FormalPara Key Summary Points

Why carry out this study?

This postmarketing survey was conducted in compliance with the Good Postmarketing Study Practice ordinance of the Ministry of Health, Labor and Welfare (MHLW).

To date, this is the first real-world experience of the topical mechanistic target of rapamycin (mTOR) inhibitor sirolimus 0.2% gel (Rapalimus®, Nobelpharma Co., Ltd., Tokyo, Japan) for tuberous sclerosis complex (TSC)-related cutaneous manifestations over 52 weeks of treatment.

What was learned from the study?

In this postmarketing surveillance, the improvement in the overall cutaneous manifestations with topical sirolimus 0.2% gel treatment at 52 weeks was 74.8%.

The overall incidence rate of adverse events (AEs) and adverse drug reactions (ADRs) was 24.6% and 18.4%, respectively.

Age and duration of use showed a significant association with both effectiveness and safety, whereas total dosage showed significant association with effectiveness.

Topical sirolimus 0.2% gel may be useful in the management of TSC-related cutaneous manifestations.

Introduction

Tuberous sclerosis complex (TSC) is an autosomal dominant rare genetic disorder that affects one in every 6000–10,000 live births globally [1,2,3]. TSC is caused by loss-of-function mutations in either TSC1 or TSC2 genes, which encode hamartin and tuberin, respectively, that inhibit the tumor-suppressive activity of the mechanistic target of rapamycin (mTOR), affecting various organs including the skin, central nervous system, eyes, heart, lungs, and kidneys [1,2,3]. Cutaneous manifestations such as hypomelanotic macules, facial angiofibroma, periungual fibromas, shagreen patches, fibrous cephalic plaque, and confetti skin lesions affect more than 90% of patients [4, 5].

Pharmacological (topical or oral mTOR inhibitors) and non-pharmacological (surgical or excision) treatment options are available for the treatment of TSC cutaneous symptoms [3]. The use of topical mTOR inhibitors provides a painless, non-scarring option, while oral mTOR inhibitors typically show improvement in the skin condition of patients. According to the most recent international TSC guidelines, mTOR inhibitors can be appropriate therapeutic options for large or disfiguring lesions as well as painful lesions or those prone to bleeding [3]. Although the use of systemic mTOR inhibitors for other indications showed improvement in the skin condition of patients [3], the risk–benefit ratio often precludes their use for TSC cutaneous manifestations alone. Subsequently, topical sirolimus was suggested as a safe and effective approach for treating facial angiofibroma [3]. The efficacy and safety of topical sirolimus 0.2% gel in the management of facial angiofibroma and other cutaneous manifestations were established [6,7,8]. The gel was approved in Japan in 2018 for the treatment of TSC-related cutaneous lesions, and recently approved in the USA (HYFTOR™) for the treatment of facial angiofibroma. In this article, we present the findings of interim analyses of postmarketing surveillance (PMS) conducted in Japan aimed to better understand the real-world effectiveness and safety of topical sirolimus 0.2% gel for the management of TSC-related cutaneous manifestations. In addition, the demographics and baseline patient characteristics associated with the efficacy and safety of topical sirolimus 0.2% gel for treating TSC-related manifestations were analyzed.

Methods

Study Design and Participants

The general drug use survey of topical sirolimus 0.2% gel (Rapalimus®, Nobelpharma Co., Ltd., Tokyo, Japan) is an ongoing multicenter PMS in Japan for the treatment of TSC-related cutaneous manifestations. The diagnosis of TSC was based on the diagnostic criteria in the Japanese guidelines, modified TSC Clinical Consensus Conference 2012 criteria [1, 3]. Data were collected on patient background factors such as age, gender, height, weight, time of onset of symptoms, time of acquiring a definite diagnosis, clinical symptoms of TSC, allergy history, medical history, complications, and prior treatment. During a routine medical check-up, data on symptom evaluation were collected.

This PMS was conducted in compliance with the Good Postmarketing Study Practice (GPSP) ordinance of the Ministry of Health, Labor and Welfare (MHLW). MHLW approval was subject to all patients using the medication being monitored. According to the MHLW’s GPSP ordinance, the study’s entire protocol does not need to receive approval from an ethical committee. Informed consent was not required under GPSP.

