Topical Sirolimus Ointment for Cutaneous Angiofibromas in Subjects With Tuberous Sclerosis Complex

This is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study designed
to assess the safety and efficacy of topically-applied sirolimus for the treatment of
cutaneous angiofibromas in pediatric subjects with TSC. The investigational product is
sirolimus (0.2% and 0.4%), administered as an ointment formulation for topical administration
during the double-blind treatment period. Subjects entering the open-label treatment period
will receive sirolimus 0.2% administered as an ointment formulation for topical
administration.

Study subjects will be enrolled at 3-5 investigational sites in the United States (US).
Approximately 45 subjects who meet the study entry criteria will randomly assigned in a 1:1:1
ratio to receive 1 of 3 treatments. Subjects, or a parent/guardian, will apply the study
medication topically to the cutaneous angiofibromas on the face once daily at night before
going to bed for 12 weeks. Subjects who complete the doubleblind phase of the study, with an
overall compliance rate >80%, as determined by the number of dose days divided by the total
of days between visits, will be offered entry into an open-label period for an additional 12
weeks.The maximum study duration for each subject will be approximately 32 weeks and includes
a screening period of up to 4 weeks, a blinded treatment period of 12 weeks, optional open
label period of 12 weeks, and a follow-up period of 4 weeks.

An interim analysis will be performed when all subjects have completed the double-blind phase
(Visit 5 - Week 12). The data will be unblinded to assess for efficacy and results reported.

Inclusion Criteria:

1. Generally healthy males or non-pregnant females aged 2 to 18 years, inclusive, at the
time of screening.

2. Diagnosis of TSC with visible facial angiofibromas of at least grade 2 but not greater
than grade 4, inclusive, based on the IGA.

3. Females of childbearing potential must have a negative urine pregnancy test and if
sexually active or become sexually active during the study, must agree to use an
effective form of birth control for the duration of the study. Females using oral
contraceptives must also use a barrier method of contraception during the study.
Sexually active male subjects and/or their female partners should also use appropriate
contraception.

Effective contraception is defined as follows:

- Oral/implant/injectable/transdermal/estrogenic vaginal ring contraceptives,
intrauterine device, condom with spermicide, diaphragm with spermicide.

- Abstinence or partner's vasectomy are acceptable if the female agrees to
implement one of the other acceptable methods of birth control if her partner
changes.

4. The subject and/or their parent or guardian must be willing and able to provide
written informed consent/assent.

5. Willing and able to comply with all trial requirements.

6. Subject or parent/guardian must be able to complete the subject self-assessment survey
in English.

7. Subjects should be in good general health based on the subject's medical history,
physical exam, and impression of the study doctor.

Exclusion Criteria:

8. Has severe facial angiofibromas of Grade 5 based on the IGA assessment.

9. Has any chronic or acute medical condition, that in the opinion of the investigator,
may pose a risk to the safety of the subject during the trial period, or may interfere
with the assessment of safety or efficacy in this trial.

10. Has received oral therapy of an mTOR inhibitor (sirolimus, temsirolimus, or
everolimus) or other dermatologic treatment to facial angiofibromas within 4 weeks of
Baseline.

11. Is currently receiving any form of immunosuppression therapy or has previously
experienced significant immune dysfunction.

12. Has a history of sensitivity to any component of the investigational product.

13. Is pregnant, plans to become pregnant during the course of the study, or is
breastfeeding.

14. Has other dermatologic conditions, pigmentation, scarring, pigmented lesions or
sunburn in the treatment area that would preclude or prevent adequate assessment of
changes to their facial angiofibromas.

15. Has facial hair (e.g., beard, sideburns, mustache) that could interfere with study
assessments.

16. Has had laser surgery, cryotherapy to facial angiofibromas within 6 months preceding
study entry.

17. Requires the use of any concomitant medication that, in the investigator's opinion,
has the potential to cause an adverse effect when given with the investigational
product or will interfere with the interpretation of the study results (see Section
16.1 Appendix 1 for Potential Drug Interactions).

18. Has participated in another clinical trial or received an investigational product
within 3 months prior to screening.