An Open-Label Study Evaluating the Safety and Efficacy of AMO-01 for the Treatment of Seizures in Phelan-McDermid Syndrome

Authors

• Tess Levy
• J Lloyd Holder
• Joseph P Horrigan
• Michael F Snape
• Alison McMorn
• Christina Layton
• Hailey Silver
• Kate Friedman
• Hannah Grosman
• Slayton Underwood
• Danielle Halpern
• Jessica Zweifach
• Paige M Siper
• Alexander Kolevzon

Language

English

Publication Date

4-10-2025

Journal

Human Genetics and Genomics Advances

DOI

10.1016/j.xhgg.2024.100393

PMID

39690738

PMCID

PMC11772936

PubMedCentral® Posted Date

12-16-2024

PubMedCentral® Full Text Version

Post-print

Abstract

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene. Approximately 25% of individuals with PMS have epilepsy. Treatment of epilepsy in PMS may require multiple anticonvulsants, and in a minority of cases, seizures remain poorly controlled. Converging lines of evidence in different experimental models indicate that the Ras-ERK pathway is implicated in the pathophysiology of seizure generation and neurobehavioral symptoms in PMS. The goal of this study was to evaluate the safety, tolerability, and efficacy in treating seizures in adults and adolescents with PMS using AMO-01, a Ras-ERK pathway inhibitor. A single 6-hour intravenous infusion of AMO-01 at 120 mg/m2 was administered to six participants using an open-label design. Safety was assessed during the infusion and for 4 weeks post-infusion. Caregivers completed seizure diaries and recorded individual seizures during a baseline period and for 4 weeks following the infusion. Exploratory clinical and biomarker assessments were completed throughout the study. AMO-01 was well tolerated, with no serious adverse events (AEs) reported. All AEs were mild or moderate in severity. Seizures were reduced by at least 25% compared to baseline at each follow-up (weeks 1, 2, and 4). Exploratory clinical measures did not change significantly from baseline, but visual evoked potentials (VEPs) and phosphorylated ERK blood levels revealed trending changes in a subset of participants. These results provide preliminary support for the safety of AMO-01 and its efficacy in reducing seizures in adults with PMS. Future placebo-controlled studies with larger sample sizes and repeated dosing are warranted.

Keywords

Humans, Male, Seizures, Female, Adult, Chromosome Disorders, Adolescent, Young Adult, Chromosomes, Human, Pair 22, Treatment Outcome, Anticonvulsants, Chromosome Deletion, Middle Aged, AMO-01, shank3, Phelan-McDermid syndrome, PMS, seizures, epilepsy, autism spectrum disorder, ASD

Published Open-Access

yes

Recommended Citation

Levy, Tess; Holder, J Lloyd; Horrigan, Joseph P; et al., "An Open-Label Study Evaluating the Safety and Efficacy of AMO-01 for the Treatment of Seizures in Phelan-McDermid Syndrome" (2025). Duncan NRI Faculty and Staff Publications. 207.
https://digitalcommons.library.tmc.edu/duncar_nri_pub/207