Effectiveness Evaluation

Improvement in the overall cutaneous manifestations with the use of topical sirolimus 0.2% gel was evaluated by physician at 52 weeks after the treatment initiation or at the time of withdrawal/dropout using the following seven-point scale: “markedly improved,” “improved,” “somewhat improved,” “unchanged,” “somewhat worsened,” “worsened,” or “not evaluable.” The proportion of patients who were rated as “markedly improved” or “improved” to the total number of patients evaluated is defined as the “improvement rate.” The relationship between demographics and baseline characteristics and the improvement rate was analyzed. Improvement in individual lesions, facial angiofibroma, hypomelanotic macules, shagreen patches, fibrous plaque, and periungual fibroma was graded by physician on a three-point scale as “improved,” “unchanged,” or “worsened” at 4, 12, 26, 38, and 52 weeks after initiating topical sirolimus 0.2% gel or at the time of withdrawal/dropout. The proportion of patients who were evaluated as “improved” to the total number of patients evaluated is defined as the “responder rate.”

Safety Evaluation

Adverse events (AEs) occurring during the first 52 weeks after initiating topical sirolimus 0.2% gel treatment or within 28 days after discontinuing the therapy were investigated. AEs and adverse drug reactions (ADRs; events for which the causal relationship with this drug could not be ruled out) were classified by preferred term and system organ class according to the Medical Dictionary for Regulatory Activities/Japanese version MedDRA/J ver. 23.1. The relationship between demographics and baseline characteristics and the ADR incidence rate was analyzed.

Patient Satisfaction Level

The patient satisfaction level with topical sirolimus gel 0.2% treatment was recorded and graded on the following seven-point scale: “very satisfied,” “satisfied,” “somewhat satisfied,” “neither satisfied nor dissatisfied,” “somewhat dissatisfied,” and “not evaluable.”

Statistical Analysis

Descriptive statistics are presented for the demographics and baseline characteristics. The categorical variables are presented as numbers and frequencies, whereas continuous variables were presented as mean and standard deviation. For improvement rates two-sided 95% confidence intervals (CI) were estimated. The association of demographics and baseline characteristics with the effectiveness and safety of topical sirolimus 0.2% gel was analyzed using chi-squared tests for nominal data and the Cochran–Armitage trend test for ordinal data. The two-sided level of significance was set at 0.05. Statistical analysis was performed using SAS 9.4 software.

Results

Participants

In this multicenter PMS, 866 patients were enrolled from 388 sites (305 centers) across Japan. Of the 670 patients whose forms were available, 35 patients were excluded (32 patients were lost to follow-up and 3 patients were without drug administration) and 635 patients were included in the safety analysis. For the effectiveness analysis, 630 patients were included, excluding five patients because of off-label use (the use for suppression of recurrence after pulse laser treatment of simple hemangioma in three patients, the use for nevus sebaceous in one patient, and the use for eccrine poroma in one patient). The patients’ disposition is presented in Fig. 1.

Fig. 1
figure 1

Patient disposition

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Demographics

The demographics and baseline characteristics of the patients included in the efficacy and safety analysis sets are presented in Table 1. The patients’ mean age was 22.9 ± 14.3 years, with 53.9% of them being female. In the overall population, incidence of intellectual disability was 53.9%, renal impairment was 12.6%, hepatic impairment was 2.7%, and epilepsy was 67.9% at baseline.

Table 1 Demographics and baseline characteristics of the patients included in the efficacy and safety analysis sets
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Discontinuation of Topical Sirolimus 0.2% Gel

Overall, 174 patients (27.4%) discontinued topical sirolimus 0.2% gel treatment or dropped out within 52 weeks of its initiation for one or more reasons, with 38 patients (21.8%) discontinuing the drug because of AEs. Other reasons for discontinuation include personal reasons such as self-discontinuation and refusal of administration (31.0%), transfer to another hospital (21.3%), completion of treatment (15.5%), inadequate response (13.2%), and death (1.1%). Approximately 1.6%, 8.4%, 9.0%, 4.6%, and 3.9% of patients discontinued or dropped out at 0–4, 4–12, 12–26, 26–38, and 38–52 weeks, respectively.

Effectiveness of Topical Sirolimus 0.2% Gel on Overall Cutaneous Manifestations

The overall improvement rate for topical sirolimus 0.2% gel over a 52-week period was 74.8% (95% CI − 70.2, 79.1), with 59 patients (15.3%) rated as “markedly improved” and 229 patients (59.5%) rated as “improved.” The effectiveness increased steadily over time, rising from 41.2% (95% CI − 27.6, 55.8) at week 4 to 74.8% (95% CI − 70.2, 79.1) at week 52. Figure 2a presents the improvement rate of topical sirolimus 0.2% gel at various time points.

