NNZ-2591
Also known as: Cyclo-L-glycyl-L-2-allylproline, Cyclic glycine-proline analog
Key Facts: NNZ-2591
- Category
- Cognitive
- FDA Status
- Not FDA Approved
- Clinical Status
- Investigational - Phase 3 (Koala, NCT07281079) in Phelan-McDermid syndrome, recruiting as of 2026; positive open-label phase 2 results in Phelan-McDermid, Angelman and Pitt Hopkins syndromes. FDA Fast Track, Rare Pediatric Disease and Orphan Drug designations. Not approved anywhere.
- Banned in Sport (WADA)
- Not named on the WADA list, but it has no human therapeutic approval anywhere, so the S0 catch-all (non-approved substances) prohibits it at all times.
- Administration
- Oral liquid
- Typical Dose
- 12 mg/kg twice daily (phase 2 target trial dose)
- Frequency
- Twice daily
- Duration
- 13 weeks in phase 2 and phase 3 trials, with 12-month open-label extensions
How does NNZ-2591 work?
Cyclic glycine-proline is thought to fine-tune IGF-1 activity in the brain by changing how IGF-1 binds to its carrier protein IGFBP-3. A 2014 Scientific Reports study proposed that cGP nudges IGF-1 activity up when it is low and down when it is high, a normalizing effect rather than a simple boost. NNZ-2591 adds an allyl group to the proline ring, making it resistant to enzymes and able to reach the brain after oral dosing. Trial protocols also describe reduced neuroinflammation and support for synapse function in animal models. It is a close cousin of trofinetide in spirit (both are small IGF-1-derived molecules from the same company), but the exact way it helps in these genetic syndromes has not been pinned down in humans.
What does the research show?
The human data so far come from three small, open-label phase 2 trials of 13 weeks each, all with twice-daily oral dosing titrated up to a target of 12 mg/kg. In Phelan-McDermid syndrome (18 children, published in Neurology Genetics in 2026), 10 of 14 efficacy measures improved significantly from baseline, including clinician and caregiver global ratings, behavior, sleep and communication, and the drug was well tolerated with mostly mild to moderate side effects. Angelman syndrome (reported August 2024) showed a mean CGI-I of 3.0, with 11 of 13 children rated improved by clinicians. Pitt Hopkins syndrome (reported May 2024) showed improvement in 6 of 11 children on clinician-rated severity. The big caveat: none of these had a placebo group, and rare-disease trials with caregiver-rated outcomes are especially prone to placebo effects. A planned Prader-Willi trial was withdrawn before enrolling anyone. The real test is Koala, a randomized, double-blind, placebo-controlled phase 3 trial in about 160 children aged 3 to 12 with Phelan-McDermid syndrome (first patient dosed February 2026; estimated primary completion late 2027), with an open-label extension started in 2026. The FDA has given the program Fast Track, Rare Pediatric Disease and Orphan Drug designations. Neuren has also started work in neonatal hypoxic-ischemic encephalopathy, which is still preclinical.
What doses have been studied?
Typical Dosingⓘ
Community experience
12 mg/kg twice daily (phase 2 target trial dose)
4-12 mg/kg twice daily (trial titration)
Twice daily
These are clinical trial doses in children with specific genetic syndromes, titrated under medical supervision. They are not recommendations. There is no approved product, and nothing sold outside trials has been verified as the real compound.
Research Dosingⓘ
Scientific studies
Clinical trial doses only (investigational, not approved for any use)
Doses from Studies
4 mg/kg BID titrated to 12 mg/kg BID
Twice-daily oral dosing for 13 weeks vs placebo
Duration
13 weeks in phase 2 and phase 3 trials, with 12-month open-label extensions
Administration
Oral liquid
When and how is NNZ-2591 taken?
Best Time to Take
Twice daily (trial schedule)
Twice daily in clinical trials
Food Recommendation
With or without food
Why This Timing?
Trials give it twice daily by mouth. No timing relative to sleep or meals has been established.
What are the side effects of NNZ-2591?
Not everyone experiences these effects. Individual responses vary based on dosage, duration, and personal factors.
- ●Psychomotor hyperactivity (most common in the Phelan-McDermid trial)
- ●Decreased appetite
- ●Fever
- ●Sleepiness
- ●Mostly mild to moderate events in phase 2
- ●No clinically significant lab or ECG changes reported in phase 2
- ●Long-term safety unknown; human data come from small trials in children
References
- https://pubmed.ncbi.nlm.nih.gov/41450730/
- https://clinicaltrials.gov/study/NCT07281079
- https://announcements.asx.com.au/asxpdf/20260206/pdf/06w0xr42ylsbty.pdf
- https://cdn.clinicaltrials.gov/large-docs/41/NCT05025241/Prot_003.pdf
- https://clinicaltrials.gov/study/NCT05011851
- https://pubmed.ncbi.nlm.nih.gov/24633053/
Research This Peptide Further
Frequently Asked Questions
What does NNZ-2591 do?
NNZ-2591 is Neuren Pharmaceuticals' second drug, a synthetic analog of cyclic glycine-proline (cGP), a small ring-shaped molecule the body makes when it breaks down IGF-1. It is taken by mouth and is being developed for rare childhood neurodevelopmental disorders: Phelan-McDermid syndrome is furthest along, with the first-ever phase 3 trial in that disease started in late 2025, and Angelman and Pitt Hopkins syndromes behind it. Phase 2 results looked encouraging, but they were small open-label studies, so nobody knows yet whether it truly works.
How does NNZ-2591 work?
Cyclic glycine-proline is thought to fine-tune IGF-1 activity in the brain by changing how IGF-1 binds to its carrier protein IGFBP-3. A 2014 Scientific Reports study proposed that cGP nudges IGF-1 activity up when it is low and down when it is high, a normalizing effect rather than a simple boost. NNZ-2591 adds an allyl group to the proline ring, making it resistant to enzymes and able to reach the brain after oral dosing. Trial protocols also describe reduced neuroinflammation and support for synapse function in animal models. It is a close cousin of trofinetide in spirit (both are small IGF-1-derived molecules from the same company), but the exact way it helps in these genetic syndromes has not been pinned down in humans.
Is NNZ-2591 FDA approved?
No, NNZ-2591 is not currently FDA approved. Current status: Investigational - Phase 3 (Koala, NCT07281079) in Phelan-McDermid syndrome, recruiting as of 2026; positive open-label phase 2 results in Phelan-McDermid, Angelman and Pitt Hopkins syndromes. FDA Fast Track, Rare Pediatric Disease and Orphan Drug designations. Not approved anywhere.
Is NNZ-2591 banned in sport?
Not named on the WADA list, but it has no human therapeutic approval anywhere, so the S0 catch-all (non-approved substances) prohibits it at all times.
What are the side effects of NNZ-2591?
Reported side effects include: Psychomotor hyperactivity (most common in the Phelan-McDermid trial), Decreased appetite, Fever, Sleepiness, Mostly mild to moderate events in phase 2. Individual responses vary based on dosage, duration, and personal health factors.
What is the typical dose of NNZ-2591?
Community-reported common dose: 12 mg/kg twice daily (phase 2 target trial dose) (Twice daily). Range: 4-12 mg/kg twice daily (trial titration). Administration: Oral liquid. Community-reported doses. Not medical advice. Consult healthcare provider.
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