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CAPSTONE-1: New antiviral superior to placebo at reducing influenza symptoms

SAN DIEGO — Treatment with the cap-dependent endonuclease inhibitor S-033188 was superior to placebo in alleviating influenza symptoms, and the agent was superior to both placebo and the antiviral oseltamivir in virologic outcomes, according to data from the phase 3 CAPTSTONE-1 trial presented here.

S-033188, which is being developed by Shionogi, is a small molecule inhibitor of the cap-dependent endonuclease with a novel mechanism of action. It showed “excellent” in vitro and in vivo antiviral activity against both A and B viruses, and it is active against both H5N1 and H7N9 avian influenza viruses, according to Simon Portsmouth, MD, medical director of Shionogi. The drug is being studied as a single, one-time oral dosing regimen for the treatment of influenza.

CAPSTONE-1 is a multicenter, randomized, double blind, placebo- and active-controlled study of more than 1,400 otherwise healthy patients aged 12 to 64 years who were diagnosed with symptomatic, uncomplicated influenza. Patients aged 20 to 64 years were randomly assigned to receive either a single oral administration of 40 mg or 80 mg of S-033188, depending on body weight; placebo; or 75 mg of oseltamivir twice a day for 5 days. Patients aged 12 to 19 years were randomly assigned to receive either a single dose of S-033188 or placebo. The study’s primary endpoint was time to the alleviation of influenza symptoms (TTAS). The researchers also monitored changes from baseline in virus titer, time to cessation of viral shedding, and time to resolution of fever and a return to pre-influenza health status.

Portsmouth and colleagues found that the median TTAS was significantly shorter in the S-033188 group compared with placebo — 53.7 hours vs. 80.2 hours (P < .0001). TTAS was similar between the S-033188 and oseltamivir groups.

Results also showed that patients who received S-033188 had significantly greater reductions since baseline in viral titer at all time points except for day 3, when compared with oseltamivir, and day 5, when compared with placebo.

The time to resolution of fever — a “more objective endpoint,” Portsmouth said — was 24.5 hours for S-033188 and 42 hours for placebo, a difference of 17.5 hours (P < .0001).

The median time to the cessation of viral shedding was 24 hours in patients treated with S-033188, 72 hours in patients treated with oseltamivir (P < .0001) and 96 hours in those who received placebo (P < .0001).

The time to return to a pre-influenza health status, which is one of the more important endpoints, Portsmouth noted, was 129.2 hours in patients who received S-033188 and 168.8 hours in patients in the placebo arm — a difference of almost 40 hours — but this finding was not statistically significant.

S-033188 was generally well-tolerated, researchers said, with a lower overall incidence of treatment-emergent adverse events (20.7%) compared with oseltamivir (24.8%) and placebo (24.6%).

“This is a new and effective antiviral drug, and the development program is ongoing,” Portsmouth concluded.

The international nonproprietary name of S-033188 is baloxavir marboxil. – by John Schoen

Reference:

Portsmouth S, et al. Abstract LB-2 Presented at: IDWeek; Oct. 4-8, 2017; San Diego.

Disclosures: The authors are employed by Shionogi.

SAN DIEGO — Treatment with the cap-dependent endonuclease inhibitor S-033188 was superior to placebo in alleviating influenza symptoms, and the agent was superior to both placebo and the antiviral oseltamivir in virologic outcomes, according to data from the phase 3 CAPTSTONE-1 trial presented here.

S-033188, which is being developed by Shionogi, is a small molecule inhibitor of the cap-dependent endonuclease with a novel mechanism of action. It showed “excellent” in vitro and in vivo antiviral activity against both A and B viruses, and it is active against both H5N1 and H7N9 avian influenza viruses, according to Simon Portsmouth, MD, medical director of Shionogi. The drug is being studied as a single, one-time oral dosing regimen for the treatment of influenza.

CAPSTONE-1 is a multicenter, randomized, double blind, placebo- and active-controlled study of more than 1,400 otherwise healthy patients aged 12 to 64 years who were diagnosed with symptomatic, uncomplicated influenza. Patients aged 20 to 64 years were randomly assigned to receive either a single oral administration of 40 mg or 80 mg of S-033188, depending on body weight; placebo; or 75 mg of oseltamivir twice a day for 5 days. Patients aged 12 to 19 years were randomly assigned to receive either a single dose of S-033188 or placebo. The study’s primary endpoint was time to the alleviation of influenza symptoms (TTAS). The researchers also monitored changes from baseline in virus titer, time to cessation of viral shedding, and time to resolution of fever and a return to pre-influenza health status.

Portsmouth and colleagues found that the median TTAS was significantly shorter in the S-033188 group compared with placebo — 53.7 hours vs. 80.2 hours (P < .0001). TTAS was similar between the S-033188 and oseltamivir groups.

Results also showed that patients who received S-033188 had significantly greater reductions since baseline in viral titer at all time points except for day 3, when compared with oseltamivir, and day 5, when compared with placebo.

The time to resolution of fever — a “more objective endpoint,” Portsmouth said — was 24.5 hours for S-033188 and 42 hours for placebo, a difference of 17.5 hours (P < .0001).

The median time to the cessation of viral shedding was 24 hours in patients treated with S-033188, 72 hours in patients treated with oseltamivir (P < .0001) and 96 hours in those who received placebo (P < .0001).

The time to return to a pre-influenza health status, which is one of the more important endpoints, Portsmouth noted, was 129.2 hours in patients who received S-033188 and 168.8 hours in patients in the placebo arm — a difference of almost 40 hours — but this finding was not statistically significant.

S-033188 was generally well-tolerated, researchers said, with a lower overall incidence of treatment-emergent adverse events (20.7%) compared with oseltamivir (24.8%) and placebo (24.6%).

“This is a new and effective antiviral drug, and the development program is ongoing,” Portsmouth concluded.

The international nonproprietary name of S-033188 is baloxavir marboxil. – by John Schoen

Reference:

Portsmouth S, et al. Abstract LB-2 Presented at: IDWeek; Oct. 4-8, 2017; San Diego.

Disclosures: The authors are employed by Shionogi.

    Perspective
    Photo of Andrew Pavia

    Andrew T. Pavia

    We have not had a new class of antiviral for influenza in almost 20 years, and we desperately need one. The drugs we have are at risk of developing resistance — we have seen that before. Having a whole new class is very exciting. This is the first phase 3 study, and it suggests that it would not have made it this far in development if there was not an impressive clinical benefit. We will need more studies, and they will have to be done in U.S. patients but hopefully, in the next 2 to 3 years, we will have a drug that we can use for drug-resistant influenza — perhaps a better drug than the ones we have now. More importantly, this would be something we can use if there was a pandemic that involved neuraminidase inhibitor resistance.

    • Andrew T. Pavia, MD
    • George and Esther Gross Presidential Professor
      Chief, division of pediatric diseases
      University of Utah

    Disclosures: Pavia reports no relevant financial disclosures.

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