AASLD 2012: Daclatasvir + Asunaprevir + BMS-791325 Cures Hard-to-treat Hepatitis C Patients


Twelve weeks of treatment with a 3-drug combination of new hepatitis C direct-acting antivirals that included neither pegylated interferon nor ribavirin led to sustained virological response 12 weeks after completion of treatment (SVR12) in up to 94% of previously untreated patients with hepatitis C genotype 1 in a preliminary Phase 2 trial with 16 patients, Gregory Everson from the University of Colorado reported at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) this week in Boston.

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The combination of drugs, under development by Bristol-Myers Squibb, contained 3 classes of direct-acting antiviral agents that target different stages of HCV replication:

The study was designed to provide preliminary information on whether adding BMS-791325 to asunaprevir and daclatasvir would improve the efficacy of an interferon-sparing regimen in patients with difficult-to-treat HCV genotype 1a, and whether a higher dose of this drug had a substantial effect on efficacy. The study was also designed to test whether it was possible to shorten the treatment duration to 12 weeks when using this 3-drug combination in all patients, or to shorten treatment according to sub-genotype.

Another study described earlier at the conference showed that while daclatasvir and asunaprevir dual therapy was effective for most people with easier-to-treat HCV genotype 1b, those with genotype 1a needed to add interferon, ribavirin or potentially another direct-acting drug.

Everson's study compared 12- and 24-week treatment regimens, and also 2 doses of BMS-791325 (75 mg and 150 mg twice daily). All patients received asunaprevir (200 mg twice daily) and daclatasvir (60 mg once daily).

Participants were randomized to receive either 75 mg or 150 mg BMS-791325 twice-daily, and then were further randomized to receive either 12 or 14 weeks of treatment.

The results presented at AASLD comprised SVR12 results from the patients randomized to receive 75 mg BMS-791325 for 12 weeks, and SVR4 results (continued undetectable HCV 4 weeks after completing treatment) from those randomized to receive the 75 mg dose for 24 weeks.

Investigators recruited 15 treatment-naive chronic hepatitis C patients to each arm of the Phase 2a, open-label study. All had HCV genotype 1 infection.

The participants' median age was 48 years, half were men, 75% were white, 25% were African American, and mean baseline HCV viral load was 6.3 log IU/mL. Only 28% of patients had the IL28B CC mutation predicting favorable response to interferon-containing therapy, and 75% had genotype 1a HCV infection, both indicators of a harder-to-treat patient population.

All patients had a successful treatment response, with viral load falling below the limit of detection (LLOQ) by week 4 of therapy, and all had an end-of-treatment response.

With further follow-up, 94% of patients in each group had a sustained virological response at 4 weeks after the completion of therapy. Amongst those treated for 12 weeks, the SVR12 rate remained the same.

In each arm the non-responders were individuals who either withdrew from the study for reasons other than adverse events or viral breakthrough, or who were lost to follow-up.

By implication, all patients with HCV genotype 1a and a non-CC IL28B host genotype achieved a sustained virological response at week 4 or week 12.

Treatment was well tolerated. There were no discontinuations because of adverse events. The most common side effects were headache, diarrhea, and general weakness. Each of these occurred in over 10% of patients. Only 1 serious adverse event was reported, but this was not thought to be due to the study treatment. No serious (grade 3-4) elevations in liver enzymes or bilirubin were observed.

"Further investigation of this regimen in the treatment of HCV is warranted," the researchers concluded. Phase 3 licensing studies will begin shortly. Results from the higher 150 mg BMS-791325 dose arm are still awaited, as are longer term data that confirm the lack of viral breakthrough beyond 4 weeks after completion of treatment in the 24 week treatment group.



GT Everson, KD Sims, M Rodriguez-Torres, et al. An Interferon-free, Ribavirin-free 12-Week Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-791325 Yielded SVR4 of 94% in Treatment-Naive Patients with Genotype (GT) 1 Chronic Hepatitis C Virus (HCV) Infection. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract LB-3.

Other Source

Bristol-Myers Squibb. Investigational Triple DAA Regimen of Daclatasvir, Asunaprevir and BMS-791325 Achieved SVR12 of 94% in Treatment-Naive Patients with Genotype 1 Chronic Hepatitis C Infection in Phase II Trial. Press release. November 12, 2012.