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. 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 (ZAN, 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 ZAN as we propose here, is poised to address a significant unmet medical need. Transdermal drug delivery offers a number of improvements over other delivery systems. The drug directly enters the systemic circulation, circumventing absorption and first-pass barriers typical for oral delivery. It avoids skin puncture by syringe needles, eliminating pain and patient visits to a clinician. Transdermal delivery of ZAN could allow large numbers of patients to be reached during an influenza outbreak, which will be particularly important in light of the added risk during the ongoing COVID-19 pandemic. While ZAN itself cannot cross the human skin barrier at therapeutic rates, Microneedle (MN) - enhanced transdermal delivery is an elegant, efficient, and painless method for increasing the skin permeation of many drugs, including ZAN. Our novel drug-device combination product, TSR-066, consists of a swellable MN patch, which will continuously deliver ZAN over 5 days. This CRP proposal will support optimization and scale-up of the ZAN MN formulation and subsequent IND- enabling toxicology studies in minipigs. We have obtained agreement with the FDA on the preclinical studies needed in order to open the IND, as well as on the Phase I clinical development plans and the 505(b)2 regulatory strategy. In addition to the experimental work proposed here, we will develop a robust IP expansion strategy for the current ZAN MN product, as well as future product candidates that stand to benefit from MN-enabled delivery. The end result of this work will be a novel, transdermal delivery approach for ZAN, which will expand its reach into patient groups for which Relenza® is contraindicated and allow for simple administration for ZAN for both treatment and prevention of the flu. We have assembled a team of expert advisors and collaborators to ensure successful completion of this research plan.

Project Narrative TSRL is developing a novel transdermal delivery product of zanamivir for the treatment and prevention of the flu. The proposed research will establish the proof-of-concept that effective treatment of the flu can be achieved with a patch.