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AbbVie Interferon-free Hepatitis C Combo Gets FDA 'Breakthrough' Status

An all-oral regimen of 3 new direct-acting antiviral agents, with or without ribavirin, has been designated by the U.S. Food and Drug Administration (FDA) as a "breakthrough therapy" for people with genotype 1 chronic hepatitis C, AbbVie (formerly Abbott) announced this week.

The direct-acting antiviral (DAA) combination consists of the HCV protease inhibitor ABT-450 with a ritonavir booster to raise drug levels, the non-nucleoside polymerase inhibitor ABT-333, and the NS5A replication complex inhibitor ABT-267, which has been tested both with and without ribavirin.

According to findings from the Phase 2 Aviator study reported at the recent EASL International Liver Congress in Amsterdam, the 4-drug regimen produced 24-week post-treatment sustained virological response (SVR24) rates of more than 90% for both treatment-naive individuals and prior interferon null responders treated for either 12 or 24 weeks. The treatment-naive SVR24 rate for the 3 direct-acting antivirals without ribavirin was 87%.

Treatment was generally safe and well-tolerated, with fewer than 2% of study participants experiencing serious adverse events or discontinuing treatment early for this reason. Ritonavir (Norvir) -- which is widely used as a pharmacoenhancer for HIV protease inhibitors -- works by inhibiting cytochrome P450 liver enzymes that process other drugs. It can cause various side effects including metabolic abnormalities, but this is expected to be less of a concern with 3 months of hepatitis C treatment compared with the lifelong therapy required for HIV.

The FDA's "breakthrough therapy" designation, established in 2012, is "intended to expedite the development and review of drugs for serious or life-threatening conditions." The criteria include "preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy." 

Breakthrough criteria are more stringent than those of the older "fast track" designation, which requires that "nonclinical or clinical data demonstrate the potential to address unmet medical need." The breakthrough designation "conveys all of the fast track program features...as well as more intensive FDA guidance on an efficient drug development program," according to the agency.

The AbbVie triple DAA combo is now undergoing Phase 3 trials in more than 2000 patients in 29 countries, according to a company press release. The studies are evaluating a 12-week course for people without liver cirrhosis, and both 12 and 24 weeks for cirrhotic patients, who do not respond as well to treatment. The trials are using ABT-450/ritonavir and ABT-267 in a once-daily coformulation, while ABT-333 is taken twice-daily.

5/8/13

Sources

AbbVie. AbbVie's Investigational HCV Regimen Receives Breakthrough Therapy Designation from the U.S. Food and Drug Administration. Press release. May 6, 2013.

KV Kowdley, E Lawitz, F Poordad, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267 and ABT-33 +/- ribavirin in patients with chronic genotype 1 infection: results from the Aviator study. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 3.

U.S. Food and Drug Administration. Frequently Asked Questions: Breakthrough Therapies. Updated April 8, 2013.