NNZ-2591

What is NNZ-2591?

NNZ-2591 (international nonproprietary name ercanetide) is an orally administered synthetic analogue of cyclic glycine-proline (cGP), a small endogenous molecule associated with the insulin-like growth factor 1 (IGF-1) system. It is being developed by Neuren Pharmaceuticals, the Australian-New Zealand company behind trofinetide (Daybue), for a set of rare genetic neurodevelopmental disorders: Phelan-McDermid syndrome, Pitt-Hopkins syndrome and Angelman syndrome. A point of accuracy that most coverage gets wrong, and that matters for anyone trying to understand what this molecule is: NNZ-2591 is not a peptide. It is a 2,5-diketopiperazine — a cyclic dipeptide — with molecular formula C10H14N2O2 and a molecular weight of 194.23 daltons (PubChem CID 11735696), formally cyclo-L-glycyl-L-2-allylproline. Its parent, cGP, is the glycine-proline diketopiperazine (C7H10N2O2, 154.17 Da), and NNZ-2591 is precisely cGP with an allyl group added at the 8a position corresponding to proline C2. The primary literature is explicit about this, using 'diketopiperazine' in the paper titles themselves. It appears on this site because its lineage, its mechanism and its sibling compound are all peptide biology, not because it meets a strict definition of a peptide. The relationship to trofinetide is a common source of confusion. Both come from Neuren, both stabilise the proline C2 position against enzymatic degradation, and both trace back to IGF-1. But they are siblings rather than variants: trofinetide is a linear tripeptide analogue (glycyl-2-methylprolyl-glutamate, C13H21N3O6, 315.32 Da) of GPE, the N-terminal tripeptide of IGF-1, while NNZ-2591 is a cyclic dipeptide analogue of cGP. Different parent metabolite, different molecular class, different indications. As of late 2026 NNZ-2591 holds no marketing approval in any jurisdiction. It has US orphan drug designation across its programs, FDA Rare Pediatric Disease designation in Phelan-McDermid syndrome, FDA Fast Track in Phelan-McDermid, Pitt-Hopkins and Angelman syndromes, and an EU orphan designation in Phelan-McDermid syndrome.

What NNZ-2591 Is Investigated For

NNZ-2591 is a rare-disease drug-development story, not a compound anyone can obtain or take. Its entire clinical footprint is four completed trials and two that are recruiting, all run by a single sponsor. The published evidence is one trial: an open-label, single-group Phase 2 in 18 children aged 3-12 with Phelan-McDermid syndrome, in which safety and pharmacokinetics were the primary endpoints and the 14 efficacy assessments were secondary. Significant improvement from baseline was reported in 10 of those 14 assessments at week 13. Two further Phase 2 trials — in Pitt-Hopkins syndrome (16 children dosed) and Angelman syndrome (16 dosed, 13 completing) — reported positive topline results through stock-exchange announcements but have never been published in a peer-reviewed journal, which is a meaningful gap given that they are the basis for two Fast Track designations. The methodological caveat applies to all three and should be read before any of the numbers: these were single-group, open-label studies with no placebo arm, 13 weeks in duration, with between 13 and 18 evaluable participants, and several of the efficacy instruments were bespoke syndrome-specific scales developed with the sponsor and patient advocacy groups. Clinician- and caregiver-rated global impression scores in an unblinded trial of severely affected children are exactly the setting where expectancy effects are largest. The Pitt-Hopkins announcement contains a result usually omitted from secondary coverage: while all four purpose-built PTHS measures improved significantly, the ten efficacy measures not designed for Pitt-Hopkins showed no statistically significant change. What changes the picture is that a genuine randomised controlled trial now exists. The Koala study (NCT07281079), a Phase 3 randomised double-blind placebo-controlled trial in 160 children with Phelan-McDermid syndrome, began recruiting in November 2025 under an FDA-agreed design intended to support a New Drug Application. A companion open-label extension (NCT07593391, 180 participants) provides long-term safety follow-up — it is an extension, not a second pivotal efficacy trial, and should not be counted as one. Until Koala reports, every efficacy claim about NNZ-2591 rests on uncontrolled data. The Prader-Willi program is the part of the story that is usually left out: a Phase 2 was registered in 2023, never dosed a single participant, and was withdrawn with the registry reason 'Revised development strategy.'

