An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome
Summary: 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 con...
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Elsevier
2025-04-01
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| Series: | HGG Advances |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247724001337 |
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| author | Tess Levy J. Lloyd Holder, Jr. 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 |
| author_facet | Tess Levy J. Lloyd Holder, Jr. 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 |
| author_sort | Tess Levy |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-c54a70acd46c4307bd9e6e1a1b4739e3 |
| institution | Kabale University |
| issn | 2666-2477 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | HGG Advances |
| spelling | doaj-art-c54a70acd46c4307bd9e6e1a1b4739e32025-01-13T04:19:13ZengElsevierHGG Advances2666-24772025-04-0162100393An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndromeTess Levy0J. Lloyd Holder, Jr.1Joseph P. Horrigan2Michael F. Snape3Alison McMorn4Christina Layton5Hailey Silver6Kate Friedman7Hannah Grosman8Slayton Underwood9Danielle Halpern10Jessica Zweifach11Paige M. Siper12Alexander Kolevzon13Seaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Pediatrics, Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USAAMO Pharma, Godalming, UK; Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC 27710, USAAMO Pharma, Godalming, UKAMO Pharma, Godalming, UKDepartment of Psychology, University of Rochester, Rochester, NY 14627, USASeaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USASeaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Psychology, Drexel University, Philadelphia, PA 19104, USASeaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USASeaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USASeaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USASeaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USASeaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2666247724001337AMO-01shank3Phelan-McDermid syndromePMSseizuresepilepsy |
| spellingShingle | Tess Levy J. Lloyd Holder, Jr. 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 An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome HGG Advances AMO-01 shank3 Phelan-McDermid syndrome PMS seizures epilepsy |
| title | An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome |
| title_full | An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome |
| title_fullStr | An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome |
| title_full_unstemmed | An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome |
| title_short | An open-label study evaluating the safety and efficacy of AMO-01 for the treatment of seizures in Phelan-McDermid syndrome |
| title_sort | open label study evaluating the safety and efficacy of amo 01 for the treatment of seizures in phelan mcdermid syndrome |
| topic | AMO-01 shank3 Phelan-McDermid syndrome PMS seizures epilepsy |
| url | http://www.sciencedirect.com/science/article/pii/S2666247724001337 |
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