Core Insights - Recent advances in understanding the pathogenesis of venous malformations (VMs) highlight the PI3K/AKT/mTOR pathway as a key driver of disease proliferation, leading to increased off-label use of systemic rapamycin (sirolimus) for treatment [1][4] - A systematic review of 26 studies involving 98 patients treated with rapamycin for VMs supports the clinical potential of Palvella's QTORIN™ 3.9% rapamycin anhydrous gel, which is currently under evaluation in the Phase 2 TOIVA trial [2][3] Company Overview - Palvella Therapeutics, Inc. is a clinical-stage biopharmaceutical company focused on developing therapies for serious, rare genetic skin diseases without FDA-approved treatments [7] - The company is developing a pipeline based on its patented QTORIN™ platform, with QTORIN™ rapamycin being its lead product candidate [7] Industry Context - There is a significant unmet clinical need for effective treatments for cutaneous VMs, with no FDA-approved pharmacologic options currently available [2][6] - The estimated number of diagnosed patients with cutaneous VMs in the U.S. exceeds 75,000, highlighting the urgency for targeted therapies [5][6] Clinical Findings - The systematic review indicates that off-label use of rapamycin has shown efficacy in improving various clinical signs, including bleeding and quality of life, despite inadequate responses to standard treatments [4] - A targeted, topical formulation of rapamycin could provide clinical benefits by achieving therapeutic levels in the dermis while minimizing off-target effects associated with oral rapamycin [4] Regulatory Status - In April 2024, the FDA granted Fast Track Designation to QTORIN™ rapamycin for the treatment of VMs, indicating the potential for expedited development and review [5]