cGP analog · Phelan-McDermid syndrome
An experimental oral drug from Neuren Pharmaceuticals for rare genetic neurodevelopmental conditions. Chemically it is cyclo-L-glycyl-L-2-allylproline, a small ring-shaped molecule modeled on cyclic glycine-proline (cGP), a natural breakdown product of insulin-like growth factor 1 (IGF-1). Its most advanced program is Phelan-McDermid syndrome, a SHANK3-related condition with no approved treatment.
IGF-1 is a growth factor with important roles in brain development and in how connections between nerve cells adapt1. cGP, a small metabolite of IGF-1, showed activity of its own in rat brain-injury studies, and cell and modeling work suggests it acts as a buffer: by changing how much IGF-1 is held by its binding protein IGFBP-3, it raised IGF-1 activity when IGF-1 was scarce and damped it when it was in excess2. NNZ-2591 is a cGP analog modified for better bioavailability; in rats it was stable in blood and reached the brain after injection under the skin3.
In a Shank3-deficient mouse model and in nerve cells grown from patients' stem cells, IGF-1 itself improved defects1. Whether NNZ-2591 corrects IGF-1 signaling in people has not been shown.
Human data so far come from studies without a placebo group. In an open-label phase 2 trial, 18 children with Phelan-McDermid syndrome (aged 3 to 12 at screening) took NNZ-2591 by mouth for 13 weeks; clinicians rated 16 of 18 as improved on a syndrome-specific global scale, and 10 of 14 secondary measures, including behavior, sleep, and gut symptoms, improved from baseline1. Without a control group, these changes cannot be separated from expectation or natural variation. Open-label phase 2 studies in Angelman syndrome5 and Pitt Hopkins syndrome6 are registered as completed.
A randomized, double-blind, placebo-controlled phase 3 trial in children with Phelan-McDermid syndrome started in late 2025 and is recruiting4. Earlier work was in rats: given after hypoxic-ischemic brain injury, NNZ-2591 reduced tissue damage and improved motor function3.
Not approved by the FDA or by any other regulator found. It remains an investigational drug given only within clinical trials.
Evidence comes from the 18-child phase 2 study. Seventeen of 18 had at least one adverse event, mostly mild to moderate. The most common was hyperactivity (four children), then lower appetite, fever, and sleepiness (three each); one severe episode of hyperactivity, judged possibly drug-related, resolved the next day. Three children left the study for events judged unrelated (two COVID-19, one seizures). No deaths or clinically significant lab or ECG changes were reported1. Placebo-controlled and long-term data are not yet published.
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