SAFETY AND EFFICACY OF THE NEURAMINIDASE INHIBITOR GG167 IN EXPERIMENTAL HUMAN INFLUENZA

Objective. - The current study evaluated whether intranasal administra tion of the sialic acid analog 4-guanidino-Neu5Ac2en (GG167), an inhib itor of influenza virus neuraminidase, was effective and safe in eithe r preventing or treating experimental human influenza. Methods. - Four randomized, double-blind, placebo-controlled trials involving three p rophylaxis limbs, two early treatment limbs, and one delayed treatment limb were conducted. Setting. - Isolation in individual rooms. Partic ipants. - Susceptible (serum hemagglutination-inhibition antibody tite r less than or equal to 1:8) adult volunteers (n=166) were inoculated intranasally with 10(5) TCID50 influenza A/Texas/91 (H1N1) virus. Inte rvention. - GG167, 3.6 to 16 mg, was administered intranasally two or six times daily beginning 4 hours before inoculation (prophylaxis) or 1 or 2 days afterward (early or delayed treatment). Main Outcomes. - V irological measures were frequency of infection based on viral sheddin g and/or seroconversion (prophylaxis) or quantitative viral shedding b ased on titers and duration of virus recovery (treatment). Clinical me asures were the frequency of febrile illness and symptom severity scor es. Results. - Intranasal GG167 was well tolerated for both prophylaxi s and therapy, For all dose groups combined, GG167 prophylaxis was 82% effective in preventing laboratory evidence of infection and 95% effe ctive in preventing febrile illness (P<.01 vs placebo). Early treatmen t with GG167 reduced peak viral titers by 2.0 log(10), the median dura tion of viral shedding by 3 days, and the frequency of febrile illness by 85% (P<.05 for each comparison). Other measures of illness were re duced by approximately 50% to 70% in the GG167 dosing groups. Twice da ily dosing was as effective as six times daily. Conclusions. - Direct respiratory administration of the selective neuraminidase inhibitor GG 167 appears safe and effective for both prevention and early treatment of experimental influenza. Influenza virus neuraminidase is important for viral replication in humans.