Last week, the results of a clinical trial testing the effectiveness of topical rapamycin as a treatment for BHD were published in PLOS ONE (Gijezen et al., 2014). The study was performed by Professor Dr Maurice van Steensel’s team at the Maastricht University Medical Centre.
19 patients were enrolled in the trial, and were given two topical treatments – a 0.1% Sirolimus oral solution, and a placebo treatment containing just the solvent – and asked to use each treatment on different sides of their face every day for six months. The study was double-blind, randomised, facial left-right controlled, so patients and doctors did not know which side of their face was being treated with the drug. The cosmetic appearance, size and number of patients’ fibrofolliculomas were then assessed at 3 months and 6 months.
Cosmetic appearance was reported by both doctors and patients. Doctors reported no improvement in 17 patients, and improvements on both facial sides in 2 patients. 9 patients reported improvement with rapamycin treatment, 7 reported no improvement at all, and 5 patients reported improvement with placebo. Thus, rapamycin does not appear to improve the cosmetic appearance of fibrofolliculomas.
A reduction in the number of fibrofolliculomas was observed in 6 rapamycin treated facial sides, and 7 placebo sides. Additionally, at three months, difference in size of measured fibrofolliculomas was not statistically significant. Thus rapamycin did not significantly reduce the number of fibrofolliculomas or halt their growth in this trial.
13 patients reported one or more side effects on the rapamycin treated facial side, including burning, redness (erythema), dryness and itching, and one patient had to leave the trial after 3 months due to a tearing eye. However, 11 patients reported similar side effects with the placebo treatment, suggesting that many of the side effects were caused by the solvent the drug was dissolved in – which included ethanol – rather than the drug itself.
These results suggest that topical Rapamycin is not an effective treatment for fibrofolliculomas. Since this trial was started, two papers have been published showing that under certain conditions FLCN activates mTOR signalling. If this is the case in skin cells, rapamycin would not be predicted to treat fibrofolliculomas, which may explain the results of the trial.
On the other hand, FLCN has been seen to inhibit mTOR signalling in other studies, making rapamycin an appropriate treatment to test. This is a very small study, with only 19 patients completing the trial, meaning that any effects of rapamycin treatment would have to be quite large to conclusively prove any effect, and subtle or stratified effects would not be found. It is also possible that the dose of Sirolimus was not high enough to affect fibrofolliculomas.
Studies in TSC have shown that Sirolimus is better tolerated when dissolved in an emollient (Foster et al., 2012, Koenig et al., 2012). Thus it is possible that if the drug were delivered in this way, higher doses could be used, or treatment could be tolerated for longer due to fewer side effects. If taken at a higher dose, or for longer, it is possible that rapamycin may still prove to be an effective treatment to prevent fibrofolliculoma growth, or to improve the appearance of existing lesions.
- Foster RS, Bint LJ, & Halbert AR (2012). Topical 0.1% rapamycin for angiofibromas in paediatric patients with tuberous sclerosis: a pilot study of four patients. The Australasian journal of dermatology, 53 (1), 52-6 PMID: 22309333
- Gijezen LM, Vernooij M, Martens H, Oduber CE, Henquet CJ, Starink TM, Prins MH, Menko FH, Nelemans PJ, & van Steensel MA (2014). Topical rapamycin as a treatment for fibrofolliculomas in birt-hogg-dubé syndrome: a double-blind placebo-controlled randomized split-face trial. PloS one, 9 (6) PMID: 24910976
- Koenig MK, Hebert AA, Roberson J, Samuels J, Slopis J, Woerner A, & Northrup H (2012). 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. Drugs in R&D, 12 (3), 121-6 PMID: 22934754