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EASL Paris: 100% Cure Rate with AL-335, Odalasvir, and Simeprevir for 6 or 8 Weeks

A triple regimen containing 2 experimental hepatitis C drugs -- AL-335 and odalasvir -- plus simeprevir taken for either 6 or 8 weeks cured all previously untreated, non-cirrhotic patients with HCV genotype 1 in a small study, while a dual regimen without simeprevir cured 90%, according to findings presented last week at the EASL special conference New Perspectives in Hepatitis C Virus Infection - The Roadmap for Cure in Paris.

Direct-acting antiviral therapy that combines drugs targeting different steps of the hepatitis C virus (HCV) lifecycle -- usually taken for 12 weeks -- is highly effective, but researchers continue to explore new combinations that can be used for a shorter duration, thereby improving convenience and reducing cost. Ideally such therapy would be pangenotypic, meaning it is active against all HCV genotypes and can be used throughout the world without the need for prior genotypic testing.

Edward Gane from the University of Auckland and colleagues evaluated the pharmacokinetics, safety, and efficacy of regimens containing the investigational HCV polymerase inhibitor AL-335, being developed by Alios BioPharma (a subsidiary of Janssen), Achillion's pangenotypic second-generation NS5A inhibitor odalasvir (formerly ACH-3012), and Janssen's approved HCV protease inhibitor simeprevir (Olysio).

Early studies of AL-335 demonstrated potent antiviral activity even against drug-resistant HCV, and viral load reductions of up to 4.8 log IU/mL in a 7-day monotherapy study. In 2014 Gane reported high cure rates in a Phase 2 trial evaluating odalasvir plus Gilead Sciences' approved HCV polymerase inhibitor sofosbuvir (Sovaldi) in previously untreated genotype 1 patients.

The current ongoing Phase 2a study (ALS-335-604) will include up to 16 cohorts of 20 participants each, testing various dosing regimens of AL-335 plus odalasvir, with or without simeprevir, taken for 6 or 8 weeks.

Last week's presentation covered the first 4 cohorts, which enrolled an easier-to-treat population of previously untreated genotype 1 patients without liver cirrhosis. People with genotype 3 and those with compensated cirrhosis are included in later cohorts.

This interim analysis included 80 treatment-naive chronic hepatitis C patients. About two-thirds were men, most were white, and the mean age was about 53 years. About 80% had harder-to-treat HCV genotype 1a, the rest 1b, with a mean baseline HCV viral load of about 6.2 log IU/mL. The average FibroScan liver stiffness score was approximately 6.0 kPa, suggesting mostly mild to moderate fibrosis.

Participants in this open label study received AL-335 at doses of 400 or 800 mg once-daily (QD), odalasvir at 50 mg once-daily or every-other-day (QOD), and simeprevir at 75 or 100 mg once-daily. They were allocated to 4 cohorts:

• Cohort 1: AL-335 400 mg QD + odalasvir 50 mg QD + simeprevir 100 mg QD for 8 weeks;
• Cohort 2: AL-335 800 mg QD + odalasvir 50 mg QOD for 8 weeks (no simeprevir);
• Cohort 3: AL-335 800 mg QD + odalasvir 50 mg QOD + simeprevir 75 mg QD for 8 weeks;
• Cohort 4: AL-335 800 mg QD + odalasvir 50 mg QOD + simeprevir 75 mg QD for 6 weeks.

Results

• 100% of participants in the 3 cohorts receiving triple therapy achieved sustained virological response at 12 weeks after completing treatment (SVR12).
• In the dual therapy cohort that did not receive simeprevir, the SVR12 rate fell to 90%.
• The 2 relapsers in Cohort 2 developed NS5A mutations that confer resistance to odalasvir.
• Treatment was generally safe and well-tolerated.
• There were 1 serious adverse event leading to treatment discontinuation -- an atrioventricular block (a type of heart rhythm abnormality) considered probably related to the study drugs.
• A majority of adverse events were mild, with the most common being headache (18 reports), fatigue (15), respiratory tract infections (11), and bruising (9).
• There were few grade 3 or higher laboratory abnormalities and no clinically relevant echocardiogram changes.

Based on these findings, the researchers concluded that AL-335 + odalasvir with or without simeprevir "was highly effective in treatment-naive patients with HCV genotype 1 without cirrhosis." They added that these results support evaluation of triple combinations in people with genotype 3 or cirrhosis.

A larger Phase 2b trial (NCT02765490) evaluating 800 mg AL-335 + 25 mg odalasvir + 75 mg simeprevir, all once-daily for 6 or 8 weeks, is expected to begin enrollment this fall for treatment-naive and treatment-experienced non-cirrhotic patients with HCV genotypes 1, 2, 4, 5, and 6.

9/28/16

Reference

E Gane, M McClure, D Apelian, et al. Short duration treatment with AL-335 and odalasvir (ODV), with or without simeprevir (SMV), in treatment naive patients with hepatitis C virus (HCV) genotype (GT) 1 infection. New Perspectives in Hepatitis C Virus Infection - The Roadmap for Cure. Paris, September 23-24, 2016.Abstract 178.

Other Source

Achillion Pharmaceuticals. Achillion Announces 100% SVR12 in the 6-Week and 8-Week Cohorts in Janssen’s Phase 2 Trial Evaluating the Triple Combination Treatment Regimen Including Odalasvir, AL-335, and Simeprevir for Genotype 1 Treatment-Naive HCV. Press release. September 23, 2016.