Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza

Objective. - The current study evaluated whether intranasal administration of the sialic acid analog 4-guanidino-Neu5Ac2en (GG167), an inhibitor of influenza virus neuraminidase, was effective and safe in either preventing or treating experimental human influenza. Methods. - Four randomized, double-blind, placebo-controlled trials involving three prophylaxis limbs, two early treatment limbs, and one delayed treatment limb were conducted. Setting. - Isolation in individual rooms. Participants. - Susceptible (serum hemagglutination-inhibition antibody titer less than or equal to 1:8) adult volunteers (n=166) were inoculated intranasally with 10(5) TCID50 influenza A/Texas/91 (H1N1) virus. Intervention. - 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. - Virological measures were frequency of infection based on viral shedding and/or seroconversion (prophylaxis) or quantitative viral shedding based on titers and duration of virus recovery (treatment). Clinical measures were the frequency of febrile illness and symptom severity scores. Results. - Intranasal GG167 was well tolerated for both prophylaxis and therapy, For all dose groups combined, GG167 prophylaxis was 82% effective in preventing laboratory evidence of infection and 95% effective in preventing febrile illness (P<.01 vs placebo). Early treatment with GG167 reduced peak viral titers by 2.0 log(10), the median duration of viral shedding by 3 days, and the frequency of febrile illness by 85% (P<.05 for each comparison). Other measures of illness were reduced by approximately 50% to 70% in the GG167 dosing groups. Twice daily dosing was as effective as six times daily. Conclusions. - Direct respiratory administration of the selective neuraminidase inhibitor GG167 appears safe and effective for both prevention and early treatment of experimental influenza. Influenza virus neuraminidase is important for viral replication in humans.