Triple Combination of Oseltamivir, Amantadine, and Ribavirin is Highly Synergistic Against Multiple Strains of Influenza A
Session VII – Jack Nguyen
Title of Contribution:
Triple Combination of Oseltamivir, Amantadine, and Ribavirin is Highly Synergistic Against Multiple Strains of Influenza A
Author(s):
Jack Nguyen1, Justin Hoopes2, Elizabeth Dreibe3, Menno de Jong4, Gregory Went1
Affiliation(s):
1 Adamas Pharmaceuticals, Emeryville, CA; 2 Utah State University, Logan, UT; 3Translational Genomics, Flagstaff, AZ; 4University of Amsterdam, The Netherlands
Abstract:
Influenza A viruses cause significant mortality and morbidity seasonally and pose a serious pandemic risk. One of the greatest obstacles in treating influenza is the development of drug resistance. H1N1 viruses resistant to oseltamivir, the main antiviral used for seasonal influenza and government pandemic stockpiles, have emerged globally and are dominant in many regions. Virtually all circulating strains of influenza A are resistant to one or the other of the two classes of anti-influenza drugs. As a result, there is a significant risk of the emergence of multi-drug resistant influenza. Thus, both emerging drug resistance and the limited effectiveness of current drugs for treating severe influenza represent a large unmet need for novel anti-viral strategies.
The value of a three-drug combination has yet to be realized in influenza, but it has in HIV, where certain combinations of three drugs were needed for effective treatment and prevention of resistance. We tested the effectiveness of single, double and triple combinations of approved antiviral agents (oseltamivir, amantadine, and ribavirin) against seasonal and avian viruses. The three drugs were specifically chosen to have different mechanisms of action. We found the triple combination to be highly synergistic over specific concentration ranges in in vitro models. The synergy and efficacy of the triple combination were superior to all double combinations and monotherapy, and the synergy was maintained across multiple influenza subtypes. Importantly, we found that the triple combination was effective against viruses that were previously resistant to one of the components of the triple combination.
Our data demonstrate that the triple combination of oseltamivir, amantadine, and ribavirin is highly effective at treating influenza A infection, and may represent a durable therapeutic option for seasonal and pandemic influenza. With our collaborators, we are advancing our proprietary triple combination antiviral drug formulation, which optimizes blood levels for maximum efficacy and to impede the emergence of resistance, into global clinical development for the treatment of severe influenza.
