Investigational Triple DAA regimen of daclatasvir, asunaprevir and BMS-791325 achieved SVR12 of 94% in treatment-naïve patients with genotype 1 chronic hepatitis C infection in Phase II trial

Bristol-Myers Squibb Company (NYSE: BMY) today announced for the first time Phase II data demonstrating that the 12-week Triple DAA treatment regimen of daclatasvir (DCV), asunaprevir (ASV), and BMS-791325 achieved sustained virologic response 12 weeks post-treatment (SVR12) in 94% (15/16) of treatment-naïve, genotype 1 chronic hepatitis C patients. The remaining one patient had undetectable viral load at the end of treatment and was lost to follow-up until approximately 24 weeks post-treatment; in preliminary data, this patient has achieved SVR24. The Phase II results from this interferon-, ribavirin- and ritonavir-free investigational regimen combining three different classes of direct-acting antivirals (DAAs) – an NS5A replication complex inhibitor (DCV), an NS3 protease inhibitor (ASV) and an NS5B non-nucleoside polymerase inhibitor (BMS-791325) – were presented today at the American Association for the Study of Liver Diseases congress in Boston.

One serious adverse event was reported in this study and was determined by the investigator to be unrelated to study drug. There were no discontinuations due to adverse events. Headache was the most common adverse event in the study (31%, 10/32).

“We are encouraged that this 12-week daclatasvir-based regimen with compounds in different classes of DAAs achieved SVR12 in a majority of patients without the use of interferon, ribavirin or ritonavir,” said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb. “The development of regimens for hepatitis C with the potential to avoid the use of ribavirin and ritonavir is an important approach in this therapeutic area, and we look forward to studying it further.”

Phase II studies of this investigational Triple DAA regimen are ongoing. Phase III development is anticipated to begin in 2014.

Daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in Phase III development. Asunaprevir is an oral, NS3 protease inhibitor in Phase III development with daclatasvir. BMS-791325 is a non-nucleoside inhibitor of the NS5B polymerase, currently in Phase II development for hepatitis C as a component of daclatasvir-based treatment regimens.

Study Design and Results

This open-label, two-part Phase II study is designed to evaluate the safety and antiviral activity of the investigational hepatitis C treatment regimen of DCV, ASV and BMS-791325 in treatment-naïve patients with genotype 1 chronic hepatitis C infection. The primary endpoint of the study is viral load below the lower limit of quantitation (LLOQ; HCV RNA <25 IU/mL) at 12 weeks post-treatment (SVR12).

Data presented at AASLD are from an interim analysis of Part 1 of the study. In Part 1, 32 patients were randomized 1:1 (n=16/arm) into two groups.

• Group 1: 24 weeks of treatment with DCV 60 mg QD, ASV 200 mg BID, BMS-791325 75 mg BID
• Group 2: 12 weeks of treatment with DCV 60 mg QD, ASV 200 mg BID, BMS-791325 75 mg BID

In Part 2 of the study, patients were assigned to the same DAA regimen for 24 or 12 weeks, with BMS-791325 dosed at 150 mg BID (Groups 3 and 4, respectively). Part 2 is ongoing and results are not yet available.

Virologic Response

• Group 1 (24 week treatment): 94% (15/16) achieved undetectable viral load by the end of treatment and sustained through SVR4. Two patients discontinued study drugs prior to the protocol-defined last treatment visit, one due to inability to comply with study procedures (poor venous access) who achieved SVR4, and one withdrew consent and is lost to follow up.
• Group 2 (12 week treatment): 100% (16/16) achieved undetectable viral load by the end of treatment and 94% (15/16) achieved SVR12. The remaining one patient was lost to follow-up after completing treatment but did return approximately 24 weeks post treatment and in preliminary data, has achieved SVR24. One patient discontinued study drugs prior to the protocol-defined last treatment visit (due to poor/non-compliance) and achieved SVR12.
• Viral load declined rapidly in both groups and was below LLOQ in all patients (32/32) by week 4.
• There was no viral breakthrough during treatment and no post-treatment relapse.

Safety

There were no deaths, discontinuations due to adverse events (AEs), or serious adverse events (SAEs) due to study drugs. Most AEs were mild to moderate in severity. The most common AEs (≥10% total) were headache (Group 1: 25%, 4/16; Group 2: 38%, 6/16), diarrhea (Group 1: 13%, 2/16; Group 2: 38%, 6/16), and asthenia (Group 1: 13%, 2/16; Group 2: 19%, 3/16).

No Grade 3-4 elevations in liver enzymes (ALT/AST) or bilirubin were observed. One grade 3 AE (headache) resolved after seven days with continued study treatment and one grade 3–4 laboratory abnormality (lymphopenia) was recorded in Group 2 at a single study visit concomitant with influenza. All other AEs were grade 1 or 2.

About Bristol-Myers Squibb’s Commitment to Liver Disease

Bristol-Myers Squibb is studying a portfolio of compounds that aims to address unmet medical needs across the liver disease continuum, including hepatitis C, hepatitis B and liver cancer. The Company’s hepatitis C pipeline includes compounds with different mechanisms of action, pursuing both biologics as well as small molecule direct-acting antivirals. These compounds are being studied as part of multiple treatment regimens with the goal of increasing SVR rates across diverse patient types and geographies.

Daclatasvir is an NS5A replication complex inhibitor that is being extensively studied as a key component of potential DAA-based hepatitis C treatment regimens. Studied in more than 3,000 patients to date, daclatasvir is in Phase III development. Asunaprevir is an NS3 protease inhibitor in Phase III development for hepatitis C as a component of daclatasvir-based treatment regimens, and has been studied in more than 1,200 patients to date. BMS-791325 is a non-nucleoside inhibitor of the NS5B polymerase, currently in Phase II development for hepatitis C as a component of daclatasvir-based treatment regimens.

About Hepatitis C

Hepatitis C is a virus that infects the liver and is transmitted through direct contact with infected blood and blood products. An estimated 170 million people worldwide are infected with hepatitis C, with genotype 1 being the most prevalent genotype. Up to 90 percent of those infected with hepatitis C will not clear the virus and will become chronically infected. Twenty percent of people with chronic hepatitis C will develop cirrhosis and, of those, up to 25 percent may progress to liver cancer.