FDA Approves Zepatier (Grazoprevir/Elbasvir) for Hepatitis C Genotypes 1 and 4

The U.S. Food and Drug Administration (FDA) this week announced its approval of Merck's Zepatier -- a once-daily coformulation containing the hepatitis C virus (HCV) protease inhibitor grazoprevir and NS5A inhibitor elbasvir -- for the treatment of HCV genotypes 1 and 4. In several Phase 3 studies grazoprevir/elbasvir taken for 12 weeks demonstrated cure rates exceeding 90% for various groups including people with liver cirrhosis, HIV/HCV coinfected patients, and people who inject drugs.

"Today’s approval provides another oral treatment option for patients with genotypes 1 and 4 HCV infections without requiring use of interferon," Edward Cox, MD, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, stated in a FDA press release.

The development of direct-acting antiviral agents used in interferon-free regimens has revolutionized hepatitis C treatment. While previously approved agents -- including Gilead Sciences' sofosbuvir/ledipasvir (Harvoni), AbbVie's Viekira Pak and Technivie, and Bristol-Myers Squibb's daclatasvir (Daklinza) -- can cure a majority of people with HCV genotype 1 or 4, there is still room for additional options for hard-to-treat patients and competition could reduce the high cost of treatment.

The safety and efficacy of Zepatier taken with or without ribavirin for 12 or 16 weeks was evaluated in clinical trials of 1373 participants with chronic HCV genotype 1 or 4 with or without cirrhosis, according to the FDA. Overall sustained virological response rates at 12 weeks post treatment (SVR12) ranged from 94% to 97% for genotype 1 and from 97% to 100% for genotype 4.

Studies presented at the EASL International Liver Congress last April showed sustained virological response rates of 90% or higher for previously untreated people (C-EDGE treatment-naive), prior non-responders to interferon-based therapy (C-EDGE treatment-experienced), patients unsuccessfully treated with a first-generation HCV protease inhibitor (C-SALVAGE), people with HIV/HCV coinfection(C-EDGE Co-infected), and patients with advanced liver disease (C-SALT) or chronic kidney disease (C-SURFER). The C-EDGE CO-STAR study, presented at the recent AASLD Liver Meeting, showed a cure rate of 92% for injection drug users receiving opioid substitution therapy. Trials are described in more detail in a Merck press release announcing the approval.

The FDA had given grazoprevir/elbasvir "breakthrough therapy" status for the treatment of genotype 1 hepatitis C patients with end-stage kidney disease on hemodialysis and for people with HCV genotype 4. While most of the above studies also included a small number of people with HCV genotype 6 -- which is rare in the U.S. but more common in parts of Asia -- the FDA did not include that genotype in its approval.

In order to maximize cure rates, the duration of grazoprevir/elbasvir treatment, and whether or not to include ribavirin, should be tailored according to specific characteristics of individual patients and their virus, including treatment history. The product label recommends that people with genotype 1a should be tested for viral genetic variations associated with drug resistance before starting therapy. Most treatment-naive and previously treated people will be bale to take grazoprevir/elbasvir for 12 weeks, but some hard-to-treat patients should extend therapy to 16 weeks.

Grazoprevir/elbasvir was generally safe and well-tolerated across studies, with few serious adverse events or discontinuations due to adverse events. The most common side effects were fatigue, headache, and nausea. Some people who took grazoprevir/elbasvir with ribavirin also developed anemia. About 1% of study participants experienced substantial liver enzyme elevations, and patients with moderate or severe liver impairment should not use grazoprevir/elbasvir, according to the product label.

Zepatier should not be used with certain medications due to the potential for drug-drug interactions, including several HIV protease inhibitors, efavirenz (Sustiva), and strong cytochrome P450 3A inducers such as carbamazepine, rifampin, or St. John’s Wort. Further contraindications and warnings are summarized in the Merck press release and described in full in the Zepatier prescribing information (http://www.merck.com/product/usa/pi_circulars/z/zepatier/zepatier_pi.pdf).

Given that many people with chronic hepatitis C have not yet been treated due to cost constraints, Merck set the list price for Zepatier at $54,600 for a 12-week course. This is below the list prices for Harvoni and Viekira Pak, but the company believes it is in the range of actual net prices for the other regimens after discounts. Some patients may have lower out-of-pocket medication costs for Zepatier, depending on their insurance plan.

Privately insured people may be eligible for Merck's co-pay assistance program, which could reduce the cost to as little as $5 per prescription (www.merckaccessprogram-zepatier.com). In addition, Merck’s Patient Assistance Program provides free medications to eligible patients who are uninsured or underinsured (www.merckhelps.com or 1-800-405-5810).

1/28/16

Sources

U.S. Food and Drug Administration. FDA approves Zepatier for treatment of chronic hepatitis C genotypes 1 and 4. Press release. January 28, 2016.

Merck. Merck Receives FDA Approval of Zepatier (Elbasvir and Grazoprevir) for the Treatment of Chronic Hepatitis C Virus Genotype 1 or 4 Infection in Adults Following Priority Review. Press release. January 28, 2016.