Cap-dependent endonuclease (CEN) resides in the PA subunit of influenza virus polymerase and mediates the “cap-snatching” process during viral mRNA biosynthesis. S-033188 is a potent, selective, small molecule inhibitor of CEN. Here we report clinical and virologic outcomes from a global Phase 3 study CAPSTONE-1.
This was a multicenter, randomized, double-blind, placebo- and active-controlled study. Key eligibility criteria included 12 to 64 years of age, fever (axillary temperature ≥ 38.0°C), ≥ 1 general symptom and ≥ 1 respiratory symptom (moderate to severe), and ≤ 48 hours from symptom onset. Patients between 20 and 64 years of age were randomized in 2:2:1 ratio to receive a single oral administration of S-033188, placebo, or 75 mg oseltamivir BID for 5 days. Patients between 12 and 19 years of age were randomized in 2:1 ratio to receive either a single oral administration of S-033188 or placebo. The primary efficacy endpoint was time to alleviation of influenza symptoms (TTAS) in the infected intent to treat population. Viral titer and RNA content were determined from pre- and post-dose nasal/throat swabs.
A total of 1,436 patients were randomized. TTAS was significantly shorter in the S-033188 group than in the placebo group (median TTAS: 53.7 hours vs 80.2 hours, p<0.0001). Median time to cessation of viral shedding was 24 hours in patients treated with S-033188, compared to 72 hours in those treated with oseltamivir (p<0.0001) and 96 hours for placebo (p<0.0001). Patients in the S-033188 group had significantly greater reductions from baseline in both viral titer and RNA content than those in oseltamivir or placebo groups at all time-points until Day 3 (compared with oseltamivir) or Day 5 (compared with placebo). S-033188 was generally well tolerated, with overall incidence of treatment-emergent adverse events lower than that seen with oseltamivir.
Treatment with S-033188 was superior to placebo in alleviating influenza symptoms, and superior to both oseltamivir and placebo in virologic outcomes. Safety profile of S-033188 compared favorably to that of oseltamivir.
M. Arai, Shionogi & Co Ltd: Employee , Salary
K. Tsuchiya, Shionogi & Co., Ltd.: Employee , Salary
T. Uehara, Shionogi & Co., Ltd.: Employee , Salary