Phase 1 Clinical Trial to Assess the Pharmacokinetics, Safety and Tolerance of a Zanamivir Transdermal System in Healthy Subjects

Abstract Yearly influenza epidemics strike millions of people, resulting in up to 500,000 deaths. Fatalities caused by most seasonal influenza viruses is <0.03%, with significant mortality in the young and elderly populations. Presently, influenza treatment is only partially effective, and some influenza strains are resistant to the currently marketed therapeutics, adamantanes and the neuraminidase inhibitor Tamiflu®), and even the recently approved cap- dependent endonuclease inhibitor baloxavir marboxil (Xofluza®). Zanamivir (ZAN, Relenza®), remains highly active against oseltamivir-resistant influenza strains, however, its therapeutic impact is severely limited by its route of administration, oral inhalation, which renders it unsuitable for patients with compromised respiratory systems. Therefore, the development of a novel delivery alternative for ZAN will address a significant unmet medical need. Transdermal drug delivery offers several improvements over other delivery systems. The drug directly enters the systemic circulation, avoiding syringe needles, and could allow large numbers of patients to be reached during an influenza pandemic outbreak. ZAN itself cannot cross the human skin barrier at therapeutic rates, however, microarray-enabled 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 microarray patch (MAP), which continuously delivers ZAN over 5 days. This delivery approach for ZAN will expand its reach into patient groups for which Relenza® is contraindicated. Based on the well-established preclinical and clinical safety of ZAN, TSRL has achieved an agreement with the FDA that TSR-066 can be developed using a 505(b)2 regulatory strategy. Upon collection of sufficient data to support the change in the route of administration under our ongoing SBIR grants, TSRL plans to submit an investigational new application (IND) in 2024. This Fast-Track SBIR will allow for the planning and conduct of a Phase 1 clinical trial to assess the pharmacokinetics, safety and tolerance of TSR-066 in healthy subjects. During the Phase I portion of the grant, we will assemeble the clinical development team, develop the clinical protocol, investigator brochure, consent form, case report form, budget, and manual of operations. These documents will be prepared through collaboration with BIA Clinical Group, LLC and reviewed by our scientific collaborators, the clinical research unit utilized for the study, and participating Clinical Research Organizations. The Phase II portion of the grant will be the actual conduct of the trial. We have formed a collaborative network of researchers and drug development specialists that will allow us to successfully complete the proposed research plan.