History & Discovery

NNZ-2591 comes out of the same Auckland research programme that produced trofinetide, and the two compounds are best understood as parallel bets on the same idea. From the 1990s, work at the University of Auckland on insulin-like growth factor 1 established that small fragments and metabolites associated with IGF-1 had neuroprotective activity of their own, distinct from IGF-1 receptor signalling. Two such molecules became drug candidates: GPE, the N-terminal glycine-proline-glutamate tripeptide, and cyclic glycine-proline, a diketopiperazine associated with the same system. Both are unstable and impractical as drugs in native form, and in both cases the chemistry solution was the same — modify the proline C2 position to resist enzymatic degradation. GPE plus a methyl group gave NNZ-2566, later named trofinetide. cGP plus an allyl group gave NNZ-2591, later assigned the international nonproprietary name ercanetide. The preclinical case was built by Jian Guan and colleagues across the late 2000s. The founding 2007 Neuropharmacology paper showed that NNZ-2591 was plasma-stable, crossed the blood-brain barrier regardless of injury status, and reduced hypoxic-ischemic brain damage more potently than cGP itself. A 2009 British Journal of Pharmacology study extended this to a Parkinson model with treatment begun after motor deficits had already appeared, and a 2010 study showed protection against scopolamine-induced memory impairment. The mechanistic account came together in 2014, when Guan's group published the IGFBP-3 competition model in Scientific Reports, proposing that cGP works by shifting the balance between bound and bioavailable IGF-1 — and, unusually, in whichever direction homeostasis requires. Neuren took NNZ-2591 into clinical development aimed squarely at rare genetic neurodevelopmental disorders rather than at the stroke and brain-injury indications the preclinical work had explored. A Phase 1 in 28 healthy volunteers ran from 2020 to 2021. Four Phase 2 trials followed in 2022 and 2023: Phelan-McDermid syndrome, Angelman syndrome, Pitt-Hopkins syndrome, and Prader-Willi syndrome. The first three completed and reported positive topline results. The fourth never dosed a participant and was withdrawn from the registry with the stated reason 'Revised development strategy' — Neuren publicly described the programme as paused, citing a burdensome safety-monitoring schedule, and no formal termination announcement has been issued. Regulatory momentum accumulated through 2024 and 2025: US orphan drug designation across the programmes, FDA Rare Pediatric Disease designation in Phelan-McDermid syndrome in July 2024, Fast Track for Pitt-Hopkins in February 2025, and Fast Track extended to Phelan-McDermid and Angelman in October 2025. An EU orphan designation for Phelan-McDermid syndrome has been in place since January 2021, with sponsorship transferred to Orphix Consulting in July 2024. The decisive chapter began in November 2025, when Neuren started recruiting Koala — a Phase 3 randomised, double-blind, placebo-controlled trial in 160 children with Phelan-McDermid syndrome, running to an FDA-agreed design intended to support a New Drug Application, and described by the company as the first-ever Phase 3 trial in this condition. For a molecule whose entire efficacy case has so far rested on uncontrolled open-label studies, it is the first real test.

How It Works

Your body makes a growth factor called IGF-1 that matters a great deal for brain development. Most of the IGF-1 in your blood is not free to act — it is held by carrier proteins, and only the unbound portion does anything. Your body also makes a tiny molecule called cyclic glycine-proline that competes for those same carriers, which nudges the balance of free versus bound IGF-1. The interesting part is that it appears to push in whichever direction is needed: raising IGF-1 activity when there is too little, lowering it when there is too much. NNZ-2591 is a laboratory-made copy of that small molecule, modified so it survives digestion and reaches the brain, so it can be taken as an oral liquid. The idea is to restore normal IGF-1 signalling in genetic conditions where it has gone awry, rather than simply flooding the system with more growth factor.

