ACH-3102 and sovaprevir show potent activity, high barrier to resistance in early studies

Achillion Pharmaceuticals' second-generation NS5A inhibitor ACH-3102 demonstrated potent activity against genotype 1a and 1b hepatitis C virus and can be safely co-administered with the company's investigational protease inhibitor sovaprevir (formerly ACH-1625), according to studies presented at the 48^th International Liver Congress (EASL 2013) last month in Amsterdam.

Andrew Muir from Duke Clinical Research Institute and colleagues reported findings from a phase 1b trial of ACH-3102 in non-cirrhotic patient with hard-to-treat HCV genotype 1a. A total of 14 treatment-naive participants received a single dose of 50, 150 or 300mg ACH-3102 or placebo. A majority had baseline NS5A resistance mutations in a genotypic analysis. Pharmacokinetic, viral load and safety data were collected for 35 days.

Viral load reductions ranged from 3.52 to 3.93 log₁₀. Following these promising results, a lower 25mg dose versus placebo was tested in nine additional patients, yielding a reduction of 4.04 log₁₀. HCV RNA declined rapidly and remained below baseline levels until 15 days post-dosing. ACH-3102 was well tolerated at all doses, with no serious adverse events or discontinuations due to safety concerns.

"These data provide evidence that ACH-3102 is a safe and well-tolerated second-generation NS5A inhibitor with potent anti-viral activity against both wild-type HCV virus and NS5A-resistant viral variants, making it a promising candidate for future use in the treatment of chronic HCV infection," the researchers concluded.

James Hui from Achillion Pharmaceuticals and colleagues found no clinically significant pharmacokinetic interactions between ACH-3102 and sovaprevir in healthy HCV negative volunteers, paving the way for combined use in interferon-free regimens.

In a prior phase 1b study, sovaprevir monotherapy demonstrated robust antiviral activity against genotype 1 HCV, including virus with pre-existing resistance mutations. A phase 2a study showed that adding sovaprevir to pegylated interferon/ribavirin improved virological response.

Eric Lawitz from Alamo Medical Research and colleagues reported that another second-generation protease inhibitor candidate, ACH-2684, showed potent viral suppression of genotype 1 HCV in patients with and without liver cirrhosis. At tested doses of 100mg once daily, 400mg once daily and 400mg twice daily, ACH-2684 monotherapy demonstrated mean maximum HCV RNA reductions ranging from 3.36 to 4.16 log₁₀. Again, the drug appeared safe and well tolerated in both cirrhotic and non-cirrhotic patients.

Concurrent with EASL, Achillion announced updated interim safety and efficacy results from a phase 2 pilot study evaluating a dual oral regimen of once-daily ACH-3102 plus ribavirin in easier-to-treat treatment-naive patients with HCV genotype 1b and the favourable IL28B CC gene variant.

All of the eight enrolled patients completed twelve weeks of treatment with no virological breakthrough, according to an Achillion press release; 75% had HCV RNA < 25 IU/mL at the end of treatment and 63% achieved early sustained virological response four weeks after completing therapy (SVR4). ACH-3102 remained active in the presence of up to six baseline mutations known to confer resistance to first-generation NS5A inhibitors. ACH-3102 was safe and well tolerated with no significant adverse events.

"The preliminary results from this novel study of a single DAA, an NS5A inhibitor, plus ribavirin demonstrates the safety, high barrier to resistance, and preliminary efficacy of ACH-3102," Muir stated in the press release. "The profound activity of ACH-3102 as a single DAA, along with its safety profile and lack of virologic breakthrough to date makes this a very promising compound to study further in combination with other oral agents, including sovaprevir, for the treatment of HCV."

ACH-3102 and sovaprevir are currently being tested together as a dual regimen in a phase 2 trial.