BOSTON--(Bristol-Myers Squibb Company (NYSE: BMY) today announced new Phase II data demonstrating that the dual regimen of the investigational NS5A replication complex inhibitor daclatasvir (DCV) and the investigational NS3 protease inhibitor asunaprevir (ASV), without interferon or ribavirin, achieved high rates of sustained virologic response 12 weeks post-treatment (SVR12) in patients with genotype 1b (GT1b) hepatitis C virus (HCV) who were prior null responders to alfa interferon and ribavirin (alfa/RBV). In this study, the DCV/ASV Dual regimen achieved SVR12 in 78% (14/18) and 65% (13/20) of GT1b patients when asunaprevir was dosed twice daily (Group A1) or once daily (Group A2), respectively.)--
“The high response rates seen in this study with daclatasvir and asunaprevir are encouraging as we seek interferon- and ribavirin-free hepatitis C regimens for this difficult-to-treat patient population.”
These results were presented today at the American Association for the Study of Liver Diseases congress in Boston, along with data from this same study on the safety and efficacy of quadruple therapy with DCV/ASV/alfa/RBV in predominantly GT1a prior null responders.
In the patients treated with the DCV/ASV Dual regimen therapy, there were no serious adverse events related to study drug or discontinuations due to adverse events. Overall, headache was the most common adverse event in the DCV/ASV Dual regimen groups (Group A1: 44%, Group A2: 40%).
“We continue to see a significant unmet need for treatment approaches that improve response rates in patients with hepatitis C genotype1b who have not responded to prior therapy, with currently available treatment regimens achieving low cure rates of 30 to 40%,” said Brian Daniels, MD, senior vice president, Global Development and Medical Affairs, Research and Development, Bristol-Myers Squibb. “The high response rates seen in this study with daclatasvir and asunaprevir are encouraging as we seek interferon- and ribavirin-free hepatitis C regimens for this difficult-to-treat patient population.”
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. The DCV/ASV Dual regimen is part of a global registrational program and a registrational program specific to Japan, where the majority of HCV patients have GT1b.
Study Design and Results
The expansion of this randomized, open-label, phase IIa study evaluated the antiviral activity and safety of the combination of DCV and ASV with and without alfa/RBV in 101 HCV genotype 1 prior null responders to alfa/RBV. The primary endpoint of the study was the proportion of patients achieving undetectable viral load (HCV RNA < LLOQTND) 12 weeks post-treatment (SVR12).
Patients received one of five treatment regimens for 24 weeks. Genotype 1b infected patients were randomized to receive one of four treatment regimens for 24 weeks (two DCV/ASV Dual treatment groups, two DCV/ASV/Alfa/RBV Quad treatment groups). Genotype 1a infected patients were randomized to receive one of two treatment regimens for 24 weeks (two DCV/ASV/Alfa/RBV Quad treatment groups). A fifth group (DCV/ASV/RBV Triple therapy) included both GT1a and GT1b infected patients and enrolled separately. The DCV/ASV Dual treatment groups received DCV 60 mg once daily and ASV 200 mg either twice daily (Group A1) or once daily (Group A2).
- In Group A1 (DCV + ASV 200 mg BID), 78% (14/18) of patients achieved SVR12. Of the four patients who did not achieve SVR12, one patient was missing a viral load measurement at 12 weeks post-treatment and one had transient viremia (detectable viral load). Both of these patients had undetectable viral load on subsequent visits.
- In Group A2 (DCV + ASV 200 mg QD), 65% (13/20) of patients achieved SVR12
- With DCV/ASV Dual therapy, eight total patients experienced virologic breakthrough1 – two Group A1 patients and six Group A2 patients. All received rescue therapy with the addition of alfa/RBV to their regimen. One Group A2 patient relapsed post-treatment at week 4.
- An analysis of HCV sequences confirmed that five of the six Group A2 patients with virologic breakthrough had baseline polymorphisms that confer DCV resistance (NS5A domain). Additionally, at breakthrough, seven patients had confirmed resistance to both DCV and ASV.
In the patients treated with DCV/ASV Dual therapy, there were no serious adverse events due to study drug, no deaths, and no treatment discontinuations due to adverse events (AEs). Most AEs were mild to moderate in severity. The most common AEs (≥40% in any group) were:
DCV + ASV 200 mg BID
DCV + ASV 200 mg QD
|Headache||44% (8/18)||40% (8/20)|
|Diarrhea||28% (5/18)||40% (8/20)|
|Weakness (asthenia)||28% (5/18)||30% (6/20)|
|Fatigue||28% (5/18)||10% (2/20)|
|Insomnia||22% (4/18)||15% (3/20)|
* Adverse events in groups A1 and A2 includes patients who had alfa/RBV added to their regimen
Grade 3-4 AEs in Group A2 included neutropenia in one patient receiving alfa/RBV as rescue therapy. SAEs in Groups A1 and A2 included panic attack, forearm fracture, viral gastroenteritis, and prostate cancer; all were determined by study investigators to be unrelated to study therapy. Grade 3-4 ALT/AST elevations were infrequent and none were accompanied by elevated total or direct bilirubin. All AST/ALT elevations improved without intervention. All patients in groups A1/A2 with cytopenias were receiving alfa/RBV as rescue therapy.
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 DAAs. 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.
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.
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 Forward Looking Statement
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1 Virologic breakthrough defined as ≥ 1 log increase from nadir in HCV RNA, HCV RNA ≥ LLOQ on or after Week 8, and confirmed HCV RNA < LLOQ-TD on or after Week 8 (DUAL and TRIPLE arms only)