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The Development of a Topical
Therapy for Facial Angiofibromas in
TSC
Bench to Bedside Medicine
Mary Kay Koenig, MD & Hope Northrup, MD
Department of Pediatrics
The University of Texas Medical School
Houston
TSC & the Skin
• Hypo-pigmented macules
TSC & the Skin
• Shagreen patch
TSC & the Skin
• Ungual Fibromas
TSC & the Skin
• Facial Angiofibromas
Facial Angiofibromas
•
•
•
•
•
Benign Skin Tumors seen in patients with TSC
Appear around puberty
Worsen over time
No effective treatments
Disfiguring
Facial Angiofibromas
• Dermal basal cells contain a single mutant copy
of either TSC1 or TSC2
• A second hit occurs resulting in loss of
heterozygosity and cell growth at a rate faster
than the ability to slough dead cells
• Visible facial lesions appear over time
• TSC mutant cells also secrete vascular growth
factors resulting in red appearance to the
lesions
Facial Angiofibromas
TSC & mTOR
Rapamycin
• Naturally occurring substance
• Discovered in 1965
• Binds mTOR and inhibits it’s action, thus
preventing cell division and growth
• Also decreases levels of VEGF
Rapamycin
• Approved by the FDA in 1999 as an
immunosuppressant drug to be used post renal
transplant
• Side effect profile well defined:
• Immunosuppression
• Oral Ulcers
• Skin Breakdown
• Poor wound healing
• Hyperlipidemia
• Thrombocytopenia
Rapamycin
• Theoretically, the action of rapamycin should
suppress abnormal cell growth in TSC
replacing the action of the malfunctioning
proteins
Rapamycin & the Skin
• Rapamycin has a molecular weight of 914.2
grams allowing for it’s absorption
through the superficial layers of
the epidermis
• With the appropriate delivery system, a topically
applied formulation of rapamycin should be able
to penetrate the superficial dermal layers to
reach the deep basal layers implicated in the
formation of facial angiofibromas
Topical Rapamycin Therapy to Alleviate
Cutaneous Manifestations of TSC & NF-1
PI:
Mary Kay Koenig, MD
Co-PIs:
Hope Northrup, MD
Adelaide A. Hebert, MD
Joshua A. Samuels, MD
John M. Slopis, MD
Study Coordinator:
Joan M. Roberson, BSN
Contributors:
Laura Lester, Laura Marusinec, Audrey Woerner
Support:
Society for Pediatric Dermatology Pilot Project Award
Race Across America for Neurofibromatosis
Topical Rapamycin Therapy to Alleviate
Cutaneous Manifestations of TSC
Trial Objectives
I
Determine if a topically applied formulation of
rapamycin can be used safely
II
Determine if the topically applied formulation
of rapamycin is effective at decreasing:
• the appearance of facial angiofibromas in TSC
Topical Rapamycin Therapy to Alleviate
Cutaneous Manifestations of TSC
• Study Design – randomized, double-blind, placebocontrolled
60 subjects
3 arms
- 30 TSC
- 30 NF-1
- Placebo
- Low Dose
- High Dose
• Study drug applied topically each night to skin surface
• Followed for 6 months to assess for improvements in
size and/or appearance of fibromatous lesions
Results to Date
• Enrolled 28 TSC subjects
• Two patients voluntarily withdrew because of
discomfort with study product application
– burning
– tingling
– eye watering
TSC Arm Results
• 6 month data in TSC arm shows a reduction in
the appearance of facial angiofibromas in 73%
of subjects on treatment vs 38% of subjects on
placebo
Before
Treatment
After
Treatment
Side Effects/Adverse Events
• Subjects seen monthly to assess for known side
effects
– Lipid levels
– CBC
– Skin breakdown
- Oral ulcers
- Infections
• Two Major Adverse Events
– Hospitalization for aspiration pneumonia/septic shock
– Hospitalization for hypertensive crisis
• Rapamycin levels undetectable in all subjects
Future Directions
• Data publication later this year
• Multi-Center Trail pending involving 200 TSC
subjects at 10 sites across the country (funding
approved)
Thank You
• Society for Pediatric Dermatology
• Race Across America for Neurofibromatosis
• Research Team:
–
–
–
–
–
Joan Roberson, RN
Hope Northrup, MD
Adelaide Hebert, MD
Joshua Samuels, MD
John Slopis, MD
• Collaborators:
– Audrey Woerner, MD
– Laura Lester, MD
– Laura Marusinec, MD
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