Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: The OPuS-2 study.

BACKGROUND: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1-INH-HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS-2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo. METHODS: OPuS-2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator-confirmed attacks. RESULTS: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack-free during the 84-day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE-QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated. CONCLUSIONS: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.

Safety, pharmacokinetics, and pharmacodynamics of avoralstat, an oral plasma kallikrein inhibitor: phase 1 study.

BACKGROUND: Avoralstat is a potent small-molecule oral plasma kallikrein inhibitor under development for treatment of hereditary angioedema (HAE). This first-in-human study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of avoralstat. METHODS: This double-blind, placebo-controlled, ascending-dose cohort trial evaluated avoralstat single doses of 50, 125, 250, 500, and 1000 mg and multiple doses up to 2400 mg daily (100, 200, 400, and 800 mg every 8 h [q8 h] up to 7 days). RESULTS: Avoralstat (n = 71) was generally well tolerated with no signals for a safety concern; there were no serious adverse events (AEs) or discontinuations due to AEs, and compared to placebo (n = 18), no notable difference in AEs. Four moderate severity AEs were reported in two subjects; syncope after a single 250 mg dose (one subject) and abdominal pain, back pain, and eczema after multiple doses of 800 mg avoralstat (one subject). For multiple-dose cohorts, the incidence of gastrointestinal AEs was highest at the 2400 mg/day dose. Elimination of avoralstat was bi-exponential with a terminal half-life of 12-31 h. Inhibition of plasma kallikrein was observed at all doses, and the degree of inhibition was highly correlated with avoralstat concentrations (R = 0.93). Mean avoralstat concentrations at doses ≥400 mg q8 h met or exceeded plasma kallikrein EC50 values throughout the dosing interval. CONCLUSION: Avoralstat was well tolerated, and drug exposure was sufficient to meet target levels for inhibition of plasma kallikrein. Based on these results, the 400 mg q8 h dose was selected for further evaluation in patients with HAE.

All-oral therapy with nucleotide inhibitors sofosbuvir and GS-0938 for 14 days in treatment-naive genotype 1 hepatitis C (nuclear).

Sofosbuvir and GS-0938 are distinct nucleotide analogues with activity against hepatitis C virus (HCV) in vitro. We evaluated the antiviral activity and safety of sofosbuvir and GS-0938 alone and in combination in HCV genotype 1 patients. In this double-blind study, 40 treatment-naïve patients were randomly assigned to 4 treatment cohorts: (i) GS-0938 for 14 days, (ii) GS-0938 for 7 days followed by GS-0938 plus sofosbuvir for 7 days, (iii) sofosbuvir for 7 days followed by GS-0938 plus sofosbuvir for 7 days and (iv) GS-0938 plus sofosbuvir for 14 days. In each arm, 8 patients received active drug and 2 placebo. After 7 days of dosing, patients in all 4 dose groups experienced substantial reductions in HCV RNA, with median declines (Q1, Q3) of -4.50 (-4.66, -4.24) in Cohort 1, -4.55 (-4.97, -4.13) in Cohort 2, -4.65 (-4.78, -4.17) in Cohort 3 and -4.43 (-4.81, -4.13) in Cohort 4; patients receiving placebo had essentially no change in HCV RNA (+0.07 log(10) IU/mL). Seven days after the end of treatment, the proportions of patients with HCV RNA <15 IU/mL were 4 (50%), 8 (100%), 7 (88%) and 5 (63%) for Cohorts 1-4, respectively, vs 0 for placebo. No viral breakthrough or resistance mutations were observed. No serious adverse events or Grade 3 or 4 adverse events were reported. Sofosbuvir and GS-0938-alone and in combination--were well tolerated and led to substantial reductions in viral load. Sofosbuvir is undergoing further investigation as a possible backbone of an all-oral regimen for chronic HCV.