Fig. 2
figure 2

Effectiveness of topical sirolimus 0.2% gel. a Total improvement rate (N = 600) and b responder rate of the individual cutaneous manifestations

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Effectiveness of Topical Sirolimus 0.2% Gel on Individual Lesions

Facial angiofibroma, hypomelanotic macules, shagreen patches, fibrous plaque, and periungual fibroma was observed in 596, 303, 209, 163, and 157 patients, respectively. Responder rates of improvement in the individual lesions at week 52 were 86.2%, 14.4%, 25.9%, 60%, and 25.5% of patients, respectively. Figure 2b presents the responder rate of the individual lesions at various time points.

Adverse Events

The overall incidence of AEs and serious AEs (SAEs) was 24.6% and 2.4%, respectively. The AEs with an incidence of at least 1%, as determined by preferred term, were acne (4.7%), application site irritation (2.8%), dry skin (2.2%), application site erythema (1.6%), acneiform dermatitis (1.4%), and stomatitis (1.3%). AEs and SAEs by preferred term are listed in Table 2, and the complete list of AEs and SAEs is presented in Supplementary Material Table S1.

Table 2 Safety profile of topical sirolimus 0.2% gel treatment (N = 635)
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Overall, 117 patients (18.4%) experienced ADRs. The ADRs with an incidence of at least 1%, as determined by preferred term, include acne (3.9%), application site irritation (2.8%), dry skin (2.2%), application site erythema (1.6%), acneiform dermatitis (1.4%), and skin irritation (1.1%). More than half of these ADRs occurred for the first time by week 12, with 5.2% (n = 33), 6.1% (n = 39), 5.0% (n = 30), 2.7% (n = 14), and 1.2% (n = 6) occurring within 0–4, 4–12, 12–26, 26–38, and 38–52 weeks. One serious ADR resulting in drug discontinuation was reported in one patient (0.2%) with application site hemorrhage, who eventually recovered (Table 2).

Adverse Events of Special Interest

The incidence of photosensitivity as an ADR of topical sirolimus 0.2% gel treatment was 0.47% (3/635). Photosensitivity reaction was observed 162 and 74 days after treatment initiation in two female patients aged 13 and 24 years, respectively; solar dermatitis was observed 16 days after treatment initiation in a male patient aged 16 years. Although these AEs were mild and all three patients recovered, the possibility of a causal relationship between these AEs and topical sirolimus 0.2% gel cannot be ruled out.

Factors Affecting the Effectiveness and Safety of Topical Sirolimus 0.2% Gel

The association of demographics and baseline characteristics of the patients with the improvement rate of cutaneous manifestations or safety of topical sirolimus 0.2% gel use is presented in Table 3. Among demographics and baseline characteristics, age, duration of use, and total dosage showed significant association with the overall improvement rate of cutaneous manifestations with topical sirolimus 0.2% gel use. A trend of higher improvement rate with lower age was observed for cutaneous manifestations with significant differences observed among the age groups (< 15, ≥ 15 to < 65, and ≥ 65 years, p = 0.010). Further subgrouping the patients aged ≥ 15 to < 65 years into 10-year intervals revealed a similar trend that the younger the age, the higher the improvement rate (p = 0.042, Supplementary Material Table S2). There was a significant trend that the longer the duration of drug use, the higher the improvement rate relative to 11% with < 30 days of use (p < 0.001). Similarly, there was a significant trend that the higher the total dose, the higher the improvement rate, relative to 58.6% with a total dose < 20 g (p = 0.005).

Table 3 Demographics and baseline characteristics of the included patients affecting improvement rate and safety of topical sirolimus 0.2% gel at week 52
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The incidence of ADRs was lower in the younger age group with a significant difference observed among the age groups (< 15, ≥ 15 to < 65, and ≥ 65 years, p = 0.011). However, the incidence rate of ADRs was similar among the age groups with no significant difference (p = 0.477) observed when the ≥ 15 to < 65-year age group was subdivided into 10-year intervals (Supplementary Material Table S2). We observed statistically significant (p = 0.021) differences in the ADR incidence rate in pediatric subgroups, with the 12- to 15-year age group showing the highest ADR incidence (22.0%), followed by the 3- to 6-year age group (12.1%), the 6- to 12-year age group (8.3%), and the < 3-year age group (0%). There was a significant trend that the longer the duration of use, the lower the ADR incidence, relative to a 35% incidence rate with < 30 days of use (p = 0.001).

