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Updated: May 8, 2025
A Semi-Quantitative Drug Affinity Responsive Target Stability DARTS assay for studying Rapamycin/mTOR interaction
Published on: August 27, 2019
Preventative treatment of tuberous sclerosis complex with sirolimus: Phase I safety and efficacy results
Jamie K Capal1, David M Ritter2, David Neal Franz2
1Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Objective:
Tuberous sclerosis complex (TSC) results from overactivity of the mechanistic target of rapamycin (mTOR). Sirolimus and everolimus are mTOR inhibitors that treat most facets of TSC but are understudied in infants. We sought to understand the safety and potential efficacy of preventative sirolimus in infants with TSC.
Methods:
We conducted a phase 1 clinical trial of sirolimus, treating five patients until 12 months of age. Enrolled infants had to be younger than 6 months of age with no history of seizures and no clinical indication for sirolimus treatment. Adverse events (AEs), tolerability, and blood concentrations of sirolimus measured by tandem mass spectrometry were tracked through 12 months of age, and clinical outcomes (seizure characteristics and developmental profiles) were tracked through 24 months of age.
Results:
There were 92 AEs, with 34 possibly, probably, or definitely related to treatment. Of those, only two were grade 3 (both elevated lipids) and all AEs were resolved by the age of 24 months. During the trial, 94% of blood sirolimus trough levels were in the target range (5-15 ng/mL). Treatment was well tolerated, with less than 8% of doses held because of an AE (241 of 2941). Of the five patients, three developed seizures (but were well controlled on medications) at 24 months of age. Of the five patients, four had normal cognitive development for age. One was diagnosed with possible autism spectrum disorder.
Interpretation:
These results suggest that sirolimus is both safe and well tolerated by infants with TSC in the first year of life. Additionally, the preliminary work suggests a favorable efficacy profile compared with previous TSC cohorts not exposed to early sirolimus treatment. Results support sirolimus being studied as preventive treatment in TSC, which is now underway in a prospective phase 2 clinical trial (TSC-STEPS).
Insights
Preventative sirolimus is safe and well-tolerated in infants with tuberous sclerosis complex (TSC). Early treatment shows promising efficacy, supporting further investigation in a phase 2 trial for TSC.
Area of Science:
- Pediatric Neurology
- Pharmacology
- Genetics
Background:
- Tuberous sclerosis complex (TSC) is a genetic disorder caused by mechanistic target of rapamycin (mTOR) overactivity.
- Sirolimus and everolimus are mTOR inhibitors used to manage TSC, but their use in infants is understudied.
Purpose of the Study:
- To evaluate the safety and potential efficacy of preventative sirolimus in infants diagnosed with TSC.
- To assess adverse events, tolerability, and sirolimus blood concentrations in infants up to 12 months of age.
Main Methods:
- A phase 1 clinical trial involving five infants younger than 6 months with TSC, no prior seizures, and no current indication for sirolimus.
- Monitoring of adverse events, tolerability, sirolimus trough levels via mass spectrometry up to 12 months, and clinical outcomes (seizures, development) up to 24 months.
Main Results:
- 92 adverse events (AEs) were recorded, with 34 possibly/probably/definitely related to treatment; only two were grade 3 and all resolved by 24 months.
- 94% of sirolimus trough levels were within the target range (5-15 ng/mL), and treatment was well tolerated with <8% of doses held.
- Three of five infants developed seizures (well-controlled) by 24 months; four had normal cognitive development, and one was diagnosed with possible autism spectrum disorder.
Conclusions:
- Sirolimus appears safe and well-tolerated in infants with TSC during the first year of life.
- Preliminary efficacy suggests a favorable profile compared to historical TSC cohorts not receiving early sirolimus.
- Results support further study of sirolimus as a preventive treatment for TSC, as initiated in the TSC-STEPS phase 2 trial.
