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Merck Submits Grazoprevir/ Elbasvir for FDA Approval, BMS Gets Breakthrough Status for Daclatasvir

Merck has requested U.S. Food and Drug Administration (FDA) approval for its promising grazoprevir/elbasvir coformulation for people with hepatitis C virus genotypes 1, 4, or 6, the company recently announced. In related news, Bristol-Myers Squibb said that the FDA has granted Breakthrough Therapy status for daclatasvir plus sofosbuvir for people with advanced cirrhosis and liver transplant recipients.

The development of direct-acting antiviral agents that can be used in interferon-free regimens has brought about a revolution in hepatitis C treatment. While regimens approved to date -- Gilead Sciences' sofosbuvir/ledipasvir (Harvoni) and AbbVie's "3D" Viekira Pak -- cure most people with HCV genotype 1, better options are still needed for people with other genotypes and some people with advanced liver disease or other complications and contraindications.

Grazoprevir/Elbasvir

Grazoprevir is an HCV NS3/4 protease inhibitor and elbasvir is a NS5A inhibitor. The combination is being studied as a once-daily single-tablet regimen (100 mg/50 mg). Both drugs have demonstrated activity against multiple genotypes of HCV. The FDA previously granted grazoprevir/elbasvir Breakthrough Therapy status for the treatment of genotype 1 hepatitis C patients with end-stage renal disease on hemodialysis and for patients with HCV genotype 4.

At the recent EASL International Liver Congress researchers presented data showing cure rates exceeding 90% for previously untreated and treatment-experienced hepatitis C patients (C-EDGE treatment-naive and C-EDGE treatment-experienced), those with prior treatment failure (C-SALVAGE), people with HIV/HCV coinfection (C-EDGE coinfected), patients with advanced liver disease (C-SALT), and people with chronic kidney disease (C-SURFER).

Within 60 days of the company's submission, the FDA will determine whether it will accept the application for review, according to a Merck press release. The company also plans to submit license applications in the European Union and other markets by the end of 2015.

Daclatasvir + Sofosbuvir

In related news, the FDA last month granted a Breakthrough Therapy designation for daclatasvir, to be used with the already-approved sofosbuvir, for patients with advanced liver disease.

Daclatasvir, a pangenotypic NS5A inhibitor, was initially being tested with sofosbuvir, but Gilead pulled out of Phase 3 trials to focus on ledipasvir, which was combined with sofosbuvir in the Harvoni coformulation. Ledipasvir, however, is primarily active against HCV genotype 1.

BMS previously requested FDA approval for a combination of daclatasvir plus its HCV protease inhibitor asunaprevir, which has high cure rates for HCV genotype 1b. This combo was approved in Japan, but the company decided to withdraw its FDA request for U.S. approval and the FDA requested further information about use of daclatasvir with other drugs. Stand-alone daclatasvir was approved in the European Union in August 2014.

The new Breakthrough Therapy designation for daclatasvir and sofosbuvir is supported by data from the ALLY-1 trial, also presented at the International Liver Congress, demonstrating good sustainedresponse rates for hepatitis C patients with advanced liver cirrhosis or recurrent HCV infection after liver transplantation. The FDA is also evaluating daclatasvir plus sofosbuvir for people with HCV genotype 3.

"Our daclatasvir clinical development program focuses on addressing high unmet medical needs still encountered in the treatment of hepatitis C despite the advent of new therapies," Douglas Manion, MD, Head of Specialty Development, stated in a Bristol-Myers Squibb press release. "This Designation recognizes the importance of developing a new treatment option for post-liver transplant and cirrhotic patients, who are among the most challenging patient populations to treat with currently available regimens."

6/10/15

Sources

Merck. Merck Submits U.S. New Drug Application for Grazoprevir/Elbasvir, an Investigational Once-Daily, Single Tablet Combination Therapy, for Treatment of Chronic Hepatitis C Genotypes 1, 4, and 6 Infection. Press release. May 28, 2015.

Bristol-Myers Squibb. Bristol-Myers Squibb Receives Amended U.S. FDA Breakthrough Therapy Designation for Investigational Daclatasvir-based Hepatitis C Regimen. Press release. May 20, 2015.