The effectiveness and safety of the topical sirolimus 0.2% gel did not significantly differ between patients who received and did not receive oral mTOR inhibitors (64.9% vs. 62.9%, p = 0.689 and 22.8% vs. 17.3, p = 0.169, respectively). The improvement rate and safety of topical 0.2% sirolimus gel did not differ significantly between patients with renal impairment and those without (56.3% vs. 64.2%, p = 0.169 and 16.3% vs. 18.8%, p = 0.587, respectively), or between patients with hepatic impairment and those without (52.9% vs. 63.5%, p = 0.375 and 23.5% vs. 18.3%, p = 0.585, respectively).

Patient Satisfaction Level

The majority of patients were satisfied with the treatment. Overall, the patient satisfaction rate was found to be 53.0% when “very satisfied” and “satisfied” were evaluated as satisfied with their skin condition (Fig. 3).

Fig. 3
figure 3

Percentage distribution of patients based on the satisfaction level with their skin condition following topical sirolimus 0.2% gel treatment for TSC-related cutaneous manifestations

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Discussion

We present the findings of 52-week PMS in Japan on the effectiveness and safety of topical sirolimus 0.2% gel treatment for TSC-related cutaneous manifestations. The majority of patients (74.8%) showed improvement in the overall TSC-related cutaneous lesions at 52 weeks of treatment with topical sirolimus 0.2% gel, with facial angiofibroma showing the highest responder rate (86.2%). During the 52-week AE review period, 18.4% of patients experienced ADRs with topical sirolimus 0.2% gel. Efficacy was associated with age, duration of use, and total dosage. Safety was associated with age and duration of use. To the best of our knowledge, this is the first real-world evidence of topical sirolimus 0.2% gel and first to investigate the factors influencing the effectiveness and safety of topical sirolimus 0.2% gel in patients with TSC-related cutaneous manifestations. More than half of the patients (53.0%) were very satisfied or satisfied with topical sirolimus 0.2% gel treatment.

The clinical evidence for the effectiveness and safety of topical sirolimus 0.2% gel was established in previous studies [6,7,8]. Wataya-Kaneda et al. reported topical sirolimus 0.2% gel as an optimal concentration for the management of facial angiofibroma on the basis of a 12-week double-blind, placebo-controlled, dose-finding, phase II clinical trial which evaluated the improvement factor as measured by tumor size reduction and a lessening of the redness of the three target tumors [8]. The efficacy and safety of sirolimus 0.2% gel were further confirmed in a 12-week, placebo-controlled phase III clinical trial (n = 62; 27 pediatric and 35 adult patients) in Japan. After 12 weeks of treatment, 17% were rated as “markedly improved” and 43% as “improved” on the basis of composite improvement in the facial angiofibroma size and color, whereas none of the patients in the placebo group (n = 32) were rated “improved” [7]. Similarly, the response rates of cephalic plaques in the sirolimus group at week 8 (31%) and 12 (46%) were significantly higher (all p = 0 0.03) than those in the placebo group (0% and 6%, respectively) [7]. The 52-week long-term extension study revealed a rapid improvement rate in the facial angiofibroma during the first 12 weeks of treatment and gradually increased thereafter, reaching 78.2% at week 52. The rate of improvement in cephalic plaques increased over time, reaching 66.7% at 52 weeks. At week 52 of treatment, the improvement rate for hypomelanotic macules was 72.2%. Overall, 89.8% of patients rated their level of satisfaction as “very satisfied” or “satisfied” at 52 weeks of treatment [6]. Initial rapid improvement observed with topical sirolimus 0.2% gel may reach a plateau with no further dramatic improvement in the skin condition over time [9]. However, treatment continuation may be required for the maintenance of skin condition and to avoid recurrence. In a study by Wataya-Kaneda et al. [8], treatment discontinuation after 12 weeks of treatment with topical sirolimus 0.2% gel resulted in decreased response rates at week 4 of follow-up of treatment withdrawal, reflecting the transient mTOR inhibition by topical sirolimus. In a study conducted in the USA, the efficacy and safety of compounded topical sirolimus in patients over the age of 13 years showed improvement in 73% of patients with facial angiofibroma compared with 38% of patients treated with placebo [10]. The effectiveness of topical sirolimus was further established in a number of clinical trials and meta-analyses [9, 11,12,13].

Wataya-Kaneda et al. reported long-term safety of topical sirolimus 0.2% gel for the treatment of cutaneous manifestations in Japan, with discontinuations due to AEs (primary endpoint) observed only in two (2.1%) patients, eye irritation and erythema for one patient and contact dermatitis for another. Both AEs were mild, occurred within 1 week of treatment, and resolved without the need for clinical intervention [6]. In this real-world setting, 21.8% of patients discontinued the drug because of AEs. However, serious ADR resulting in drug discontinuation was reported in one patient with application site hemorrhage, who eventually recovered.

