Capal Jamie K, Ritter David M, Franz David Neal, Griffith Molly, Currans Kristn, Kent Bridget, Bebin E Martina, Northrup Hope, Koenig Mary Kay, Mizuno Tomoyuki, Vinks Alexander A, Galandi Stephanie L, Zhang Wujuan, Setchell Kenneth D R, Kremer Kelly M, Prada Carlos M, Greiner Hansel M, Holland-Bouley Katherine, Horn Paul S, Krueger Darcy A
Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Ann Child Neurol Soc. 2024 Jun;2(2):106-119. doi: 10.1002/cns3.20070. Epub 2024 Apr 22.
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.
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.
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.
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).
结节性硬化症复合体（TSC）由雷帕霉素机制靶点（mTOR）过度激活引起。西罗莫司和依维莫司是治疗TSC多方面症状的mTOR抑制剂，但在婴儿中的研究较少。我们旨在了解预防性使用西罗莫司对TSC婴儿的安全性和潜在疗效。
我们进行了一项西罗莫司的1期临床试验，治疗5名患者至12个月龄。入选婴儿必须小于6个月龄，无癫痫病史且无西罗莫司治疗的临床指征。通过串联质谱法测定的西罗莫司不良事件（AE）、耐受性和血药浓度在12个月龄前进行跟踪，临床结局（癫痫特征和发育情况）在24个月龄前进行跟踪。
共有92例AE，其中34例可能、很可能或肯定与治疗有关。其中，只有2例为3级（均为血脂升高），所有AE在24个月龄时均得到缓解。在试验期间，94%的西罗莫司血药谷浓度处于目标范围（5 - 15 ng/mL）。治疗耐受性良好，因AE停药的剂量不到8%（2941剂中的241剂）。5名患者中，3名在24个月龄时出现癫痫（但药物控制良好）。5名患者中，4名认知发育正常。1名被诊断为可能患有自闭症谱系障碍。
这些结果表明，西罗莫司在TSC婴儿生命的第一年既安全又耐受性良好。此外，与未接受早期西罗莫司治疗的先前TSC队列相比，这项初步研究显示出良好的疗效。结果支持将西罗莫司作为TSC的预防性治疗进行研究，目前正在进行一项前瞻性2期临床试验（TSC - STEPS）。
