- Category: HCV Treatment
- Published on Tuesday, 06 December 2011 00:00
- Written by Liz Highleyman
Most treatment-naive chronic hepatitis C patients who added the experimental HCV NS5A inhibitor daclatasvir (BMS-790052) to pegylated interferon/ribavirin achieved undetectable viral load at 12 and 24 weeks, according to data presented at the at the 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011) last month in San Francisco.
Daclatasvir is the first direct-acting agent to target the HCV NS5A replication complex; the function of NS5A is not fully understood, but it appears to play an important role in viral replication.
Christophe Hézode and fellow investigators with the multinational Phase 2b COMMAND-1 study (AI444010)evaluated triple therapy using daclatasvir plus pegylated interferon/ribavirin vs standard therapy.
The analysis included 395 previously untreated chronic hepatitis C patients. About 70% were men, about 85% were white, and the median age was approximately 50 years; 30% had the favorable IL28B CC gene pattern and liver cirrhosis was not an exclusion criterion. Most had HCV genotype 1 (about 75% with difficult-to-treat subtype 1a), but 30 people had genotype 4.
Participants were randomly assigned to receive 20 mg or 60 mg daclatasvir once-daily plus pegylated interferon and ribavirin for either 24 or 48 weeks, or else pegylated interferon/ribavirin with placebo for 48 weeks. Patients with good virological response at weeks 4 and 12 were eligible for shorter treatment and were re-randomized to receive either triple therapy for another 12 weeks (24 weeks total) or 12 weeks of pegylated interferon/ribavirin alone.
Among genotype 1 patients, HCV viral load declined faster and to a greater extent in both daclatasvir dose arms compared with the standard therapy arm:
- Week 4 unquantifiable (< 25 IU/mL): 85% in the daclatasvir 20 mg arm, 76% in the 60 mg arm, and 24% in the placebo arm;
- Week 4 rapid virological response or RVR (undetectable): 60%, 57%, and 15%, respectively;
- Week 12 unquantifiable: 84%, 84%, and 53%, respectively;
- Week 12 complete early virological response (cEVR): 78%, 75%, and 43%, respectively;
- Week 4 and 12 extended RVR: 54%, 54%, and 14%, respectively;
71% of participants in the 20 mg daclatasvir arm and 72% in the 60 mg arm met the criteria for shorter therapy (unquantifiable at week 4 and undetectable at week 12).
- Among patients in this group who received 12 weeks of triple therapy followed by 12 weeks of pegylated interferon/ribavirin alone, 96% and 94%, respectively, had undetectable HCV RNA at week 24 (end-of-treatment response);
- Among those who received triple therapy for all 24 weeks, end-of-treatment response rates were 88% and 100%, respectively.
- RVR and cEVR rates were about 15% higher for people with subtype 1a compared with 1b.
- Genotype 1 patients with the favorable IL28B CC pattern had higher response rates than those with the CT or TT patterns; however, people with the less favorable patterns saw larger improvements in cEVR relative to standard therapy.
- Looking at genotype 4 patients, 58% in the daclatasvir 20 mg arm and 100% in the 60 mg had undetectable HCV RNA at week 12, compared with 50% in the placebo arm.
- Viral breakthrough rates were 7% in the daclatasvir 20 mg arm, 10% in the 60 mg arm, and 3% in the standard therapy arm; no breakthrough occurred among patients with good early response.
Daclatasvir was generally well-tolerated:
- Nausea and dry skin were reported 10% more often in the daclatasvir arms vs the placebo arm, but rates of anemia were similar;
- Rates of serious adverse events (6%-8%) and drug discontinuation for this reason (4%-8%) were similar across arms;
- Rates of skin rash were similar across arms (24%, 22%, and 28%, respectively); 1 patient in each daclatasvir arm and none in the placebo arm discontinued for this reason.
Once-daily daclatasvir plus pegylated interferon/ribavirin "provided higher rates of early virologic response compared with placebo plus pegylated interferon/ribavirin," the researchers concluded.
Adverse event profiles were similar in the daclatasvir and standard therapy arms, they continued, and safety profiles were comparable for daclatasvir used for 12 or 24 weeks.
These findings, Hézode said, "suggest that a vast majority of [IL28B] CC patients can be treated with a shorter duration" of therapy. He added that the new data "strongly support initiation of Phase 3 trials."
Investigator affiliations: CHU Henri Mondor, Creteil, France; Liver Centre, Toronto Western Hospital, Toronto, Ontario, Canada; Vancouver Island Health Authority, University of British Columbia, Victoria, British Columbia, Canada; Monash Medical Centre, Monash University, Melbourne, Victoria, Australia; Fundacion de Investigacion de Diego, San Juan, Puerto Rico; Univ of Alberta, Edmonton, Alberta, Canada; Mercy Medical Center, Baltimore, MD; Options Health Research, LLC, Tulsa, OK; National Liver Institute, Shebeen El Kom , Egypt; Tropical Medicine and Hepatology Department, Cairo University, Cairo, Egypt; Alamo Medical Research, San Antonio, TX; Metropolitan Research, Arlington, VA; Liver Unit, Hôpital Cochin, Paris, France; Copenhagen University Hospital, Hvidovre, Denmark; Scripps Clinic, La Jolla, CA; Hopital Saint Joseph, Marseille, France; Hopital Saint-Antoine, Paris, France; Baylor College of Medicine, Houston, TX; University of North Carolina at Chapel Hill, Chapel Hill, NC; Karolinska Institutet, Stockholm, Sweden; Azienda Ospedaliero Universitaria Pisana, Pisa, Italy; University of Colorado, Aurora, CO; JW Goethe University, Frankfurt, Germany; Indiana University Medical Center, Indianapolis, IN; Johns Hopkins University, Baltimore, MD; Bristol-Myers Squibb, Wallingford, CT.
C Hezode, GM Hirschfield, W Ghesquiere, et al. BMS-790052, A NS5A Replication Complex Inhibitor, Combined with Peginterferon Alfa-2a and Ribavirin in Treatment-Naive HCV- Genotype 1 or 4 Patients: Phase 2b AI444010 Study Interim Week 12 Results. 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD 2011). San Francisco, November 4-8, 2011. Abstract 227.
Bristol-Myers Squibb. 12-Week On-Treatment Results from Large Phase IIb Study (COMMAND-1) of Bristol-Myers Squibb’s NS5A Inhibitor Daclatasvir Support Anti-HCV Activity and Safety Profile Observed in Earlier Studies. Press release. November 8, 2011.