Topical rapamycin to treat fibrofolliculomas in Birt-Hogg-Dubé syndrome

Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder
characterized by the occurrence of benign, mostly facial, hair follicle tumors
called fibrofolliculoma, multiple lung cysts and spontaneous pneumothorax and
an increased renal cancer risk. The fibrofolliculomas can be quite disfiguring
and are usually the reason that patients come to medical attention. They
usually appear after the age of 25 years and are progressive. Typically
presenting around the nose, they can spread onto the ears, neck and trunk.
Although they do not grow beyond 3-4mm in size, their numbers increase with age
so that patients can eventually have hundreds of tumors. Presently, ablative
laser is the preferred treatment. In addition, surgical interventions like
excision and shaving and elektrocoagulation are performed. Disadvantages of
these treatments are the risk of complications (scarring, hypo-and
hyperpigmentation), recurrence (from lasertherapy is known that
fibrofolliculomas recur after 2-3 years.) and the fact that these treatments do
not prevent the growth of new fibrofolliculomen. A topical treatment that is
suitable for chronic use and reduces the number of tumors and/or prevents the
growth of new ones would be preferable but is not yet available. New insights
from genetic and cell biological studies now suggest a potential topical
therapy. BHD syndrome is caused by germline mutations in the BHD gene coding
for the protein folliculin. Strongly conserved in evolution, folliculin*s
function is mostly unknown. We now know, from research on mouse models and our
own human data, that in BHD syndrome there is possibly deregulation of mTOR
signalling. mTOR, mammalian target of rapamycin, is a multiprotein-complex that
is a central player in cellular growth regulation and energy sensing. Thus, BHD
syndrome belongs in a larger family of disorders characterized by mTOR
deregulation, such as tuberous sclerosis complex (TSC). In TSC, as in BHD,
patients develop facial hair follicle tumors called angiofibroma. These tumors
strongly resemble fibrofolliculoma and are increasingly seen as a variant of
the latter. Very recent findings indicate that angiofibromas of TSC respond
favorably to the mTOR inhibitor rapamycin - they disappear after some months of
oral rapamycin. This mode of administration has potential side effects that are
not acceptable in the context of BHD syndrome. However, there are several
studies showing that topical application is safe and may be a feasible
strategy. Rapamycin oral solution 1mg/ml has already been used off-label for a
non-related mucosal and skin disorder and was both safe and effective when
applied topically. Thus, we have theorized that rapamycin oral solution might
be used for the treatment of BHD-associated fibrofolliculomas.

Primary Objective: To determine whether topical application of rapamycin can
lead to reduction in size and/or number of fibrofolliculomas in BHD patients
and may prevent the growth of new ones.
Secondary Objectives: Safety, formula acceptability and patient satisfaction.

Double-blind placebo-controlled randomized intervention study. It's possible to
switch to an open labelled study after 3 months.

Application of rapamune 1 mg/ml oral solution to one predefined skin area on
one facial half, twice daily. The other facial half will be similarly treated
with a placebo.

Participation requires patients to apply rapamycin liquid and placebo liquid
twice daily.
Participation in the study will take the patient 5 minutes a day, plus the 4
control visits that will take approximately 30 minutes.
Local irritation due to the excipient, which contains alcohol, is possible but
this can be easily controlled. An allergic reaction to one of the ingredients
of rapamune is also possible. In this case we will stop treating this specific
patient with rapamune. There will be one biopsy for patients who have not yet
undergone one. A skin biopsy is taken by means of a 3 mm punch after injection
of local anesthetic which is briefly painful. A properly taken biopsy will
leave no or minimal scarring.
Previous studies have shown that topical application of rapamycin is safe and
does not lead to therapeutic plasma levels. The benefit for the patients is in
the potential reduction in facial tumor size and number. For BHD patients in
general the benefit will be an easily used topical treatment with which
fibrofolliculomas may be treated or prevented.