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Upcoming catalysts in Q4 2014

Credit: Peter Hermes Furian/Alamy

After the recent successful launch of the breakthrough hepatitis C virus (HCV) drug sofosbuvir (Sovaldi; Gilead), the fourth quarter of 2014 is poised to see the entrance of additional competitors to the market. The US Food and Drug Administration (FDA) is expected to deliver decisions on three marketing applications for HCV drugs: a fixed-dose combination (FDC) of sofosbuvir and ledipasvir (developed by Gilead); a dual combination regimen of daclatasvir and asunaprevir (developed by Bristol-Myers Squibb); and a triple-combination regimen of ABT-450 (boosted with low-dose ritonavir), ABT-267 and ABT-333 (developed by AbbVie).

Following an FDA regulatory decision, which is due by 10 October, the sofosbuvir–ledipasvir FDC is forecasted to earn US$2.5 billion in US revenue over the next year, with Gilead expected to capture a majority share of the population infected with genotype 1 HCV. The sofosbuvir–ledipasvir FDC is the most efficacious of the three combinations up for FDA review and is comprised of a nucleotide polymerase inhibitor prodrug (sofosbuvir) and an inhibitor of HCV non-structual protein 5A (NS5A) (ledipasvir). The FDC holds both breakthrough therapy and priority review designations. Notably, three Phase III studies (namely, ION-1, ION-2 and ION-3), which were conducted in a total of ~2,000 patients, support the approval of the FDC application; in all of these studies, >93% sustained viral response (SVR) rates were achieved 12 weeks post-treatment, with or without ribavirin. Importantly, results from ION-3 support the use of an 8-week regimen in treatment-naive, non-cirrhotic patients with genotype 1 HCV. Many physicians anticipate a positive decision from the FDA and look forward to a single-pill, interferon (IFN)-free regimen that is highly effective in genotype 1 patients. Although a sofosbuvir and ribavirin regimen is effective in individuals with genotype 2 or genotype 3 HCV (after a 12- to 24-week treatment), the current approved treatment paradigm for patients with genotype 1 HCV is a 12-week combination of sofosbuvir, ribavirin, and pegylated (PEG)-IFN (or, off-label, an IFN-free combination with simeprevir (Olysio; Johnson & Johnson)). As a number of patients are IFN-intolerant or unwilling to use IFN therapies, physicians have been 'warehousing' their genotype 1 patients in anticipation of the next-generation combinations.

Up next for consideration by the FDA is Bristol-Myers Squibb's dual combination of the NS5A inhibitor daclatasvir and NS3 protease inhibitor asunaprevir, which is currently under priority review with a Prescription Drug User Fee Act (PDUFA) date of 30 November. Designated as a breakthrough therapy, daclatasvir–asunaprevir has shown acceptable SVR rates of 82–90% in the genotype 1b population from the Phase III HALLMARK study. This study evaluated over 600 patients with genotype 1b HCV who were null- or partial-responders to PEG-IFN–ribavirin (PR), intolerant of or ineligible for PR treatment, cirrhotic or non-cirrhotic, or treatment-naive. Although acceptable viral response rates are supported by the study, a triple combination with an NS5B polymerase inhibitor (BMS-791325) is expected to enter the market in 2015 or 2016. This pending regimen is more efficacious than just treating with the dual therapy; the Phase III UNITY 1 trial reported 91% SVR rates after 12 weeks in the genotype 1a population and 100% in the genotype 1b and cirrhotic populations.

AbbVie's current triple combination regimen has also been designated as a breakthrough therapy and is under priority review with a PDUFA date of 21 December. This regimen consists of a protease inhibitor (ABT-450) with a low-dose ritonavir booster, an NS5A inhibitor (ABT-267), and a non-nucleoside polymerase inhibitor (ABT-333). The submission is supported by studies demonstrating >90% SVR rates in ~3,000 individuals with genotype 1 HCV. Assuming this regimen is conservatively priced, AbbVie can be a viable competitor to Gilead's single-pill FDC regimen. Revenue forecasts are in the range of $250 million over the next year following approval; although not at the level of Gilead's expected multi-billion revenue, this would provide patients with a possibly more affordable and similarly efficacious treatment alternative.

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Correspondence to Andrew Ang.

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Ang, A. Upcoming catalysts in Q4 2014. Nat Rev Drug Discov 13, 716 (2014).

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