Preventative Treatment of Tuberous Sclerosis Complex with Sirolimus: Preliminary Safety and Efficacy Results
Abstract number :
1.284
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2023
Submission ID :
340
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: David Ritter, MD, PhD – Cincinnati Children's Hospital Medical Center
Jamie Capal, MD – University of North Carolina Chapel Hill; David Franz, MD – Cincinnati Children's Hospital Medical Center; Molly Griffith, BS – Cincinnati Children's Hospital Medical Center; E Martina Bebin, MD, MPH – University of Alabama Birmingham; Hope Northrup, MD – University of Texas Houston; Mary Koenig, MD – University of Texas Houston; Tomoyuki Mizuno, PhD – Cincinnati Children's Hospital Medical Center; Alexander Vinks, PhD – Cincinnati Children's Hospital Medical Center; Stephanie Galandi, MS – Cincinnati Children's Hospital Medical Center; Wujuan Zhang, PhD – Cincinnati Children's Hospital Medical Center; Kenneth Setchell, PhD – Cincinnati Children's Hospital Medical Center; Carlos Prada, MD – Lurie Children's Hospital; Kelly Kremer, MD – Cincinnati Children's Hospital Medical Center; Katherine Holland-Bouley, MD, PhD – Cincinnati Children's Hospital Medical Center; Hansel Greiner, MD – Cincinnati Children's Hospital Medical Center; Paul Horn, PhD – Cincinnati Children's Hospital Medical Center; Darcy Krueger, MD, PhD – Cincinnati Children's Hospital Medical Center
Rationale: 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 disease 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 less than six months of age, not have had a prior seizure, and not have a clinical indication for sirolimus treatment. Adverse events (AEs), tolerability, seizure characteristics, and developmental profiles were tracked through 24 months of age, as was blood concentrations of sirolimus measured by tandem mass Spectrometry.
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.
Conclusions: These results show that sirolimus is both safe and well tolerated when treating infants with TSC preventatively in the first year of life. Additionally, the preliminary work suggests a favorable efficacy profile compared to previous TSC cohorts not exposed to early sirolimus treatment. Results support sirolimus being studied as preventative treatment in TSC, which is now underway in a prospective Phase 2 clinical trial (TSC-STEPS).
Funding: This study is registered at clinicaltrials.gov (NCT04595513). Funding and material support for this study was provided by the TSC Alliance, Clack Foundation, Olivia Murray Foundation, the McCann Family, Tavanta Pharmaceuticals, the FDA Office of Orphan Product Development (R01-FD007275), and NIH National Center for Advancing Translational Sciences (UL1-TR001425).
Anti-seizure Medications