Safety and Efficacy of the Sirolimus Gel for TSC Patients With Facial Skin Lesions in a Long-Term, Open-Label, Extension, Uncontrolled Clinical Trial

Abstract

Introduction Our previous clinical studies have demonstrated the short-term efficacy and safety of the sirolimus gel for patients with tuberous sclerosis complex (TSC). However, long-term clinical evidence is lacking. Our objective was to assess the safety and efficacy of long-term treatment with the sirolimus gel for the skin lesions of TSC patients. Methods We conducted a multicenter, open-label, uncontrolled clinical trial in 94 Japanese patients with TSC. Patients applied the 0.2% sirolimus gel on their face or head twice daily for > 52 weeks (maximum 136 weeks for safety). The safety endpoints were the rate of adverse event (AE)-caused discontinuation (primary endpoint) and the incidence of AEs. The efficacy endpoint was the response rate of angiofibromas, cephalic plaques, and hypomelanotic macules. Results Among 94 enrolled patients (mean age, 21 years; range 3–53 years), the rate of AE-caused discontinuation was 2.1% (2/94 patients). Although application site irritation and dry skin occurred relatively frequently, none of the drug-related AEs were serious; most of the drug-related AEs resolved rapidly. The major drug-related AEs (≥ 5% in incidence) were application site irritation (30.9%), dry skin (27.7%), acne (20.2%), eye irritation (8.5%), pruritus (8.5%), erythema (7.4%), dermatitis acneiform (6.4%), and dermatitis contact (5.3%). The response rates of angiofibromas, cephalic plaques, and hypomelanotic macules were 78.2% [95% confidence interval (CI) 68.0–86.3%], 66.7% (95% CI 51.1–80.0%), and 72.2% (95% CI 46.5–90.3%), respectively. Conclusions The gel was well tolerated for a long time by patients with TSC involving facial skin lesions and continued to be effective. Trial Registration ClinicalTrials.gov identifier: NCT02634931.

Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations

“…Topical sirolimus is safe and effective for treating facial angiofibromas 151,152 (Category 1), and it may also improve other TSC skin lesions [153][154][155] (Category 2A). Topical medication is generally applied once or twice daily and compounded by specialty pharmacies at 0.1% to 1% concentration in a variety of vehicles.…”

“…Long-term therapy will likely be required to maintain benefit. 153,154 Adverse effects of topical sirolimus are generally mild, such as application-site skin irritation, dry skin, or acne. 154 Systemic absorption of topical sirolimus is typically below the level of detection.…”

“…153,154 Adverse effects of topical sirolimus are generally mild, such as application-site skin irritation, dry skin, or acne. 154 Systemic absorption of topical sirolimus is typically below the level of detection. 151,152 Sirolimus has anticancer effects, but one study of topical sirolimus reported increased skin tumors in mice treated with a regimen of topical sirolimus and solar simulated light.…”

Characterization and Management of Facial Angiofibroma Related to Tuberous Sclerosis Complex in the United States: Retrospective Analysis of the Natural History Database

“…Various topical formulations of the mTOR inhibitor sirolimus (rapamycin) are effective and generally well tolerated for the management of facial angio broma based on several short-term studies (15,16). which was further established over the long term (17,18). Hatano et al reported improvements in health-related quality of life (HRQoL) in patients treated with sirolimus gel for the management of facial angio broma (19).…”

Improved Skin Permeability after Topical Treatment with Serine Protease: Probing the Penetration of Rapamycin by Scanning Transmission X-ray Microscopy

“… 12 Short-term efficacy and safety aspects of rapamycin gels for patients with tuberous sclerosis complex have been investigated more recently. 13 Furthermore, human skin explants treated with rapamycin were investigated in a culture medium revealing histological changes and reduced keratinocyte proliferation. 8 Rapamycin is known to act as a mammalian target of rapamycin (mTOR) inhibitor, 14 − 16 where the complexity of the mTOR pathway has been reviewed before.…”