Patient- and Clinician-Reported Meaningfulness of Treatment-Related Change Following Investigational Sirolimus Topical Gel 3.9% in Microcystic Lymphatic Malformations: Qualitative Findings From the Phase 3 SELVA Trial Show Clinical Benefit and High Treatment Satisfaction

Introduction: Microcystic lymphatic malformations (mLM) are lifelong, rare, and serious vascular anomalies associated with substantial physical and psychosocial morbidity. Currently, no FDA-approved therapeutics exist; disease management involves invasive procedures (surgery, sclerotherapy, laser) and off-label oral and topical sirolimus, all associated with inconsistent results. Sirolimus topical gel 3.9%, developed on the QTORIN™ platform to address these unmet therapeutic needs, was evaluated in the pivotal Phase 3 SELVA trial. Consistent with regulatory guidance emphasizing the patient voice in drug development, an embedded qualitative interview study characterized patient/caregiver perspectives of mLM and the meaningfulness of treatment-related change. Objective: To contextualize clinical trial efficacy endpoints through the patient/caregiver experience and evaluate treatment satisfaction following topical sirolimus 3.9% gel. Methods: Semi-structured entry (baseline) and exit (Day 168) interviews were conducted with trial participants and/or their caregivers (for participants <12 years), alongside independent clinician exit interviews; interviews were analyzed thematically. Entry interviews included 42 participants and exit interviews included 38 participants, drawn from the SELVA intent-to-treat population (N=49); 41 participants who took part in interviews were discussed during clinician interviews. Participant-reported secondary efficacy endpoints assessing disease severity and treatment-related changes (PGI-S and PGI-C) were collected throughout the trial. Together with results from the Treatment Satisfaction Questionnaire for Medication (TSQM) administered at Day 168, data outputs were compared to evaluate the meaningfulness of reported changes. Results: At entry, participants described substantial physical (bleeding/leaking, discoloration, swelling, pain), emotional (self-consciousness, anxiety, frustration), and social (clothing limitations, school/work disruption, relationship impact) burden. At Day 168, 41 of 43 participants (95.3%) achieved at least a 1-point improvement on the mLM Investigator Global Assessment (mLM-IGA; primary endpoint), and 37 (86.0%) achieved a 2-point or greater improvement, corresponding to ratings of much or very much improved. Among participants completing exit interviews, all participants reported improvement in at least 1 symptom, most commonly bleeding/leaking and color (65% each). Participants described these changes as meaningful given the chronic, progressive nature of mLM and absence of effective therapies. Clinicians independently reported improvement in at least 1 sign or symptom for 98% of participants discussed, most often in height/thickness (93%), bleeding/leaking (73%), and color/vesicle appearance (71%). Improvements elicited meaningful quality-of-life benefits, including greater participation in physical activities, increased freedom in clothing choices, and improved emotional wellbeing. At Day 168, 100% of participants reported being at least somewhat satisfied with treatment on the TSQM overall satisfaction item. Conclusions: Qualitative interviews and TSQM data converged with quantitative Phase 3 endpoints, showing that topical sirolimus 3.9% gel drove consistent, clinically meaningful improvements across patient, caregiver, and clinician perspectives, including a 95.3% response rate on the primary mLM-IGA endpoint, with 100% of participants reporting treatment satisfaction at Day 168. These concordant findings validate the interpretability of the SELVA efficacy endpoints and support topical sirolimus 3.9% gel as a potential first therapeutic option for mLM, a rare, serious, and historically underserved disease. This study was funded by Palvella Therapeutics.