Topical Rapamycin Therapy to Alleviate the Cutaneous Manifestations of Tuberous Sclerosis Complex: A Double-Blind,Randomized, Controlled Trial to Evaluate the Safety and Efficacy of Topically Applied Rapamycin

Background and Objectives

Facial angiofibromas are disfiguring facial lesions, present in up to 80% of patients with tuberous sclerosis complex. Recent elucidation of the complex cell signaling pathways that are disrupted in tuberous sclerosis indicates that rapamycin may be successful in alleviating the appearance of these lesions. The objectives of the current study were to evaluate the safety of topically applied rapamycin in patients with tuberous sclerosis complex and to determine its potential effectiveness in treatment of facial angiofibromas.

Patients and Methods

The study was a prospective, randomized, double-blind, placebo-controlled study performed at the University of Texas Health Science Center at Houston. Study subjects were recruited from the patient populations at the University of Texas Tuberous Sclerosis Center of Excellence. All subjects were over the age of 13 years and had a diagnosis of tuberous sclerosis complex. Subjects were excluded if they were using any form of rapamycin or if they were pregnant. Study subjects applied the study product to their facial angiofibromas nightly for a duration of 6 months. The investigational product contained one of three doses of rapamycin compounded with Skincerity®: (i) no rapamycin; (ii) 1 mg of rapamycin per 30 cc (0.003%); or (iii) 5 mg of rapamycin per 30 cc (0.015%). Plasma rapamycin concentrations were measured monthly to test for systemic absorption. Complete blood counts were performed monthly to test for anemia, neutropenia, or thrombocytopenia. Upon completion of the trial, subjects were asked if the formulation had improved the appearance of their facial angiofibromas.

Results

Twenty-three subjects completed the study. There was no detectable systemic absorption of rapamycin (all blood concentrations were <1.0 ng/mL). There were no significant changes in white blood cell, red blood cell, or platelet counts. Seventy-three percent of subjects in the treatment arms versus 38% of subjects in the placebo arm reported a subjective improvement in the appearance of their facial angiofibromas.

Conclusion

The application of low-dose topical rapamycin (0.003–0.015%) to the face can safely decrease the appearance of facial angiofibromas in patients with tuberous sclerosis complex.

Trial Registration

ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01031901","term_id":"NCT01031901"}}NCT01031901Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder characterized by the formation of benign tumors in multiple organ systems. Facial angiofibromas appear as red or pink papules over the central face, especially on the nasolabial folds, cheeks, and chin,[1] in people with TSC. Lesions arise in early childhood and are present in up to 80% of TSC patients.[1,2] In some patients, the lesions become confluent and can result in severe disfigurement. Although multiple treatments have been developed to alleviate the appearance of facial angiofibromas – curettage, cryosurgery, chemical peels, dermabrasion, shave excisions, and laser therapy[3–8] – these are uncomfortable and need to be repeated at periodic intervals to treat recurrence.[9]In patients with TSC, the mammalian target of rapamycin (mTOR) is aberrantly activated in fibroblast-like cells located within the dermal layer of the skin. These cells produce an epidermal growth factor, epiregulin, which stimulates epidermal cell proliferation.[10] Epidermal cells are produced at a faster rate than the ability to slough the dead cells from the skin surface.[11] This overproduction of skin cells, in conjunction with angiogenesis, results in the initial appearance and continued progression of facial angiofibromas over time.Recent elucidation of the complex signaling relationship between the tuberous sclerosis 1 (TSC1) and tuberous sclerosis 2 (TSC2) gene products and mTOR has led to an explosion of research related to the use of mTOR inhibitors, such as rapamycin, in TSC. These mTOR inhibitors are showing promise in treating multiple tumor types, including renal angiomyolipomas (AMLs), sub-ependymal giant cell astrocytomas (SEGAs), and lymphangioleiomyomatosis (LAM).[12–15]Rapamycin is a naturally occurring antifungal macrolide, first isolated from Streptomyces hygroscopicus in 1965. Rapamycin binds with high specificity to mTOR, and binding results in inhibition of mTOR activity and ultimately in downregulation of cell growth.[16] Rapamycin has a molecular weight of 914.2 grams/mol, allowing for its absorption through the superficial layers of the epidermis to the deep dermal layer implicated in the development of facial angiofibromas.The primary goal of this study was to evaluate the safety of topical rapamycin (0.003% and 0.015%) in patients with TSC. The secondary goal of this study was to evaluate the efficacy of the topical product for treatment of facial angiofibromas.