A novel rapamycin cream formulation improves facial angiofibromas associated with tuberous sclerosis complex: a double-blind randomized placebo-controlled trial

Abstract

Background: Facial angiofibromas (FAs) are a major feature of tuberous sclerosis complex (TSC). Topical rapamycin can successfully treat FAs. A new stabilized cream formulation that protects rapamycin from oxidation has been developed in 0.5% and 1% concentrations.; Objectives: To assess the efficacy and safety of a novel, stabilized topical rapamycin cream formulation.; Methods: This multicentre double-blind randomized placebo-controlled dose-response phase II/III study with a parallel design included participants aged 6-65 years with FAs of mild or moderate severity according to the Investigator's Global Assessment (IGA) scale. Participants were randomized to one of three treatment arms: topical rapamycin 0.5%, topical rapamycin 1% or placebo. Treatment was applied once daily for 26 weeks. Safety and efficacy measures were assessed at days 14, 56, 98, 140 and 182. The primary endpoint was the percentage of participants achieving IGA scores of 'clear' or 'almost clear' after 26 weeks of treatment. Secondary measures included Facial Angiofibroma Severity Index (FASI) and participant- and clinician-reported percentage-based improvement. Safety measures included the incidence of treatment-emergent adverse events and blood rapamycin concentration changes over time.; Results: Participants (n = 107) were randomized to receive either rapamycin 1% (n = 33), rapamycin 0.5% (n = 36) or placebo (n = 38). All treated participants were included in the final analysis. The percentage of participants with a two-grade IGA improvement was greater in the rapamycin 0.5% treatment group (11%) and rapamycin 1% group (9%) than in the placebo group (5%). However, this was not statistically significant [rapamycin 0.5%: odds ratio (OR) 1.71, 95% confidence interval (CI) 0.36-8.18 (P = 0.50); rapamycin 1%: OR 1.68, 95% CI 0.33-8.40 (P = 0.53)]. There was a statistically significant difference in the proportion of participants treated with rapamycin cream that achieved at least a one-grade improvement in IGA [rapamycin 0.5%: 56% (OR 4.73, 95% CI 1.59-14.10; P = 0.005); rapamycin 1%: 61% (OR 5.14, 95% CI 1.70-15.57; P = 0.004); placebo: 24%]. Skin adverse reactions were more common in patients following rapamycin application (64%) vs. placebo (29%).; Conclusions: Both rapamycin cream formulations (0.5% and 1%) were well tolerated, and either strength could lead to clinical benefit in the treatment of FA.; Competing Interests: Conflicts of interest: P.A. and L.B. are employees of AFT Pharmaceuticals Ltd. I.S. is a shareholder and director of clinical research of AFT Pharmaceuticals Ltd. H.A. is a shareholder and managing director of AFT Pharmaceuticals Ltd and the named inventor on a patent for a rapamycin cream composition. P.B. has received financial support for conference travel and/or speaker honoraria from Novartis, Biogen, Roche and PTC Therapeutics. K.R. has received honoraria for educational symposia, advisory boards and/or consultancy work from Eisai, LivaNova, Medlink Neurology, Novartis and UCB Australia Ltd. Her institution has supported clinical trials for Biogen Idec Research, Eisai, Epigenyx Therapeutics, GW Research, Janssen-Cilag, Longboard Pharmaceuticals, Marinus Pharmaceuticals, Medicure International, LivaNova, Neurocrine Biosciences, Noema Pharma, Novartis, SK Lifesciences, Takeda Pharmaceutical Company, UCB Australia, UCB Biopharma and Zogenix. C.M., A.F., Y.-H.L., M.I., E.M.-A., D.T., S.T.D., J.J., M.N., P.B., H.N.P., K.H., K.R., S.S., M.M.T., D.B. and B.P. were investigators at NCT03826628 study sites. (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)