NNZ-2591 is a synthetic analogue of cyclic glycine-proline (cGP), the glycine-proline 2,5-diketopiperazine associated with the IGF-1 system. The proposed lineage runs IGF-1 to GPE (the N-terminal glycine-proline-glutamate tripeptide) to cGP, although the source literature states the GPE-to-cGP derivation hypothetically rather than as settled fact, and the page should not be read as asserting it. The mechanism is modulation of IGF-1 bioavailability, not IGF-1 receptor agonism — an important distinction, since the GPE family explicitly does not engage IGF receptors. Circulating IGF-1 is predominantly bound to binding proteins, chiefly IGFBP-3, with only the free fraction biologically active. Guan and colleagues showed that cGP retains affinity for IGFBP-3 and competes against IGF-1 for that binding, so cGP and IGFBP-3 together set the bound-to-bioavailable ratio. The foundational 2014 Scientific Reports work reported that this produces a bidirectional effect: cGP promoted IGF-1 activity when IGF-1 was insufficient but inhibited it when IGF-1 was excessive, with mathematical modelling attributing the effect to altered binding-protein association rather than to direct receptor signalling. That homeostatic rather than agonist character is the central claim of the entire programme. The structural modification exists to solve a delivery problem. Endogenous cGP is not a practical drug; adding an allyl group at the position corresponding to proline C2 yields a compound that is, in the words of the preclinical literature, highly enzymatically resistant and centrally accessible. The 2007 founding paper reported that NNZ-2591 was stable in plasma and crossed the blood-brain barrier independent of hypoxic-ischemic injury, and found it more potent than cGP itself at reducing brain damage in lateral cortex, hippocampus and striatum. Later work extended the preclinical range to a 6-hydroxydopamine Parkinson model, where delayed treatment begun after motor deficit onset improved function, and to scopolamine-induced memory impairment in adult rats. Two complications deserve mention rather than burial. First, the memory work identified an additional, scopolamine-independent antagonist effect at muscarinic M2 acetylcholine receptors, so the pharmacology is not purely an IGF-1 story. Second, the supporting cGP literature is heavily concentrated in a single research group at the University of Auckland, and independent replication of the IGFBP-3 competition mechanism is limited. Neuren's stated hypothesis for the clinical programme is that NNZ-2591 treats these disorders by mimicking the natural actions of cyclic glycine-proline in maintaining IGF-1 homeostasis, with downstream effects proposed on MAPK/ERK signalling relevant to synaptic plasticity and on inflammatory signalling molecules. Those downstream claims appear in the discussion section of the Phase 2 publication as expectation rather than as trial findings — no biomarker data on IGF-1, IGFBP-3, cGP levels or MAPK/ERK activity were collected or reported in any of the human trials.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about NNZ-2591:

