Baloxavir: First Global Approval

Influenza antiviral drugs are important for the control of influenza, most specifically for the treatment of influenza patients with severe disease following infection with a seasonal influenza virus, a newly emerging influenza strain, or in the event of a pandemic. Many influenza antivirals that are currently under investigation in late‐stage clinical trials differ in their mechanism of action compared to drugs currently licensed for the treatment of influenza. Nitazoxanide and DAS181 target components of the host cell and alter the ability of the virus to replicate efficiently, while small molecule drugs such as T705, JNJ63623872 and S‐033188 bind to the viral polymerase complex and restrict viral replication. Monoclonal antibodies that are currently in clinical trial for the treatment of influenza most commonly are targeted to the stem region of the haemagglutinin molecule. Early findings from animal models and in vitro studies suggest that many of the new antiviral drugs when tested in combination with oseltamivir have improved effectiveness over monotherapy. Clinical trials assessing both monotherapy and combination therapy are currently under investigation. It is hoped that as new antivirals are licensed, they will improve the standard of care and outcomes for influenza patients with severe disease. Show more

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. Conclusion 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 with that of oseltamivir. Disclosures S. Portsmouth, Shionogi Inc.: Employee, Salary. K. Kawaguchi, Shionogi & Co., Ltd.: Employee, Salary. M. Arai, Shionogi & Co Ltd: Employee, Salary. K. Tsuchiya, Shionogi & Co., Ltd.: Employee, Salary. T. Uehara, Shionogi & Co., Ltd.: Employee, Salary. Show more

Abstract Background S-033447, an active form of orally available prodrug S-033188, is a novel small molecule inhibitor of cap-dependent endonuclease that is essential for influenza virus transcription and replication. In this study, we evaluated the inhibitory effect of S-033188 in combination with neuraminidase inhibitors on the replication of influenza A/H1N1 virus in cultured cells. Methods The inhibitory effects of S-033447 in combination with NA inhibitors on the cytopathic effect of A/PR/8/34 strain in Madin–Darby canine kidney cells cultured for 2 days were tested and EC50 were determined. The combination index (CI), which were obtained when S-033188 and NA inhibitor were added at the closest ratio of each EC50 value, were used for the evaluation of these combinational effects (Table 1). CI values were calculated by the Chou and Talalay method, in which combinational effect were determined according to the criteria as follows: synergistic if CI ≤ 0.8, additive if 0.8 < CI < 1.2, and antagonistic if CI ≥ 1.2. CI = (DA/A + B)/DA + (DB/A + B)/DB + (DA/A + B × DB/A + B)/(DA × DB) DA: the EC50 of S-033447 DB: the EC50 of NA inhibitor DA/A + B: the concentration of S-033447 giving 50% inhibition in combination with NA inhibitor at the closest ratio of each EC50 value DB/A + B: the concentration of NA inhibitor giving 50% inhibition in combination with S-033447 at the closest ratio of each EC50 value Results All CI values were lower than 0.8, under the condition that both S-033447 and NA inhibitor (oseltamivir acid, zanamivir hydrate, laninamivir, or peramivir trihydrate) were added at the closest ratio of each EC50 value (Table 1). Conclusion S-033447 in combination with oseltamivir acid, zanamivir hydrate, laninamivir, or peramivir trihydrate synergistically inhibited the replication of influenza A/H1N1 virus in MDCK cells. Table 1. Combination effect of S-033447 and NA inhibitor in MDCK cells infected with A/PR/8/34 strain Substance A Substance B DA (nmol/L) DB (nmol/L) DA/A+B (nmol/L) DB/A+B (nmol/L) CI Combination effect S-033447 oseltamivir acid 4.51 3171.97 1.17 586.94 0.49 synergistic S-033447 zanamivir hydrate 4.49 1565.38 1.22 305.99 0.52 synergistic S-033447 laninamivir 4.52 212.74 1.12 56.02 0.58 synergistic S-033447 peramivir trihydrate 4.41 213.77 1.13 56.66 0.59 synergistic Disclosures All authors: No reported disclosures. Show more