BMS combination cures 90% of genotype 1b hepatitis C in 24 weeks

Keith Alcorn
Published: 17 April 2014

A combination of two direct-acting antivirals developed by Bristol-Myers Squibb (BMS) cured 90% of previously untreated people with genotype 1b hepatitis C infection in 24 weeks, without the need for pegylated interferon or ribavirin, Prof. Michael Manns of Hannover Medical School, Germany, reported at the 49th Annual Meeting of the European Association for the Study of the Liver (EASL) in London last week.

The interferon- and ribavirin-free regimen combined the NS5A inhibitor daclatasvir and the protease inhibitor asunaprevir. The combination is already undergoing regulatory review in Japan and the United States for the treatment of genotype 1b infection. The two drugs are also being tested alongside a third agent, the non-nucleoside NS5b polymerase inhibitor BMS-791325, in two phase III studies.

Genotype 1b is the predominant form of hepatitis C in eastern Europe (including Russia), Turkey and southern Europe, especially Italy. Although considered easier to treat than its counterpart genotype 1, which is more common in north America, genotype 1b has until now required interferon-based treatment to cure it. Genotype 1b also predominates in Japan and China.

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 favourable genetic profile (the IL28B 'CC' gene) have a poorer response to interferon-based treatment. The majority of patients taking ribavirin develop anaemia during treatment, and some may have to discontinue treatment as a result.

The phase III HALLMARK-Dual study presented at EASL recruited 305 previously untreated patients, 205 previous non-responders and 235 patients who were ineligible for interferon treatment due to advanced fibrosis or cirrhosis, depression or neutropenia, as well as treatment-experienced patients unable to tolerate further interferon-based treatment.

Participants received daclatasvir (60mg once daily) and asunaprevir (100mg twice daily) for 24 weeks. 102 previously untreated patients were randomised to receive placebo treatment for 12 weeks, followed by 24 weeks of daclatasvir and asunaprevir. The primary outcome of the study was the proportion of participants who achieved sustained virologic response 12 weeks after completing treatment (SVR12).

The median age of study participants 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. Sixteen per cent of treatment-naive participants had cirrhosis, as did 31% of previous non-responders and 47% of interferon-intolerant patients.

Omitting the placebo 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 rate between previous null- and partial-responders but there was a substantial difference in response according to the reason for interferon treatment ineligibility. Whereas 91% of those with anaemia or neutropenia achieved SVR12, the proportion of responders fell to 80% among those with depression and 73% among those with cirrhosis or advanced fibrosis with thrombocytopenia. There was also a substantial difference in response according to baseline viral load: 92% of those with HCV RNA < 800,000 achieved SVR12, compared to 82% of those with HCV RNA > 800,000.

The majority of people who failed to achieve SVR12 experienced virologic 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).

Six patients in the previously untreated group and two 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, diarrhoea and nausea were the most common adverse events, 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 treatment showed no difference in adverse events or grade 3/4 laboratory abnormalities between the two groups.

Although less potent in previous non-responders than some of the other regimens reported 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 an early approval for daclatasvir as an individual agent, so that it may be used in combination with sofosbuvir for treatment of 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 guidelines.

Reference

Manns M et al. All-oral dual therapy with daclatasvir and asunaprevir in patients with HCV genotype 1b infection: phase 3 study results. 49th Annual Meeting of the European Association for the Study of the Liver, London, abstract O166, 2014.

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