1、Cap-dependent Endonuclease Inhibitor S-033188 for the Treatment of Influenza: Results from a Phase 3, Randomized, Double-Blind, Placebo- and Active-Controlled Study in Otherwise Healthy Adolescents and Adults with Seasonal Influenza
Simon Portsmouth, MD,1 Keiko Kawaguchi, MS,2 Masatsugu Arai, MS,3 Kenji Tsuchiya, MS,2 and Takeki Uehara, PhD2

Abstract Background 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. Method This was a multicenter, randomized, double-blind, placebo- and active-controlled study. Key eligibility criteria included 12–64 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 postdose nasal/throat swabs. Result A total of 1436 patients were randomized. TTAS was significantly shorter in the S-033188 group than that 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 with 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.

2、Antivirals in medical biodefense
J. J. Bugert, F. Hucke, P. Zanetta, M. Bassetto & A. Brancale

Abstract The viruses historically implicated or currently considered as candidates for misuse in bioterrorist events are poxviruses, filoviruses, bunyaviruses, orthomyxoviruses, paramyxoviruses and a number of arboviruses causing encephalitis, including alpha- and flaviviruses. All these viruses are of concern for public health services when they occur in natural outbreaks or emerge in unvaccinated populations. Recent events and intelligence reports point to a growing risk of dangerous biological agents being used for nefarious purposes. Public health responses effective in natural outbreaks of infectious disease may not be sufficient to deal with the severe consequences of a deliberate release of such agents. One important aspect of countermeasures against viral biothreat agents are the antiviral treatment options available for use in post-exposure prophylaxis. These issues were adressed by the organizers of the 16th Medical Biodefense Conference, held in Munich in 2018, in a special session on the development of drugs to treat infections with viruses currently perceived as a threat to societies or associated with a potential for misuse as biothreat agents. This review will outline the state-of-the-art methods in antivirals research discussed and provide an overview of antiviral compounds in the pipeline that are already approved for use or still under development.