Daclatasvir, BMS's HCV NS5A inhibitor, has demonstrated good activity against HCV, but it has not always measured up to other interferon-free combos such as Gilead Science's sofosbuvir/ledipasvir (Harvoni) or AbbVie's Viekira Pak.

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. Last year this combo was approved in Japan, where 1b is the predominant type; in the U.S., however, a majority of people have harder-to-treat genotype 1a.

Last October BMS decided to withdraw its FDA request for approval of this combination. The company wanted to proceed with daclatasvir alone, but the FDA requested more information about its use with other drugs such as sofosbuvir. Sofosbuvir (originally developed by Pharmasset) plus daclatasvir looked good in Phase 2 trials, but Gilead halted further studies of this combo to focus on its own NS5A inhibitor, ledipasvir. Once sofosbuvir was approved and on the market, however, BMS was able to proceed with Phase 3 trials on its own.

Unlike ledipasvir, which is active only against HCV genotype 1, daclatasvir also shows activity against genotype 3, which is now considered the hardest to treat since it does not respond to currently approved drugs. As reported at last year's AASLD Liver Meeting, sofosbuvir plus daclatasvir for 12 weeks cured 90% of previously untreated patients and 86% of prior non-responders in the ALLY-3 trial, which supports renewed FDA consideration. Stand-alone daclatasvir was approved in the European Union last August.

Below is an edited excerpt from a BMS press release describing the new drug application in more detail.

Bristol-Myers Squibb Announces Acceptance of New Drug Application for Investigational Daclatasvir for FDA Review for the Treatment of Hepatitis C Genotype 3

The NDA contains data to support approval for daclatasvir in combination with sofosbuvir; would be the first 12-week regimen specifically for the treatment of hepatitis C genotype 3

The application is based on a Phase III clinical trial which tested a 12-week, ribavirin-free regimen and resulted in sustained virologic response (SVR12) in 90% of treatment-naive and 86% of treatment-experienced genotype 3 HCV patients

Princeton, N.J. -- March 12, 2015 --Bristol-Myers Squibb Company (NYSE:BMY) announced today that the resubmitted new drug application (NDA) for daclatasvir, an investigational NS5A replication complex inhibitor, has been accepted for review by the U.S. Food and Drug Administration (FDA) for use in combination with sofosbuvir for the treatment of chronic hepatitis C (HCV) genotype 3. The original NDA has been amended to include data from the Phase III ALLY-3 trial, which showed high cure rates for the combination, with sustained virologic response 12 weeks after treatment (SVR12) in 90% of treatment-naive and 86% of treatment-experienced genotype 3 HCV patients. SVR12 rates were higher (96%) in non-cirrhotic genotype 3 patients, regardless of treatment history. The FDA will now review the submission within a six-month timeframe.

"The daclatasvir-based NDA seeks to address a high unmet patient need that still exists despite recent hepatitis C treatment advances. Approximately 9%-12% of HCV patients in the U.S. have genotype 3. That’s thousands of individuals in the U.S. who historically have had limited treatment options requiring at least 24 weeks of treatment," said Douglas Manion, MD, head of Specialty Development, Bristol-Myers Squibb. "We also are continuing clinical trials to determine the potential of daclatasvir-based regimens in treating a range of other high unmet-need patients, including those coinfected with HIV, HCV patients with decompensated cirrhosis, and HCV recurrence in post-transplant patients."

Genotype 3 is estimated to affect 54.3 million people worldwide, and is the second most common hepatitis C genotype after genotype 1 (83.4 million). The more aggressive nature of genotype 3 lies in the damage it causes to the liver, as it is associated with progressive disease, increased rates of steatosis and a disproportionately increased risk of hepatocellular carcinoma.

In the ALLY-3 study, the dclatasvir and sofosbuvir combination regimen was well tolerated, with no deaths, treatment-related serious adverse events, or discontinuations due to adverse events. The most frequent side effects (>5%) were headache (19.7%), fatigue (19.1%), nausea (11.8%), diarrhea (8.6%), insomnia (5.9%), abdominal pain and arthralgia (both 5.3%). Additionally, there were 17 (11.2%) treatment failures, with 16 relapses post-treatment and 1 rebound at the end of treatment. There were no viral breakthroughs in this ribavirin-free regimen.

About ALLY-3: Study Design

This Phase III open-label clinical trial enrolled 152 genotype 3 HCV patients; 101 treatment-naive patients and 51 treatment-experienced patients in 2 cohorts each received daclatasvir 60 mg and sofosbuvir 400 mg once daily for 12 weeks, with 24 weeks of follow-up. The primary endpoint was SVR12 rates, defined as HCV RNA < LLOQ target detected or not detected at follow-up week 12 in treatment-naive and treatment-experienced patients.

About Bristol-Myers Squibb’s HCV Portfolio

Bristol-Myers Squibb’s research efforts are focused on advancing late-stage compounds to deliver the most value to patients with hepatitis C. At the core of our pipeline is daclatasvir, a NS5A complex inhibitor, which continues to be investigated in multiple treatment regimens and in people with co-morbidities.

Daclatasvir was approved in Europe in August 2014, and more recently in Brazil in January 2015, for use in combination with other medicinal products across genotypes 1, 2, 3 and 4 for the treatment of chronic hepatitis C virus (HCV) infection in adults. Daclatasvir also is approved in Japan in combination with asunaprevir, a NS3/4A protease inhibitor. The daclatasvir+asunaprevir dual regimen is Japan’s first all-oral, interferon- and ribavirin-free treatment regimen for patients with genotype 1 chronic HCV infection, including those with compensated cirrhosis.

About Bristol-Myers Squibb

Bristol-Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information, please visit http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.Bristol-Myers Squibb ($BMY) is finally in line for FDA approval for its once-rejected hepatitis C daclatasvir, angling to take third place among companies with next-generation cures for the virus.

3/17/15

Source

Bristol-Myers Squibb. Bristol-Myers Squibb Announces Acceptance of New Drug Application for Investigational Daclatasvir for FDA Review for the Treatment of Hepatitis C Genotype 3. Press release. March 12, 2015.