Microneedle Delivery of Zanamivir for Treatment of Influenza

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Abstract Yearly influenza epidemics strike millions of people, causing up to 500,000 deaths. Fatality caused by most seasonal influenza viruses is <0.03%, but with significant mortality in the young and the elderly populations. When a new pathogenic influenza strain enters the population, a pandemic could kill tens of millions of people with a negative economic impact estimated to be over 150 billion dollars. Influenza virus is a NIAID category C priority biothreat, characterized as an emerging agent that is readily available and disseminated. Due to the incomplete efficacy of the current vaccines, effective drug treatment is necessary. Presently, influenza treatment is only somewhat effective, and some influenza strains are resistant to the currently marketed therapeutics, adamantanes and the neuraminidase inhibitor Tamiflu®. However, while zanamivir (Relenza®) remains highly active against oseltamivir-resistant influenza strains, its therapeutic impact is severely limited by its route of administration, via oral inhalation, which renders it unsuitable for patients with a compromised respiratory system. Therefore, development of a novel delivery alternative for zanamivir as we propose here, is poised to address a significant unmet medical need. Application of a transdermal microneedle (MN) delivery strategy to the anti-viral, and particularly anti-influenza, market offers a number of solutions to large unmet medical needs, and represents an attractive market entry strategy. Transdermal delivery systems offer a number of improvements over other delivery systems. Patches do not require swallowing, eliminating oral side effects. Permeation through the skin allows the drug to directly enter the systemic circulation and avoid any absorption and first-pass barriers a drug might encounter with oral delivery. Finally, transdermal delivery avoids skin puncture by syringe needles, eliminating pain and patient visits to a physician. Transdermal delivery of ZAN is desirable during seasonal and pandemic influenza outbreak, as large numbers of patients can be treated and the spread of the disease can be controlled. The Phase II portion of this proposal will involve formulation optimization and scale-up of the ZAN MN formulation and subsequent pharmacokinetic testing in minipigs and efficacy testing in ferrets. Human dose projections will be derived from simulation-guided PK/PD modeling and a confirmatory study in the hollow fiber infection model (HFIM). IND-enabling dermatotoxicology studies will complete the preclinical data package. All preclinical studies as well as the Phase I clinical development plans will be presented to the FDA during a pre-IND meeting. The end result of this work will be a novel, transdermal delivery approach for zanamivir with demonstrated efficacy, PK and preclinical safety data ready to open an IND application. We have assembled a team of expert advisors and collaborators to ensure successful completion of this research plan.