FOA Number: RFA-FD-23-001 FOA Title: Clinical Studies of Orphan Products Addressing Unmet Needs of Rare Diseases (R01) Clinical Trials Required Proposal Title: SELVA: A Multicenter, Phase 3 Baseline-Controlled Study Evaluating the Safety and Efficacy of PTX- 022 in the Treatment of Microcystic Lymphatic Malformations Institute: FDA Office of Orphan Products Development Study Section: N/A Summary The objective of this project is to demonstrate the safety and efficacy of PTX-022 (sirolimus) Topical Gel 3.9% w/w for patients suffering from microcystic lymphatic malformations (microcystic LM). Microcystic LM is a serious, rare, and chronic disease of the lymphatic system characterized by lymphorrhea, acute cellulitis and significant patient morbidity. Microcystic LM is an orphan disease with no FDA approved therapies and there is an urgent need to develop the first FDA approved therapy to treat this debilitating disease. Microcystic LM is usually present at birth or shortly after, with the pathology often originating in the dermis and protruding out through the epidermis and stratum corneum. Recent studies have identified that patients with microcystic LM have postzygotic mutations in PI3K leading to abnormal and increased activation in mTOR signaling as well as its downstream target vascular endothelial growth factor (VEGF). Oral sirolimus, an mTOR inhibitor which is also known as rapamycin, has demonstrated preliminary benefit in patients with microcystic LM but its use is limited by the adverse event profile, requirement for frequent blood monitoring, and limited distribution to the skin. Therefore, Palvella Therapeutics, Inc. (Palvella) is developing PTX-022, a 3.9% topical sirolimus gel designed to deliver high levels of sirolimus directly to the site of disease, the epidermis and dermis, while avoiding the systemic side effects of oral sirolimus. PTX-022 recently completed a Phase 2, 12 patient, open-label clinical study (NCT05050149). Efficacy data from the Phase 2 study demonstrated statistically significant and clinically meaningful improvements with patients treated with PTX-022. All twelve patients who entered the study were either “much improved” (n=7, 58%) or “very much improved” (n=5, 42%) on the clinician global impression of change (CGI-C) and all twelve patients improved on the patient global impression of change (PGI-C). Based on the Phase 2 data, FDA awarded PTX-022 Breakthrough Therapy Designation for the treatment of microcystic LM. Breakthrough Therapy Designation is intended to expedite the development and review of therapies for serious or life-threatening conditions and whose preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on one or more clinically significant endpoints over existing therapies. Following a collaborative Type B Meeting with FDA in April 2024, Palvella is advancing the development of PTX-022 into a registrational Phase 3 study in patients with microcystic LM. Primar...