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
Re “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.” The carrier IS clearly responsible for those side effects observed on the control side of the face. However it’s probably not due to the low concentration of ethanol (~2%). See the carrier here: http://labeling.pfizer.com/ShowLabeling.aspx?id=139 http://www.americanlecithin.com/TDS/TDS_50PG.PDF (Looks like the Phosal 50 PG is essentially undiluted, suggesting that the polysorbate 80 concentration is also very low.) In a quick lit search I see only sporadic mention of side effects like contact allergy due to propylene glycol or polysorbate 80, but these ingredients (or the combination with 6% lysolecithin etc) seem more likely responsible for the side effects of the carrier than the 2% ethanol. I agree with your suggestion that an emollient carrier may allow trial of higher doses.
However, the authors point out that this dose of rapamycin IS effective for treatment of angiofibromas in TSC, so there IS reason to expect 0.1% rapamycin to be effective for treatment of fibrofolliculomas IF the effect of mutant FLCN is mediated through mTORC1. One of the studies you quote above used 0.1%, the other used a far LOWER concentration, 0.003% -0.015%, and found even 0.003% effective (albeit subjectively!).
(Granted some treatments for TSC use a 10-fold higher dose, and this higher dose is still of interest to try in BHD. However, enterprising BHD patients could consider trying this on their own, with serolimus prescribed off-label by an interested and involved health care provider. See the recipe here: http://archderm.jamanetwork.com/article.aspx?articleid=1105295 . I’m betting this will not be effective. Let us know if it does work.)
“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.”
Or, it’s at least as likely that the effect of mutant FLCN on proliferation of fibrofolliculomas is not mediated directly through mTORC1. See for example http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038567/?report=classic “Together, our study suggests that loss of FLCN expression leads to activation of the AMPK/PGC-1α/OXPHOS/HIF signaling axis, which is an important driver of sporadic tumors in multiple organs.”
As one of the first clinicians to deliver the drug in a different vehicle and concentration, I am inclined to suggest that insufficient concentration may have been realized in subdermal tissues to claim the overall therapy ineffective.
While the original study of 1% in White Pet gave moderate results for fibromas in TS, I utilized a better vehicle to bring about a better clinical response, at a significantly lower concentration employing a penetration enhancer.
The greatest clinical (and cosmetic) response that my patients have had with topical sirolimus has been when a penetrating base or a base with a separate penetration enhancer is utilized.
The mechanisms of MTOR in he tumourigenesis and therefore the efficacy of sirolimus as an MTOR inhibitor are divergent in tuberous sclerosis and Birt-Hogg-Dube syndrome. For tuberous sclerosis there is applied data in yeasts suggesting that sirolimus may be efficacious in inhibiting the over-activity of the downstream pathway of MTOR which is unregulated in mutations causing tuberous sclerosis complexes 1 & 2. However, in Birt-Hogg-Dube syndrome there is applied data in yeasts suggesting that the mechanism of tumourigenesis is via over-inhibition ofMTOR, which infers that the use of srolumus in this condition may worsen te facial fibrofolliculomas.
The clinical trial using topical sirolimus for fibrolliculomas associated with tuberosclerosis (as opposedto Birt-Hogg-Dube syndrome) has shown promising results for tuberosclerosis. The results have not been the same for either the earlier or more recent research conducted to date for Birt-Hogg-Dube syndrome.
There are subtle differences between the genetic mutation of tuberous sclerosis and tat of Birt-Hogg-Dube syndrome. The mechaisms of mTOR in the tumourigenesis and therefore the efficiacy of sirolimus, an mTOR inhibitor, are diveregent in tuberous sclerosis and Birt-Hogg-Dube syndrome. For tuberous sclerosis there is applied data in yeasts suggesting that sirolimus may be efficacious in inhibiting the over-activity of the downstream pathway of mTOR which is unregulated in mutations causing tuberous sclerosis complexes 1 & 2. However, in Birt-Hogg-Dube syndrome there is applied data in yeasts suggesting that the mechanism of tumourigenesis is via over-inhibition of mTOR which infers that the use of sirolimus in this conditon may worsen the facial fibrofolliculomas. Recent clinical trials using topical sirolimus for fibrofolliculaoms associated with tuberous
sclerosis (as opposed to Birt-Hogg-Dube syndrome) have shown promising results for tuberous sclerosis. Recent clinical trials for Birt-Hogg-Dube have not. This divergence is consistent with the divergence in the applied data in yeasts.