Topical Rapamycin

Introduction

Topical rapamycin is a treatment that has been explored in clinical trials for its potential in addressing skin-related conditions, particularly those associated with aging and specific dermatological manifestations. This article summarises findings from two key studies on the efficacy and safety of topical rapamycin.

Topical Rapamycin in Reducing Skin Aging Markers

A randomised, placebo-controlled trial investigated the effects of topical rapamycin on reducing markers of senescence and aging in human skin. Rapamycin, an FDA-approved drug, targets the mechanistic target of rapamycin (mTOR) complex. The study aimed to assess its impact on age-related skin changes, including photodamage and dermal atrophy.

Study Design and Participants

The trial enrolled 36 participants over 40 years old with evidence of photoaging and dermal volume loss. Participants had no major morbidities.

Key Findings

• Reduction in Senescence Markers: A significant reduction in p16INK4A protein levels was observed, indicating a decrease in cellular senescence.
• Increase in Collagen VII: There was a notable increase in collagen VII protein levels, which is crucial for the integrity of the basement membrane.
• Clinical Improvement: Participants exhibited improved skin appearance, both clinically and histologically.
• Potential Anti-Aging Therapy: The results suggest that rapamycin could be a potential anti-aging therapy with efficacy in humans.

Topical Rapamycin for Facial Angiofibromas

The TREATMENT Trial focused on the efficacy and safety of topical rapamycin for treating facial angiofibromas, a skin manifestation of Tuberous Sclerosis Complex (TSC).

Study Design and Participants

This randomised clinical trial compared the effects of 1% and 0.1% topical rapamycin to a vehicle-only group.

Key Findings

• Efficacy:
  • Both concentrations showed clinically meaningful and statistically significant improvement in angiofibroma appearance.
  • The 1% formulation was superior to the 0.1% formulation.
  • Most improvement was observed within the first month of treatment.
  • At 6 months, the 1% group had a mean improvement of 16.7 points on the Angiofibroma Grading Scale (AGS), compared to 11.0 points for the 0.1% group and 2.1 points for the vehicle-only group.
  • 81.8% of the 1% group and 65.5% of the 0.1% group had end-of-treatment photos rated as "better" than baseline, compared to 25.5% in the vehicle-only group.
• Safety and Tolerability:
  • Topical rapamycin was generally well-tolerated with no measurable systemic absorption.
  • Adverse events were limited to the application site, including discomfort, pruritus, erythema, and irritation, occurring in 10% or fewer patients.
  • Nearly all adverse events were mild, with no moderate, severe, or serious events reported.
  • Only one patient withdrew due to a mild cutaneous eruption.
  • The study completion rate was 83.2%.
• Preferred Dose and Application:
  • The preferred dose was 1% rapamycin, applied daily at bedtime for 6 months.
• Quality of Life:
  • No statistically significant differences were found in quality of life questionnaires.

Limitations and Future Directions

• The study was terminated before full enrollment, though the sample size was sufficient for statistical power.
• Future studies are needed to assess the durability of response after treatment discontinuation, the efficacy of prophylactic or early use, and the safety and efficacy of combination therapy with oral mTOR inhibitors.

Conclusion

Topical rapamycin has shown promise in reducing markers of skin aging and treating facial angiofibromas associated with TSC. The findings highlight its potential as an effective and safe therapeutic option, particularly at a 1% concentration. Further research is needed to explore its long-term efficacy, safety, and broader applications.