NNZ-2591 in Children and Adolescents With Phelan-McDermid Syndrome: Single-Group, Open-Label, Phase 2 Trial Results.
A 13-week open trial of NNZ-2591 showed broad caregiver-reported gains in PMS, yet placebo effects seen in no-treatment studies could explain part of the boost.
01Research in Context
What this study did
Doctors gave 18 children and teens with Phelan-McDermid syndrome a new pill called NNZ-2591 every day for 13 weeks.
They checked communication, sleep, tummy trouble, and behavior before and after. No placebo group was used.
What they found
Caregivers and clinicians saw gains in 10 of 14 areas. Kids talked more, slept better, and had fewer meltdowns.
The pill was safe and easy to take at home.
How this fits with other research
Laposa et al. (2017) showed that parents often report big “gains” even when no treatment is given. Their no-drug group dropped 30 % on the same parent forms used here. This raises a red flag: part of the NNZ-2591 benefit could be placebo.
Christian et al. (1997) tested high-dose vitamins in autistic kids and saw zero change. NNZ-2591, a lab-made IGF-1 fragment, did better, but both studies were small and short.
Hirosawa et al. (2017) ran an earlier 8-week open trial with oxytocin in autism. Like NNZ-2591, they saw hopeful signals without a control group. Both papers remind us to wait for RCT data before celebrating.
Why it matters
You may soon meet families asking about NNZ-2591. Tell them the early open-label story is encouraging, but placebo effects are strong in PMS. Track your client’s target behaviors with direct observation, not just parent forms, while families talk to their medical team about next-phase trials.
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Start a simple daily behavior log (rate 0-3) for one target skill and one problem behavior so you have objective data if the family tries the drug.
02At a glance
03Original abstract
<h4>Background and objectives</h4>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.<h4>Methods</h4>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 <i>p</i> < 0.05 indicating significance.<h4>Results</h4>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) (<i>p</i> < 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) (<i>p</i> = 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 steady-state area under the curve (AUC<sub>24,ss</sub>) 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<sub>24,ss</sub> > 300 μg ⋅ h/mL experienced improvements in the PMS-specific CGI of Improvement scores.<h4>Discussion</h4>For children and adolescents with PMS, NNZ-2591 appeared generally safe, with clinicians and caregivers reporting meaningful improvements in important symptoms of PMS. The benefit-risk and pharmacokinetic profiles support continued evaluation of NNZ-2591 for PMS.<h4>Trial registration information</h4>ClinicalTrials.gov; NCT05025241. Submitted August 24, 2021. First participant enrolled on August 8, 2022.
, 2025 · doi:10.1212/nxg.0000000000200338