Published Phase 2 Data Highlight Potential of NNZ-2591 in Phelan-McDermid Syndrome

A group of investigators have published the final dataset of a phase 2, open-label trial (NCT05025241) testing the efficacy and safety of NNZ-2591 (Neuren Pharmaceuticals) as a potential treatment for children and adolescents with Phelan-McDermid syndrome (PMS), a rare genetic neurodevelopmental disorder. All told, the agent was safe with clinicians and caregivers reporting meaningful improvements in critical PMS symptoms.¹

Based on these data, Neuren is planning to bring NNZ-2591, synthetic analog of the insulin-like growth factor 1 (IGF-1) metabolite cyclic glycine-proline, into a phase 3 study (NCT07281079). The phase 3 study, which remains enrolling, is a follow-up to the phase 2 study to further validate the efficacy and safety of the investigational agent in patients with PMS.

The recently published phase 2 trial featured 18 patients aged 3-12 (mean age, 8.6 years) with PMS who received twice-daily oral NNZ-2591 for 13 weeks, with titration beginning in the first 6 weeks. Led by Elizabeth Berry-Kravis, MD, PhD, professor of Pediatrics and Neurological Sciences and director of the RUSH Pediatric Neurosciences F.A.S.T. Center for Translational Research at Rush University Medical Center in Chicago, the cohort included those who had a clinical PMS diagnosis and a disease-causing genetic abnormality of the SHANK3 gene.

Coming into the study, most patients had moderate-to-marked impairment based on Clinical Global Impression-Severity (CGI-S) scores (mean, 4.5). At the conclusion of the 13-week treatment period, patients experienced statistically significant improvements in the total or overall scores of 10 of the 14 efficacy assessments that covered clinically important aspects of PMS.

These improvements included scales like CGI-Improvement (week 13 mean, 2.4 [SD, 0.9]; P <.0001), Caregiver Impression of Change (CIC; mean, 2.7 [SD, 1.0]; P = .0003), CGI-S (mean, 4.1 [SD, 1.0]; P = .0156), Caregiver Top 3 Concerns total severity score (mean 20.1 [SD, 7.1]; P = .0005), PMS Clinician Domain-Specific Rating Scale (PMS-DSRS) total severity score (week 13 mean, 4.7 [SD, 2.2]; P = .0156), Quality of Life Inventory-Disability overall score (week 13 mean, 70.9 [SD, 11.7]; P = .0066), Aberrant Behavior Checklist (week 13 mean, 53.2 [SD, 21.6]; P = .0013), Behavior Problems Inventory-Short Form total frequency score (week 13 mean, 22.7 [SD, 11.1]; P = .0326), Gastrointestinal Health Questionnaire (week 13 mean, 32.1 [SD, 25.6]; P = .0013), and Child Sleep Habits Questionnaire (week 13 mean, 42.5 [SD, 5.0]; P = .0191).

READ MORE: BMB-101 Heads for Registrational Trials Following Positive Phase 2 Data in Absence Seizures, Developmental Encephalopathies

Other efficacy data revealed consistent improvements in communication, cognition/learning, and social interaction. Outside of these, statistically significant improvements were seen on fine and gross motor functions, as well as self-care skills, based on CGI-I scores at week 13.

At week 13 of NNZ-2591 treatment, statistically significant improvements were observed across multiple domains, including quality of life (QI-Disability overall score), behavior (ABC-2 total score; BPI total frequency score), gastrointestinal symptoms (GIHQ total frequency score), and sleep (CSHQ total score). Communication outcomes also improved, with significant gains in VABS-3 receptive communication (raw score change from baseline: mean, 7.5 [SD, 7.8]; median, 6.0 [−3.0, 29.0]; P = 0.0001; growth scale value change: mean, 12.1 [SD, 13.7]; median, 8.0 [−3.0, 51.0]; P = 0.0002) and expressive communication (raw score change: mean, 3.3 [SD, 5.7]; median, 3.5 [−9.0, 14.0]; P = 0.0298; growth scale value change: mean, 6.8 [SD, 9.6]; median, 7.0 [−10.0, 25.0]; P = 0.0130). Numerical improvements were also reported for other communication measures, including the ORCA total score and MB-CDI total vocabulary score.

In terms of safety, treatment-emergent adverse events (TEAEs) were reported in 17 of the 18 participants, although most TEAEs were mild to moderate in severity. There were 3 discontinuations due to TEAEs unrelated to the study drug (COVID-19: n = 2; seizures: n = 1). The most common TEAE was psychomotor hyperactivity (n = 4), while COVID-19, decreased appetite, pyrexia, and somnolence were each reported in 3 participants, with no clinically significant changes in laboratory values, electrocardiograms, or other safety parameters, and no deaths reported.

The ongoing phase 3 study for NNZ-2591 in PMS was planned in coordination with the FDA after a Type C Meeting occurred in early 2025. Expected to include 160 participants, the double-blind, placebo-controlled study used change in the Receptive Communication subdomain of the VABS-3 and the overall score in PMS Assessment of Change. At the time of the meeting, Neuren noted that the end points pair the caregiver’s assessment of change in one crucial symptom area with the clinician’s assessment of change across multiple aspects of PMS.²

REFERENCES
1. Neumeyer AM, Srivastava S, Holder JL, et al. NNZ-2591 in Children and Adolescents With Phelan-McDermid Syndrome Single-Group, Open-Label, Phase 2 Trial Results. Neurology. 2026;12(1). E200338. doi:10.1212/NXG.0000000000200338.
2. Neuren confirms primary endpoints for Phase 3 Trial of NNZ-2591 in PMS. Neuren Pharmaceuticals. April 15, 2025. Accessed January 12, 2025. https://www.neurenpharma.com/pdf/50956f1f-5257-4253-bd44-cac0635d8213/NEU-confirms-primary-endpoints-for-Phase-3-trial-in-PMS