OPERATING REVIEW CONTINUED RESEARCH ARTICLE OPEN ACCESS NNZ-2591 in Children and Adolescents With Phelan-McDermid Syndrome Single-Group, Open-Label, Phase 2 Trial Results Ann M. Neumeyer, 1 Siddharth Srivastava, 2 J. Lloyd Holder, Jr., 3 Mark A. Milad, 4 Liza Squires, 5 Nancy Elizabeth Jones, 5 Larry Glass, 5 and Elizabeth Berry-Kravis 6 Neurol Genet 2026;12:e200338. doi:10.1212/NXG.0000000000200338 Correspondence Dr. Neumeyer ANEUMEYER@mgh.harvard.edu Abstract Background and Objectives Phelan-McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder with no currently approved treatments. NNZ-2591, a synthetic analog of the insulin-like growth factor 1 metabolite cyclic glycine-proline, was evaluated in children and adolescents with PMS in a phase 2, multisite, open-label clinical trial. Methods Participants aged 3–12 years at screening received twice-daily oral NNZ-2591 for 13 weeks; doses were uptitrated from 4 mg/kg to 12 mg/kg over 6 weeks (NCT05025241). Safety and pharmacokinetic profiles were primary end points; 14 efficacy assessments were secondary end points, which included global and symptom-specific PMS assessments, quality of life, communication, behavior, adaptive behavior/self-care, gastrointestinal health, and sleep assessments. Wilcoxon signed-rank tests evaluated change from or observed change relative to baseline vs the null median, with p < 0.05 indicating significance. Results Eighteen participants received NNZ-2591 (mean [SD] age 8.6 years, mean [SD] weight: 30.4 [10.8] kg). NNZ-2591 was well tolerated; most treatment-emergent adverse events were mild to moderate. Significant improvements from baseline were observed in 10 of 14 efficacy assessments at week 13, including global and symptom-specific PMS assessments, quality of life, behavior, gastrointestinal symptoms, and sleep. At week 13, the PMS-specific Clinical Global Impression (CGI) of Improvement mean (SD) score was 2.4 (0.9) and the median (range) score was 2.0 (1.0, 4.0) (p < 0.0001), with 16 of 18 participants showing improvement; the PMS-specific Caregiver Impression of Change mean (SD) score was 2.7 (1.0) and the median (range) score was 3.0 (1.0, 5.0) (p = 0.0003), with 15 of 18 participants showing improvement. PMS-specific assessment subdomains of communication, cognition/learning, and socialization showed consistent improvements. A 24-hour steadystate area under the curve (AUC 24,ss ) was estimated for each participant using a one-compartment, linear, population pharmacokinetic model where clearance and volume of distribution parameters were scaled by body weight. Participants with an NNZ-2591 AUC 24,ss > 300 μg × h/mL experienced improvements in the PMS-specific CGI of Improvement scores. Discussion For children and adolescents with PMS, NNZ-2591 appeared generally safe, with clinicians and caregivers reporting meaningful improvements in important symptoms of PMS. The benefitrisk and pharmacokinetic profiles support continued evaluation of NNZ-2591 for PMS. Trial Registration Information ClinicalTrials.gov; NCT05025241. Submitted August 24, 2021. First participant enrolled on August 8, 2022. 1 Lurie Center for Autism, Massachusetts General Hospital, Lexington, MA; 2 Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Boston, MA; 3 Department of Pediatrics, Baylor College of Medicine, Houston, TX; 4 Milad Pharmaceutical Consulting, Plymouth, MI; 5 Neuren Pharmaceuticals, Camberwell, Australia; 6 Department of Pediatrics, Rush University Medical Center, Chicago, IL. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. e200338(1) MORE ONLINE Supplementary Material Downloaded from https://www.neurology.org by 175.32.225.128 on 19 March 2026 Neuren Pharmaceuticals Limited Annual Report 2025 13
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