Systemic Pharmacokinetics of Investigational Sirolimus Topical Gel 3.9% Under Maximal Use Conditions in Microcystic Lymphatic Malformations: Results From the Phase 3 SELVA PK-MuST

Introduction: Microcystic lymphatic malformations (mLM) are rare, serious, lifelong vascular anomalies driven by somatic PI3K/mTOR pathway mutations, causing lymphorrhea, bleeding, and susceptibility to infection. No FDA-approved therapies exist, and current invasive treatments (surgery, sclerotherapy, laser) are associated with frequent recurrence. Oral sirolimus has demonstrated clinical benefit in certain lymphatic malformations, but its efficacy in cutaneous microcystic LMs is limited because sirolimus is intrinsically difficult to deliver into skin due to its large molecular size, high lipophilicity, and poor aqueous solubility, constraining therapeutic drug concentrations in affected skin tissue. Chronic systemic administration also carries risk of immunosuppression and other mTOR-related systemic toxicities. Topical sirolimus 3.9% anhydrous gel, developed on the proprietary and patented QTORIN™ platform, was engineered for enhanced solubility and sustained dermal penetration with limited systemic absorption. A pharmacokinetic maximal use substudy (PK-MuST) was conducted as part of the Phase 3 SELVA trial to evaluate systemic exposure at the upper bound of anticipated clinical use. Objective: To characterize the systemic pharmacokinetic (PK) profile of sirolimus following topical application under maximal use conditions and to contextualize this exposure relative to known oral sirolimus PK parameters. Methods: PK-MuST enrolled 24 participants with mLM (5 children 6 to <12 years, 4 adolescents 12 to <18 years, 15 adults ≥18 years). The PK-MuST population spanned a broad range of disease severity (clear/almost clear to very severe) at PK sampling. Lesion area treated ranged from 10 to 375 cm² (up to 3.57% body surface area); 21 participants received 1 g (39 mg) and 3 received 2 g (78 mg) sirolimus gel once daily, adjusted for lesion size. Serial blood samples were collected on a single intensive PK sampling day and quantified using a proprietary, validated high-sensitivity LC-MS/MS assay (LLOQ 100 pg/mL), developed to resolve concentrations below the sensitivity of standard commercial assays (LLOQ 2 ng/mL). Results: Overall mean (SD) systemic sirolimus concentration from 1 to 24 hours postdose was 149 (365) pg/mL; all individual values remained below 2 ng/mL, and the majority of samples were below the limit of quantification. Concentrations were slightly higher in children than adolescents or adults, though still low overall (maximum 331 pg/mL in the 6 to <12-year group). Concentrations remained relatively stable over the 24-hour postdose period with no clearly defined peak. The 3 participants receiving the highest dose (78 mg/day) showed no meaningful exposure increase. Observed concentrations remained substantially below (~40-fold) therapeutic trough concentrations for the lowest dose typically used with oral sirolimus (5 ng/mL). Conclusions: Under maximal intended clinical use, systemic sirolimus exposure following topical application remained low and consistent across age, treated lesion area, and dose, well below oral sirolimus therapeutic thresholds. These findings support a favorable systemic exposure margin for topical sirolimus 3.9% anhydrous gel and, together with the efficacy and safety results of the Phase 3 SELVA trial, support its potential as a targeted, non-invasive treatment option for patients with mLM, a rare, serious disease with no currently approved therapies. This study was funded by Palvella Therapeutics.