• 01No placebo-controlled efficacy data exist for any indication. Every efficacy claim about NNZ-2591 derives from single-group open-label trials of 13-18 evaluable participants over 13 weeks — a design that routinely produces apparent improvement in paediatric neurodevelopmental disorders that does not survive blinding. The Phase 3 Koala trial (NCT07281079) is the first randomised, double-blind, placebo-controlled test and has not reported.
• 02Two of the three Phase 2 trials have never been peer-reviewed. The Pitt-Hopkins and Angelman results exist only as stock-exchange announcements, despite both underpinning FDA Fast Track designations. Until they are published, their methods, full outcome sets and adverse-event tables cannot be independently scrutinised.
• 03The Pitt-Hopkins result contains an unresolved discrepancy that secondary coverage almost always omits: all four purpose-built PTHS-specific instruments improved significantly, while the ten efficacy measures not designed for the condition showed no significant change. Whether this reflects superior sensitivity of bespoke scales or an artefact of instruments co-developed with the sponsor and advocacy groups is a real and open methodological question.
• 04No human biomarker data exist for the proposed mechanism. No published study has shown that NNZ-2591 alters IGF-1, IGFBP-3 or cGP concentrations in treated patients, and the MAPK/ERK and anti-inflammatory effects described in the Phase 2 discussion are stated as expectation rather than measured. The entire mechanistic rationale is extrapolated from cGP work, largely from one research group at the University of Auckland, without independent replication of the IGFBP-3 competition model.
• 05Human pharmacokinetics are essentially unpublished. The Phase 1 healthy-volunteer study (NCT04379869, 28 participants, completed February 2021) has posted no results and produced no publication. Beyond a steady-state exposure threshold associated with global-impression improvement, no PK parameters are in the public domain.
• 06Nothing is known beyond 13 weeks. The longest completed exposure in any trial is a single quarter. The ongoing open-label extension will produce 12-month data, but chronic safety in a paediatric population receiving a compound that modulates growth-factor bioavailability — including effects on growth trajectory and pubertal development — is entirely uncharacterised.
• 07The apparent gastrointestinal tolerability advantage over trofinetide is unverified. Diarrhea occurred in 2 of 18 NNZ-2591 participants versus 85% of patients on trofinetide in its label, which would be a decisive differentiator if real — but the comparison sets 18 open-label patients over 13 weeks against a large placebo-controlled dataset with long-term follow-up, and cross-trial adverse-event rates are not directly comparable.
• 08The Prader-Willi programme's status is ambiguous. The registry records the trial as withdrawn with zero participants enrolled and the reason 'Revised development strategy,' while the company has described it as paused. No formal termination announcement exists, so whether this indication is dead or deferred is unclear.
• 09No Phase 3 is registered for Pitt-Hopkins or Angelman syndrome despite Fast Track designation in both. Claims that an Angelman Phase 3 is underway circulate but are not supported by ClinicalTrials.gov — the only registered Phase 3 studies are the two in Phelan-McDermid syndrome.
• 10Independent, non-sponsor research is almost entirely absent. Every clinical trial of NNZ-2591 has been run by Neuren, and the total PubMed corpus naming the compound comprises seven records.

Forms & Administration

Oral liquid, administered twice daily. The Phase 2 trials uptitrated from 4 mg/kg to a target of 12 mg/kg twice daily over six weeks, then maintained that dose to week 13. The compound's enzymatic stability and blood-brain-barrier penetration — the reasons the allyl modification exists — are what make oral dosing viable, in contrast to genuine peptides of comparable intent that require injection. There is no approved product, no commercial formulation and no compounded version; supply exists only within Neuren's registered clinical trials.

Dosing & Protocols

The ranges below reflect protocols commonly discussed in the literature and by clinicians — not a prescription. Actual dosing for any individual should be determined by a qualified healthcare provider who knows the patient.

NNZ-2591 is an investigational drug approved by no regulator in any country. The doses above describe what was given under protocol in clinical trials and are recorded for reference only. They are not a prescription, not a protocol anyone should attempt to follow, and the compound is not legitimately obtainable outside a trial.

Timeline of Effects

Common Questions

Who NNZ-2591 Is NOT For

Drug & Supplement Interactions

No human drug-interaction studies have been published for NNZ-2591, and the published Phase 2 reports no interaction analysis. What follows is mechanistic reasoning rather than documented clinical events. The most relevant theoretical interactions concern the IGF-1 axis itself. Growth hormone, recombinant IGF-1 (mecasermin), and conditions or drugs that substantially alter IGFBP-3 levels would all be expected to interact with a compound whose entire mechanism is competing for IGFBP-3 binding. Because the proposed effect is bidirectional — promoting IGF-1 activity when deficient, suppressing it when excessive — the direction of any such interaction is genuinely hard to predict, which is an argument for caution rather than reassurance. The muscarinic finding deserves a mention. Preclinical work identified a scopolamine-independent antagonist effect at M2 acetylcholine receptors, so additive effects with anticholinergic medications cannot be dismissed on mechanism alone, although nothing in the clinical data speaks to it. In the trial populations, concomitant medication burden is high: anticonvulsants, psychotropics and gastrointestinal agents are common in Phelan-McDermid, Pitt-Hopkins and Angelman syndromes. The published Phase 2 reported no clinically significant changes in laboratory values or electrocardiograms, which is mildly reassuring regarding gross interactions, but 18 participants over 13 weeks cannot exclude much. No cytochrome P450, transporter or protein-binding interaction data have been published for this compound.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions