- Category: Experimental HCV Drugs
- Published on Wednesday, 16 April 2014 00:00
- Written by Keith Alcorn
A combination of 2 direct-acting antivirals developed by Bristol-Myers Squibb (BMS), daclatasvir and asunaprevir, cured 90% of previously untreated people with genotype 1b hepatitis C in 24 weeks, without the need for pegylated interferon or ribavirin, Michael Manns of Hannover Medical School reported at the 49thEASL International Liver Congress (EASL 2014) in London last week.
The regimen containing the NS5A inhibitor daclatasvir and the HCV protease inhibitor asunaprevir is already undergoing regulatory reviewin the U.S. and Japan for the treatment of HCV genotype 1b infection. The 2 drugs are also being tested alongside a third agent, the non-nucleoside NS5B polymerase inhibitor BMS-791325, in a pair of Phase 3 studies.
Genotype 1b is the predominant form of HCV in eastern Europe (including Russia), Turkey, and southern Europe, especially Italy; it also predominates in Japan and China. Although considered easier to treat than its counterpart genotype 1a, which is more common in North America, genotype 1b has until now required interferon-based therapy to cure it.
Along with Gilead’s sofosbuvir/ledipasvir combination, the new BMS combination is the first hepatitis C regimen for genotype 1b that omits both pegylated interferon and ribavirin. Pegylated interferon is poorly tolerated by the majority of people with hepatitis C, especially those with advanced liver disease. People lacking a favorable genetic profile (the IL28B CC variant) have a poorer response to interferon-based treatment. A substantial minority of patients taking ribavirin develop anemia, and some may have to discontinue treatment as a result.
The Phase 3 HALLMARK-Dual study presented at the EASL meeting recruited 305 previously untreated patients, 205 previous non-responders to pegylated interferon/ribavirin, and 235 patients who were ineligible for interferon treatment due to advanced fibrosis or cirrhosis with thrombocytopenia (low platelets), depression, or anemia or neutropenia, as well as treatment-experienced patients unable to tolerate further interferon-based therapy.
Participants received daclatasvir (60 mg once daily) and asunaprevir (100 mg twice-daily) for 24 weeks. Among the previously untreated patients, 102 were randomized to receive placebo for 12 weeks, followed by 24 weeks of daclatasvir and asunaprevir (this allowed comparison of adverse events between people taking and not taking the drugs). The primary outcome of the study was the proportion of participants who achieved sustained virological response 12 weeks after completing treatment (SVR12).
About half of study participants were women, which is unusual for hepatitis C treatment trials. The median age ranged from 55 in the treatment-naive arm to 60 in the interferon-intolerant arm. Between 58% and 72% of study participants were Caucasian by study arm, while between 22% and 32% were Asian. 16% of treatment-naive participants had cirrhosis, as did 31% of previous non-responders and 47% of interferon-intolerant patients. More than two-thirds had unfavorable IL28B non-CC gene variants.
Omitting the placebo step from the virological response analysis, 90% of previously untreated patients achieved SVR12, compared to 82% of previous non-responders and 82% of interferon-intolerant patients.
There was no difference in response rates between previous null- and partial-responders. However, there was a substantial difference according to the reason for interferon treatment ineligibility. Whereas 91% of those with anemia or neutropenia achieved SVR12, the proportion of responders fell to 80% among those with depression and 73% among those with advanced fibrosis or cirrhosis with thrombocytopenia. There was also a substantial difference in response according to baseline viral load: 92% of those with HCV RNA <800,000 IU/mL achieved SVR12, compared to 82% of those with HCV RNA >800,000 IU/mL.
The majority of people who failed to achieve SVR12 experienced virological breakthrough prior to the end of treatment (4% of treatment-naive, 13% of non-responders, and 9% of interferon-intolerant) rather than post-treatment relapse (3%, 4%, and 6% respectively).
A total of 6 patients in the previously untreated group and 2 in each of the other arms discontinued treatment due to serious adverse events, most commonly elevations in ALT/AST, which resolved after treatment ceased. Headache, fatigue, diarrhea, and nausea were the most common side effects, each affecting more than 10% of patients. A comparison of adverse events in the placebo group and the previously untreated arm during the first 12 weeks of therapy showed no difference in adverse events or grade 3/4 laboratory abnormalities between the 2 groups.
Although less potent in previous non-responders than some of the other direct-acting antiviral regimens presented at the conference, daclatasvir and asunaprevir will be an important option for patients with genotype 1b infection outside the European Union. In Europe, Bristol-Myers Squibb is pursuing early approval of daclatasvir as an individual agent, so that it may be used in combination with sofosbuvir for treatment of HCV genotypes 1, 3, and 4, or in combination with pegylated interferon and ribavirin for treatment of genotypes 1b and 4, as recommended in new EASL hepatitis C treatment guidelines.
M Manns, S Pol, I Jacobson, et al. All-oral dual therapy with daclatasvir and asunaprevir in patients with HCV genotype 1b infection: Phase 3 study results. 49thEuropean Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract O166.
Bristol-Myers Squibb. Bristol-Myers Squibb Presents Phase III Data Demonstrating that Investigational All-oral Daclatasvir and Asunaprevir Therapy Achieved SVR12 Rates of up to 90% Among Broad Range of Genotype 1b Hepatitis C Patients. Press release. April 10, 2014.