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CROI 2014: Interferon-free BMS Combo Cures 90% of Genotype 1 Hepatitis C

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An all-oral regimen of daclatasvir, asunaprevir, and BMS-791325 -- without interferon or ribavirin -- led to sustained response in approximately 90% of previously untreated hepatitis C patients, most with hard-to-treat genotype 1a, according to a study presented at the 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014) this month in Boston.

The advent of effective direct-acting antivirals has brought about a revolution in treatment for chronic hepatitis C. New regimens coming through the pipeline will eliminate interferon and ribavirin, both of which often cause difficult side effects.

Trevor Hawkins from the Southwest CARE Center in Santa Fe reported findings from a clinical trial evaluating an interferon- and ribavirin-free regimen consisting of Bristol-Myers Squibb's HCV NS5A inhibitor daclatasvir (formerly BMS-790052), the NS3 protease inhibitor asunaprevir (formerly BMS-650032), and the NS5B polymerase inhibitor BMS-791325.

After a pilot study of the triple combination taken for 12 or 24 weeks showed sustained virological response rates of around 90% with either duration at 12 and 24 weeks post-treatment (SVR12 and SVR24, respectively), the researchers conducted an expanded trial to test the 12-week regimens in a larger group of patients with genotype 1 HCV infection, including people with liver cirrhosis (study AI443-014).

This analysis included 166 treatment-naive chronic hepatitis C patients. About two-thirds were men, about 80% were white, and the median age was 54 years. Most (82%) had harder-to-treat HCV subtype 1a, the rest 1b. One-third had the favorable IL28B CC gene variation associated with good interferon responsiveness. Although 20% had advanced fibrosis (stage F3) and 18% had cirrhosis (stage F4) according to the non-invasive FibroTest biomarker index, half that many (9%) had biopsy-proven cirrhosis. People with HIV or hepatitis B coinfection were excluded.

Participants were randomly assigned to receive 30 mg daclatasvir, 200 mg asunaprevir, and either 75 or 150 mg BMS-791325, all taken twice-daily for 12 weeks. Although daclatasvir can be taken once-daily, in this trial it was taken twice-daily to support development of a coformulation with the other drugs. Prior studies have shown that 60 mg once-daily and 30 mg twice-daily daclatasvir dosing are equally effective.

Results

  • In an intent-to-treat analysis at 12 week post-treatment, 88.8% of patients in the 75 mg BMS-791325 arm and 89.5% in the 150 mg arm achieved SVR12.
  • Excluding 3 people in the 75 mg arm and 2 in the 150 mg arm who had missing data, observed SVR12 rates were 92.2% and 91.7%, respectively.
  • In an observed analysis of patient subgroups, cure rates were similarly high regardless of factors traditionally associated with poor response.
  • For people with HCV subtype 1a, the SVR12 rate was 91% using either the 75 mg or 150 mg BMS-791325 dose; for people with subtype 1b, SVR12 rates were 100% and 94%, respectively.
  • For people with the IL28B CC variant, the SVR12 rate was 96% with both doses; for those with unfavorable non-CC variants, cure rates were 91% and 89%, respectively.
  • Looking at people with liver cirrhosis, the observed SVR12 rate was 100% in the 75 mg dose arm, but 71% in the 150 mg arm (2 cirrhotic patients in this arm ended up adding pegylated interferon/ribavirin, 1 due to viral breakthrough and 1 after stopping BMS-791325).
  • For non-cirrhotic patients, cure rates were 91% and 94%, respectively.
  • Overall, 13 out of 15 participants with cirrhosis achieved SVR12.
  • 6 people in the 75 mg BMS-791325 arm experienced virological failure (2 viral breakthroughs during treatment and 4 relapses after completing therapy), as did 5 people in the 150 mg arm (3 breakthroughs and 2 relapses).
  • All relapses occurred in participants with HCV subtype 1a and happened during the first 4 weeks of post-treatment follow-up.
  • No factors other than HCV subtype -- including baseline polymorphisms -- predicted virological failure.
  • Among the 11 people with virological failure, 5 had evidence of emergent resistance to daclatasvir and asunaprevir, and 6 showed resistance to all 3 drugs.
  • Triple therapy was generally safe and well-tolerated.
  • A single participant in each BMS-791325 dose arm discontinued early due to adverse events.
  • There were a total of 3 serious adverse events, none deemed related to the study drugs.
  • The most common side effects were headache (25%), diarrhea (15%), fatigue (11%), and nausea (10%), with no major differences between dose arms.

"This 12-week, interferon- and ribavirin-free, all-oral 3-DAA regimen achieved SVR12 in >90% of patients despite high prevalence of genotype 1a, advanced fibrosis/cirrhosis, and IL28B non-CC genotypes," the researchers concluded. They added that this was a "well tolerated regimen with low rates of adverse events and treatment discontinuations, regardless of BMS-791325 dose."

The triple regimen is now being studied in the Phase 3 UNITY-1 and UNITY-2 trials, testing a twice-daily fixed-dose coformulation of all 3 drugs, using the 75 mg dose of BMS-791325. UNITY-1 is looking at non-cirrhotic patients and UNITY-2 at people with compensated cirrhosis.

Daclatasvir is also currently being tested in people with HIV/HCV coinfection. All 3 drugs in this combination are CYP3A4 substrates. Drug-drug interaction studies have shown that daclatasvir can be combined with several antiretroviral drugs, in some cases with dose adjustments. Asunaprevir can also be used with several antiretrovirals, excluding HIV protease inhibitors; interaction studies are underway for BMS-791325.

3/25/14

Reference

GT Everson, PJ Thuluvath, E Lawitz, T Hawkins, et al. All-Oral Combination of Daclatasvir, Asunaprevir, and BMS-791325 for HCV Genotype 1 Infection. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 25.