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EASL 2013: ACH-3102 and Sovaprevir Show Potent Activity, High Barrier to Resistance in Early Studies

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Achillion Pharmaceuticals' second-generation NS5A inhibitor ACH-3102 demonstrated potent activity against genotype 1a and 1b hepatitis C virus (HCV) and can be safely co-administered with the company's investigational protease inhibitor sovaprevir (formerly ACH-1625), according to studies presented at the EASL 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 300 mg 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 log. Following these promising results, a lower 25 mg dose versus placebo was tested in 9 additional patients, yielding a reduction of 4.04 log. 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 both genotype 1a and 1b 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 100 mg once-daily, 400 mg once-daily, and 400 mg twice-daily, ACH-2684 monotherapy demonstrated mean maximum HCV RNA reductions ranging from 3.36 to 4.16 log. Again, the drug appeared safe and well-tolerated in both cirrhotic and non-cirrhotic patients, with no serious adverse events or discontinuations due to safety concerns.

Concurrent with EASL, Achillionannounced 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 favorable IL28B CC gene variant.

All of the 8 enrolled patients completed 12 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 4 weeks after completing therapy (SVR4). ACH-3102 remained active in the presence of up to 6 baseline mutations known to confer resistance to first generations 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.

5/10/13

References

A Muir, J Hill, E Lawitz, et al. ACH-3102, a second generation NS5A inhibitor, demonstrates potent antiviral activity in patients with genotype 1a HCV infection despite the presence of baseline NS5A-resistant variants. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 876.

J Hui, L Robarge, H Robison, et al. No clinically significant pharmacokinetic interaction between sovaprevir and ACH-3102 in healthy volunteers. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 1201.

J Fabrycki, Y Zhao, D Patel, M Huang, et al. Findings from clinical virology studies on sovaprevir, a phase 2 HCV NS3 protease inhibitor, indicate a high pharmacological barrier to viral resistance. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 1200.

G Yang, D Patel, Y Zhao, et al. Findings from clinical virology studies on ACH-3102 are consistent with preclinical observations on its improved potency against genotype-1a HCV and resistant variants. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 1199.

E. Lawitz, J. Hill, B Vince, et al. ACH-2684 demonstrates potent viral suppression in genotype 1 hepatitis C patients with and without cirrhosis: safety, pharmacokinetic, and viral kinetic analysis. 48th Annual Meeting of the European Association for the Study of the Liver (EASL 2013). Amsterdam. April 24-28, 2013. Abstract 847.

Other Sources

Achillion Pharmaceuticals. Achillion Presents New Data on ACH-3102 to Treat Hepatitis C at the International Liver Congress. Press release. April 23, 2013.

Achillion Pharmaceuticals. Achillion Announces Updated Phase 2 Results Including Early Sustained Virologic Response on ACH-3102 Plus Ribavirin in Genotype 1b Treatment-Naive Hepatitis C Patients. Press release. April 23, 2013.

Achillion Pharmaceuticals. Achillion Initiates Phase 2 Interferon-Free Trial of Sovaprevir and ACH-3102 for Genotype 1 HCV. Press release. April 23, 2013.