position, which Robert W. Baird & Co. analyst Thomas Russo said would be "a clinically important, and unexpected, win at this stage," in an April 26 note.
Extended Virologic Response Seen as Good Predictor for RGT
Vertex backs its rationale for using RGT in prior relapsers who achieve extended virologic response with a retrospective viral dynamic simulation of prior relapsers using results from a pair of phase II studies included in the New Drug Application. The company found a sustained virologic response (SVR) rate greater than 90% in prior relapse patients who achieved extended virologic response after treatment with telaprevir.
"[Vertex] hypothesized that these interferon-sensitive subjects could be re-treated with a shorter course of therapy," the FDA briefing documents stated. "Because there are not adequate randomized, controlled trial data, we will ask the advisory committee to consider the evidence supporting effectiveness in this subgroup."
The FDA is asking the panelists to discuss the evidence supporting RGT at each of the drug reviews.
Telaprevir could also gain an advantage over boceprevir in the scope of the patient population, based on its effects in nonresponders. The agency questioned boceprevir’s potential efficacy in null responders in its briefing documents for that drug’s review.
The telaprevir briefing material, on the other hand, indicated that telaprevir might be significantly more effective than the current standard of care in curing this population. Vertex’s phase III REALIZE trial – which tested telaprevir in null responders, partial responders, and prior relapsers – produced a 31% SVR rate for null responders, compared with 3% for controls.
Another sign of confidence in the efficacy profile comes from an FDA reanalysis of the efficacy data from Vertex’s three phase III trials. In the treatment-naive population, the FDA determined that telaprevir produced an SVR rate of 79%, greater than the 75% reported by Vertex, in the phase III ADVANCE study. The SVR rate for the control group in that trial was unchanged, at 46%.
Signs of Concern About Safety, Specific Populations
In terms of the safety profile, the FDA is seeking the panel’s input on the significance of the rash that was commonly associated with telaprevir use, sometimes to a severe and treatment-limiting degree, as well as anemia, which occurred more frequently and sometimes more severely in patients receiving telaprevir than patients on standard of care. Anemia is also a concern with boceprevir, but not rash.
The FDA noted that rash was reported in 56% of patients receiving telaprevir, compared with 32% of patients receiving standard care. In most cases, the rash was mild to moderate, but it was severe in 1% of cases and resulted in treatment discontinuation in 6% of cases.
While anemia is a known toxicity related to treatment with ribavirin, the FDA noted that telaprevir (and boceprevir) exacerbates the potential for the disorder. Subjects treated with telaprevir had a higher frequency of anemia (36% vs. 15% of control group patients). Telaprevir-related anemia often was more severe than that occurring in patients not receiving telaprevir. Anemia-related serious adverse events were reported in 2.5% of patients receiving telaprevir but in less than 1% of control patients.
The FDA also asked the panel to comment on whether there are sufficient data to recommend that telaprevir be used in specific populations, including African Americans and patients with cirrhosis. Phase III data for telaprevir and boceprevir have suggested that the Vertex drug may be more efficacious in African American HCV patients, who historically have lower SVR rates than other patients on standard of care.
Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.
Vertex offers a blockbuster case for telaprevir
Vertex offers a blockbuster case for telaprevir
Vertex execs spent a good deal of this morning's FDA panel review on the hepatitis C drug telaprevir addressing one of the key safety concerns that regulators have with the drug. Tackling the rash triggered in some patients head on, the developer emphasized that only a relative handful of cases were discovered during the trial process and the patients could be quickly switched to the standard of care.
Telaprevir "produces substantial clinical benefit compared to the current treatment," Vertex Chief Medical Officer Robert Kauffman told the panel, according to a report from Reuters. There's not likely to be much argument on that point, however, and barring a nasty surprise even the safety issues aren't likely to derail telaprevir at this point.
"Rash rates (were) higher in Phase III program but discontinuation due to rash was low," messaged TheStreet's Adam Feuerstein this morning as he live-blogged the Vertex defense. And most of the cases of rash were mild to moderate, he added. Feuerstein as well as Reuters highlighted Vertex's remark that it is already gathering data on a twice-daily dosage of telaprevir, which could improve compliance compared to the thrice-daily program that the Boston biotech wants to win an endorsement on today.
"Rash rates (were) higher in Phase III program but discontinuation due to rash was low," messaged TheStreet's Adam Feuerstein this morning as he live-blogged the Vertex defense. And most of the cases of rash were mild to moderate, he added. Feuerstein as well as Reuters highlighted Vertex's remark that it is already gathering data on a twice-daily dosage of telaprevir, which could improve compliance compared to the thrice-daily program that the Boston biotech wants to win an endorsement on today.
There's intense interest in today's vote, which follows a unanimous recommendation for Merck's competing hepatitis C drug boceprevir. FDA regulators indicated in their staff review that telaprevir's cure rate in one trial hit 79 percent, even higher than Vertex investigators had reported. And while they appeared concerned about the rash and anemia triggered in some patients, regulators have also expressed a keen interest in seeing a new standard of care introduced for hepatitis C patients, who frequently can't continue on the current standard of care that is available.
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