In a 12-week phase III study, the most common drug-related AEs for topical sirolimus 0.2% gel were application site irritation (37%), dry skin (37%), and acne (7%) [8]. Similarly, in the 52-week long-term extension study, the major drug-related AEs observed were application site irritation (30.9%), dry skin (27.7%), acne (20.2%), eye irritation (8.5%), pruritus (8.5%), erythema (7.4%), acneiform dermatitis (6.4%), and contact dermatitis (5.3%). The incidences of all these drug-related AEs were reduced to half or less at week 68 after onset, and none of them were severe, and the majority subsided quickly [6]. In this real-world setting, the incidence of AEs was low, and included dry skin, application site irritation, acne, pruritus, and acneiform dermatitis. The eye irritation observed in clinical study was not observed in this real-world setting.

Previous clinical studies with the topical sirolimus 0.2% gel formulation revealed higher efficacy in children compared with adults [8, 9, 14], similar to that observed in this real-world evidence. In children, facial angiofibroma and cephalic plaques improved rapidly and showed significant differences at week 12 for facial angiofibroma. However, the final improvement rates at week 52 of treatment were comparable between adults and children [6]. The effectiveness of sirolimus gel over a short period of time in children may be attributed to an abundance of blood vessels and less thickened fibrous tissue compared to adults. In children with TSC, early intervention with topical sirolimus may help maintain the skin condition at near-normal levels [9, 11, 14]. However, concomitant use of oral mTOR inhibitors had no additive effect on the effectiveness of topical sirolimus gel in the current study. Similar findings were observed in a long-term study [6]. This could possibly be attributed to differences in sirolimus bioavailability in skin with different routes of administration.

Systemic mTOR inhibitor treatment for other TSC-related manifestations improved patients’ skin conditions [15,16,17,18,19]. Concomitant use of mTOR inhibitors also showed no significant differences on the safety of topical sirolimus 0.2% gel treatment for cutaneous manifestations [20]. In this real-world setting, the safety of topical sirolimus 0.2% gel was comparable in patients who used and those who did not use mTOR inhibitors concurrently. Systemic exposure to mTOR inhibitors is associated with serious side effects, the majority of which are related to their immunosuppressive action [21]. Previous studies found that blood sirolimus levels were low, with a maximum concentration of 0.25 ng/mL after 12 weeks of treatment [8], and that most patients had a concentration of less than 1 ng/mL during 52 weeks of treatment [6].

The improvement rate of cutaneous manifestations with topical sirolimus 0.2% gel increased over time from 41.2% at week 4 to 74.8% at week 52. This could be due to the association between improvement rate and higher total dosage and longer duration. Okanishi et al. found similar results, reporting that patients treated for at least 24 months had a significant reduction in the size of facial angiofibromas [11]. Wataya-Kaneda et al. reported that treatment with topical sirolimus 0.2% gel over 52 weeks significantly improved facial angiofibroma, cephalic plaques, and hypomelanotic macules. It was reported that 89.8% of patients were “very satisfied” or “satisfied” with sirolimus 0.2% gel treatment [6]. A previous study found a significant correlation between the improvement factor and patient satisfaction with topical sirolimus (Spearman’s correlation coefficient = − 0.477, p = 0.003) [8].

Early intervention with topical sirolimus gel appears to be effective and safe for the treatment of TSC-related cutaneous lesions, and it may keep the skin at near-normal levels in children and adults with TSC [10, 13, 14].

This study has some limitations. The major one is the lack of a control group, as this was a real-world PMS. Additionally, this is an interim analysis of a PMS that was conducted only in Japan; therefore, the findings should be interpreted accordingly with caution.

Conclusions

In this real-world setting, topical sirolimus 0.2% gel was found to be effective and generally well tolerated in the management of cutaneous manifestations, particularly facial angiofibroma, with greater than 80% responder rate by 12 weeks and 18.4% ADR incidence rate over 52 weeks in patients with TSC. The AEs with an incidence rate less than 5% include acne, application site irritation, dry skin, application site erythema, dermatitis, acneiform, and stomatitis. Among the patient demographics and baseline characteristics, age (< 15, ≥ 15 to < 65, and ≥ 65 years), duration of use, and total dosage showed a significant association with the improvement rate. Safety was associated with age (< 15, ≥ 15 to < 65, and ≥ 65 years) and duration of use. Notably, a similar safety profile was observed when the broad age group (≥ 15 to < 65 years) was further categorized by 10-year intervals. More than half of the patients in this study were very satisfied or satisfied with the treatment.