Structurally and mechanistically, HCV protease inhibitors are classified as covalent reversible inhibitors (e.g. telapravir and bocepravir), or non-covalent reversible inhibitors (e.g. ITMN-191 and TMC-435.) Achillion inhibitors are non-covalent reversible inhibitors of HCV protease. The crystal structure of the enzyme/inhibitor complex, molecular modeling and analysis of white space all provided input for the design of Achillion's protease inhibitors. Comprehensive in vitro and in vivo profiling was used for prioritization and sovaprevir was selected for advancement based upon the compound's potency, unique pharmacokinetic profile, and safety.
Crystal Structure of ACH-1625
In the replicon assay, sovaprevir is equipotent against both genotype 1a and 1b at concentrations of ~1nM.
ACH-1625: Anti HCV Potency (Replicon Assay)
Sovaprevir displays a moderate shift in potency in presence of human serum. It is anticipated that trough concentration of 35 ng/ml (43 nM) will result in 0.99 to 0.999 efficacy.
Sovaprevir is highly specific for inhibition of HCV and does not inhibit HIV, RSV, HSV-1 or HBV. Further, sovaprevir displays >4000-fold selectivity against human proteases, and because of this selectivity, sovaprevir is anticipated to be better tolerated than drug candidates like telepravir that inhibit human protease (elastase and cathepsins.)
Sovaprevir has been dosed in both IV and oral forms in two species (rat and dog.) The drug candidate is rapidly and extensively partitioned into the liver with liver/plasma ratio of 120-500 (AUCliver/AUCplasma) and shows linear liver concentrations over a wide dose range. Trough liver concentrations at human equivalent doses of 100mg are in excess of the EC50. The drug is rapidly absorbed after oral dosing.
In a comparative pharmacokinetic study of sovaprevir and telepravir (VX-950), sovaprevir showed trough liver concentration well in excess of the EC50, while telepravir was undetectable in the liver 24 hours post dosing.
Sovaprevir (ACH-1625) and VX-950: Liver and Plasma Concentrations after Oral Dosing
Sovaprevir is very well tolerated with minimal dose-related effects. High safety margins have been established in single ascending dose and 7-day repeat dose toxicology studies. In these studies, trough liver concentrations at 24 hours exceeded the protein-adjusted EC50 (35 ng/ml) by more than 1000-fold.
In June 2009, Achillion began dosing in a phase 1a/1b clinical trial of sovaprevir. The trial is a randomized, double-blind, placebo-controlled trial to investigate the safety, tolerability, pharmacokinetic profile and antiviral activity of sovaprevirafter single and multiple ascending oral doses in healthy volunteers, and oral repeat doses for 5-days in subjects with hepatitis C infection. The trial is taking place in Europe and is designed to enroll at least 54 subjects, including both healthy volunteers and HCV-infected patients.
In September 2009, Achillion announced positive safety and tolerability results from the phase 1a segments of the trial. Subjects in the phase 1a single ascending dose (SAD) segment of the study received single doses of sovaprevir ranging from 50 mg to 2000 mg. Subjects in the phase 1a multiple ascending dose (MAD) segment of the study received 5 days of sovaprevir up to a maximal dose of 2000 mg per day.
Preliminary data from the SAD and MAD trial segments demonstrated:
- No serious adverse events
- No clinically significant changes in vital signs, ECGs, or laboratory evaluations
- Adverse events were mild and transient
In December 2009, Achillion announced proof-of-concept data from the first dosing cohort in the Phase 1b study. Subjects in this cohort of HCV-infected patients received doses of 600mg twice-daily (n=9, randomized to 6 active drug, 3 placebo). Preliminary results showed that a mean reduction in viral load of 3.94 log10 was achieved in the treatment group, as compared to a mean reduction of 0.22 log10 in the placebo group. All subjects in the treatment group had viral load decline between 3.0 and 4.5 log10, and two subjects reached undetectable levels of HCV RNA. Safety results from this dosing group were similar to those observed in the Phase 1a segment of the trial. There were no serious adverse events, and no clinically significant changes in vital signs, electrocardiograms or laboratory evaluations. All reported adverse events were classified as mild or moderate, were transient and showed no apparent dose relationship. Furthermore, all patients had viral loads that remained suppressed for at least seven days after dosing was completed, maintaining a mean reduction of more than 2.0 log10 from baseline through day 12, the last day of viral load measurement in the study.
In January 2010, Achillion announced results from the second dosing cohort in the Phase 1b study. HCV-infected subjects in this cohort (n=9, randomized to 6 active drug, 3 placebo) received doses of 500mg of sovaprevir twice-daily. Preliminary results showed that a mean reduction in viral load of 4.25 log10 was achieved in the treatment group, as compared to a mean reduction of 0.29 log10 in the placebo group. Safety results from this dosing group were similar to those observed in both the Phase 1a segment of the trial and in the first cohort of HCV-infected subjects. Sustained viral suppression was also similar to the first cohort of HCV-infected subjects, with patients maintaining a mean reduction of more than 3.0 log10 from baseline through day 12, seven days after dosing was completed and the last day of viral load measurement in the study.