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.

Keywords: Angiofibromas; Cephalic plaques; Clinical trial; Hypomelanotic macules; Long-term administration; Sirolimus gel; Skin lesions; Topical sirolimus; Tuberous sclerosis complex.

Figures

Fig. 1

Patient disposition. Ninety-four patients with TSC were enrolled in the present clinical trial, 62 of whom had been enrolled in the 12-week phase 3 clinical trial (the sirolimus 0.2% gel group: 30 patients; the placebo group: 32 patients). Thirty-three patients were newly enrolled. The gel treatment was discontinued in six patients because of AEs or other reasons prior to week 52 of treatment, and 88 patients continued the treatment thereafter. All of the latter were considered to have completed the treatment. The present clinical trial was terminated when the gel became commercially available in Japan. This cohort of patients includes patients for whom the treatment was discontinued for other reasons at week 52 of treatment or later. TSC tuberous sclerosis complex, AEs adverse events

Fig. 2

Cumulative incidences of drug-related AEs. The 0.2% sirolimus gel was applied twice daily to 94 patients with TSC for a maximum of 136 weeks, and 8 drug-related AEs (incidence: ≥ 5%) expressed with the preferred terms of MedDRA were estimated by the Kaplan-Meier method and plotted separately. Event was represented by the day when an AE occurred and censored by the day of discontinuing or terminating the application of the gel. TSC tuberous sclerosis complex, MedDRA the preferred terms of the Medical Dictionary for Regulatory Activities, AEs adverse events

Fig. 3

Kaplan-Meier curves of the survival rates of drug-related AEs. The sirolimus 0.2% gel was applied to 94 patients with TSC for a maximum of 136 weeks. The durations—lasting from the day of onset to the day of recovery or disappearance—of eight drug-related AEs (incidence: ≥ 5%) expressed with the preferred terms of MedDRA were plotted separately. Event was expressed by the day when an AE recovered or disappeared, and censor by the day of discontinuing or terminating the application. AEs adverse events, TSC tuberous sclerosis complex, MedDRA Medical Dictionary for Regulatory Activities

Fig. 4

Time-course changes in the response rates of skin lesions of patients with TSC. a Angiofibromas. The whole group (n = 92), adults (n = 43), and children (n = 49) are shown. A statistically significant difference (Fisher’s exact test) was found between adults and children at week 12. b Cephalic plaques. The whole group (n = 47), adults (n = 16), and children (n = 31) are shown. c Hypomelanotic macules. The whole group (n = 18), one adult, and children (n = 17) are shown. d Oral mTORC1 inhibitors. The response rates of the 0.2% sirolimus gel were calculated as proportions of patients who were adjudicated by the IRC to “markedly improved” or “improved.” Bars represent the 95% confidence intervals. TSC tuberous sclerosis complex, mTORC1 mammalian target of rapamycin complex 1, IRC independent review committee

Fig. 5

Photographs of three patients with typical skin lesions of TSC. The 0.2% sirolimus gel was applied twice daily, and photographs were taken at baseline and at weeks 26 and 52 of treatment. a A 17-year-old female had severe angiofibromas, and her nose was totally covered by myriad reddish nodules at baseline. The nodules and reddishness reduced over time at weeks 26 and 52 of treatment. b A 22-year-old female had a relatively large plaque on the left temple. The plaque reduced in elevation over time. At week 52 of treatment, the plaque resolved nearly completely and became flat, although faint reddishness persisted. c A 10-year-old female had a hypomelanotic macule (white arrow) on the forehead at baseline. Over time, the macule became unclear and indistinct in color from the peripheral normal skin. Patients consented to publication. TSC tuberous sclerosis complex

Fig. 6

Blood sirolimus concentrations in relation to sex and age. Blood sirolimus concentrations measured by LC/MS/MS at every scheduled visit are shown in the form of box-and-whisker plots. The lower limit of detection was set to 0.1 ng/ml, and a measured value of a Patients are plotted for a stratification factor—sex (F = female, M = male). b Patients are plotted for a stratification factor—adults (Adl, ≥ 19 years)/children (Chl, 3–18 years). LC/MS/MS liquid chromatography/mass spectrometry

Fig. 7

Effects of the concurrent use of the 0.2% sirolimus gel and topical moisturizers. Time course changes in the response rates of angiofibromas by the concurrent use of topical petrolatum (a) or (b) heparinoid. Blood sirolimus concentrations are shown in the form of box-and-whisker plots for a stratification factor—topical petrolatum (c) or (d) heparinoid (Hirudoid®)—which was used concurrently as a moisturizer (N = no, Y = yes). Blood sirolimus concentrations were measured by LC/MS/MS at every scheduled visit. The lower limit of detection is set to 0.1 ng/ml, and a measured value of < 0.1 ng/ml is expressed as 0. The upper and lower borders of the boxes indicate the first and third quantiles. The median is indicated as a line within the boxes, and the whiskers represent the maximum and minimum. The outliers are shown as circles outside the whiskers. LC/MS/MS, liquid chromatography/mass spectrometry

Fig. 8

Blood sirolimus concentrations in relation to drug-related AEs and improvements in angiofibromas. Blood sirolimus concentrations measured by LC/MS/MS at every scheduled visit are shown in the form of box-and-whisker plots. The lower limit of detection was set to 0.1 ng/ml, and a measured value of a Patients are plotted by a stratification factor—“Present (Pre)/Absent (Abs)” regarding drug-related AEs. b Patients are plotted by a stratification factor—“Improved (Imp)/Nonimproved (Non)” regarding angiofibromas that were assessed by the IRC. The “improvement” group includes patients who were adjudicated to “Markedly improved” or “Improved.” AEs adverse events, LC/MS/MS liquid chromatography/mass spectrometry, IRC independent review committee