Efficacy of Topical Sirolimus (Rapamycin) for the Treatment of Microcystic Lymphatic Malformations.

Background Systemic mammalian target of rapamycin (mTOR) inhibitors are currently used in many dermatologic indications. Their topical use is recent and poorly codified. Objective To provide an overview of the topical use of mTOR inhibitors in dermatologic conditions and evaluate their efficacy and safety. Methods A literature search was performed in January 2017. Reports of all studies investigating the use of topical mTOR inhibitors in any dermatology diseases were included. The exclusion criteria were systemic use and mucosal administration. Results We included 40 studies with a total of 262 patients. In all, 11 dermatologic conditions were found, the most frequent being angiofibromas linked to tuberous sclerosis complex (157 patients). Topical mTOR inhibitors were significantly more efficient than placebo for angiofibromas (relative risk, 2.52; 95% confidence interval, 1.27-5.00; I2 = 0%). The median concentration of sirolimus was 0.1%, with a median treatment duration of 12 weeks. Topical mTOR inhibitors were well tolerated, with only mild or moderate local side effects (mostly irritative) reported. Blood level of sirolimus was not detected in 90% of patients. Limitations High heterogeneity in most studies. Conclusion This systematic review supports the efficacy of topical sirolimus for angiofibromas linked to tuberous sclerosis complex, with only local side effects reported. Other indications require further research.

Topical use of mammalian target of rapamycin inhibitors in dermatology: A systematic review with meta-analysis.

Experience of follow-up, quality of life, and transition from pediatric to adult healthcare of patients with tuberous sclerosis complex.

Formulation and characterization of a 0.1% rapamycin cream for the treatment of Tuberous Sclerosis Complex-related angiofibromas.

Cutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults. This French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm2. For patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment. ClinicalTrials.gov, NCT03972592. Registered on 3 June 2019. EU Clinical Trials Register EudraCT, 2018–001359-11.

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Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial.

Introduction Parmi les differentes affections dermatologiques associees a la sclerose tubereuse de Bourneville (STB), les angiofibromes faciaux sont les plus defigurants. Presents chez 85 % des patients, leurs repercussions sont autant physiques que psychologiques. Les moyens utilises pour les traiter tels la chirurgie, la cryotherapie, l’electrocoagulation, la dermabrasion ou le laser ont montre leur efficacite dans certains cas. Mais ils presentent des aspects contraignants pour leur mise en œuvre, notamment chez les plus jeunes, et peuvent se compliquer ou engendrer des sequelles permanentes. Depuis la demonstration de l’efficacite du sirolimus par voie systemique sur les angiofibromes, des formes topiques de ce medicament ont ete developpees. Le but de l’etude qui a ete menee est de faire le point sur l’etat de la preparation topique de sirolimus en France et de comparer ces donnees a celles trouvees dans la litterature. Materiel et methodes Un questionnaire en ligne a ete envoye aux pharmaciens de 31 centres hospitaliers universitaires (CHU) de France et de 40 centres hospitaliers membres de l’Assistance publique–Hopitaux de Paris (AP–HP), les interrogeant sur la realisation de la forme topique, les modalites de preparation, de delivrance au patient, les etudes menees ainsi que celles a venir. Une revue de la litterature scientifique et medicale, des essais cliniques ainsi que des brevets deposes ont ete menes. Resultats Onze CHU realisent frequemment cette preparation en France (taux de reponse de 55 %) ; la majorite depuis un an en moyenne. Les formes galeniques utilisees sont des pommades ou des cremes et les dosages varient de 0,1 % a 1 %. Elles sont delivrees aux patients ambulatoires par le biais de la retrocession hospitaliere. Selon nos calculs, le cout d’un pot de 25 g de sirolimus a 0,1 % est de 110 €. Les principales causes de non realisation sont le cout eleve de la preparation, le manque de donnees de securite et d’efficacite a long terme ou l’absence de demande de la part des services dermatologiques. A ce jour, plus d’une vingtaine d’articles ont ete publies sur le sujet. Cette forme topique a montre son efficacite uniquement dans des petites series de cas ou tres peu d’effets indesirables ont ete observes. Quatre essais cliniques ont ete menes ou sont en cours et deux formules de sirolimus en topique ont ete brevetees. Discussion Les formes galeniques, les dosages et modalites de preparation varient d’un etablissement a l’autre. Cette diversite est expliquee par le fait qu’a ce jour, tres peu de donnees croisant doses/degres d’etendue des lesions/formes galeniques utilisees et efficacite du traitement sont disponibles. Conclusion L’emergence d’un consensus en ce qui concerne la formulation (creme ou pommade, concentration en sirolimus…) serait une avancee pour la prise en charge des patients atteints de STB.

Traitement des angiofibromes de la sclérose tubéreuse de Bourneville par des préparations topiques à base de sirolimus : état des lieux de la préparation en France et revue de la littérature

Guillaume Bouguéon

Papers

Formulation and characterization of a 0.1% rapamycin cream for the treatment of Tuberous Sclerosis Complex-related angiofibromas.

Traitement des angiofibromes de la sclérose tubéreuse de Bourneville par des préparations topiques à base de sirolimus : état des lieux de la préparation en France et revue de la littérature