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EASL 2014: VX-135 + Daclatasvir Shows Modest Cure Rate in Phase 2 Study

Treatment with an interferon-free regimen of daclatasvir plus VX-135 for 12 weeks was safe and well-tolerated for genotype 1 chronic hepatitis C patients, but the sustained virological response rate of 83% for easier-to-treat patients did not stand up well to cure rates of 90% or higher seen with other similar combinations, according to a late-breaker poster presented at the 49thEASL International Liver Congress held recently in London.

Direct-acting antiviral agents (DAAs) have begun to revolutionize hepatitis C treatment. Gilead Sciences' recently approved nucleotide HCV polymerase inhibitor sofosbuvir (Sovaldi), Janssen's HCV protease inhibitor simeprevir (Olysio), and AbbVie's "3D" regimen are ahead of the pack, but there is still room for new agents that are effective and well-tolerated, especially if they are made available at lower cost.

Edward Gane of Auckland Clinical Studies and colleagues conducted a multicenter Phase 2a trial to evaluate the safety, tolerability, and efficacy of the uridine nucleotide polymerase inhibitor VX-135 plus the HCV NS5A replication complex inhibitor daclatasvir. VX-135 is the same type of drug as sofosbuvir, and the sofosbuvir plus daclatasvir combo has been highly effective in studies to date.

This study included 23 previously untreated genotype 1 chronic hepatitis C patients without liver cirrhosis. About half were men, most were white, and the median age was 50 years. More than three-quarters had harder-to-treat HCV subtype 1a, the rest 1b. About 40% had the favorable IL28B CC gene variant associated with interferon responsiveness and 87% had high baseline HCV viral load.

Participants were randomly assigned to receive either 100 or 200 mg VX-135 plus 60 mg daclatasvir once-daily for 12 weeks. They were followed for another 12 weeks after completing treatment to determine sustained virological response (SVR12), considered to be a cure.

Results

• By week 4 of treatment, 100% of patients receiving 100 mg VX-135 and 92% in the 200 mg arm had undetectable HCV RNA.
• End-of-treatment response rates were 82% and 92%, respectively.
• At 12 weeks post-treatment, SVR12 rates were 73% in the 100 mg arm and 83% in the 200 mg arm in an intent-to-treat analysis.
• The SVR12 rate in the 200 mg arm rose to 91% in an as-treated analysis excluding 1 participant who withdrew after a single dose.
• SVR12 rates in the 100 mg arm were 78% for people with HCV subtype 1a and 50% for those with 1b, the reverse of the typical pattern; in the 200 mg arm, cure rates 78% and 100%, respectively.
• SVR12 rates in the 100 mg arm were 100% for people with IL28 CC and 63% for those with non-CC; in the 200 mg arm, cure rates were 83% for both CC and non-CC.
• 2 people in the 100 mg arm experienced viral breakthrough during treatment, while 1 in each dose arm relapsed after completing treatment.
• Genetic deep sequencing showed that 1 relapser had detectable resistance to daclatasvir at baseline.
• Among participants with virological failure, those with viral breakthrough had evidence of resistance to both VX-135 and daclatasvir, the relapser in the 100 mg arm had only daclatasvir resistance, and the relapser in the 200 mg arm also had resistance to both drugs.
• Treatment was generally safe and well-tolerated at both VX-135 doses.
• 1 person in the VX-135 200 mg arm discontinued treatment after the first dose due to serious nausea and vomiting.
• There were no grade 3 or 4 laboratory abnormalities or notable echocardiograms (heart rhythm) changes
• The most commonly reported adverse events were fatigue, headache, nausea, dry skin, and dry mouth.

"The safety, tolerability, and efficacy results observed in treatment-naive patients with genotype 1 HCV infection treated with an all-oral, once-daily regimen of VX-135 and daclatasvir support further development of this regimen," the researchers concluded.

While this study was small, the sub-optimal sustained response rates suggest that resistance is a concern with this regimen and it might work better with the addition of a third DAA.

On May 1, however, Vertex announced that it has amended the terms of its agreement with Alios BioPharma regarding the development and commercialization of VX-135. "Based on the revised agreement and the rapid changes in the hepatitis C treatment landscape following the introduction of new oral therapies, Vertex plans to out-license VX-135 and to end further investment into research and development efforts in hepatitis C," the company stated said in a press release.

5/2/14

Reference

E Gane, C Stedman, V Garg, et al. An interferon- and ribavirin-free 12-week regimen of once-daily VX-135 and daclatasvir in treatment-naive patients with genotype 1 HCV infection. 49th European Association for the Study of the Liver International Liver Congress (EASL 2014). London, April 9-13, 2014. Abstract P1303.

Other Source

Vertex Pharmaceuticals. Vertex Reports First Quarter 2014 Financial Results and Provides Updates on Key Business Priorities. Press release. May 1, 2014.