NNZ-2591

Summary

NNZ-2591 is a synthetic analogue of the endogenous diketopiperazine cyclic Gly‑Pro, derived from the insulin‑like growth factor‑1 (IGF‑1) metabolite. It is being investigated as a neuroprotective and neurotrophic agent for rare neurodevelopmental disorders such as Phelan‑McDermid syndrome and for a range of neurological injuries in pre‑clinical models.

Mechanism of Action

Pre‑clinical work shows NNZ‑2591 crosses the blood‑brain barrier after peripheral dosing and resists enzymatic degradation. It reduces caspase‑3‑mediated apoptosis, dampens microglial activation, and promotes astrocytic reactivity, supporting tissue survival. The peptide also enhances neurogenesis, as indicated by increased doublecortin‑positive cells, and modulates cholinergic signaling by antagonising muscarinic M2 receptors, which may underlie its memory‑preserving effects. It does not act through IGF‑1 receptors, suggesting a distinct neuroplasticity‑focused pathway.

What the Research Shows

In a phase‑2, open‑label trial of 18 children with Phelan‑McDermid syndrome, twice‑daily oral NNZ‑2591 (4‑12 mg/kg) for 13 weeks was well tolerated and produced statistically significant improvements in 10 of 14 efficacy measures, including global impression, caregiver ratings, communication, cognition, socialisation, gastrointestinal symptoms and sleep. In rats, peripheral NNZ‑2591 reduced cortical, hippocampal and striatal damage after hypoxic‑ischemic injury, improved somatosensory‑motor function, and sustained cerebrospinal fluid levels for hours. In a 6‑OHDA Parkinsonian model, early intracerebroventricular dosing limited motor deficits, while delayed sub‑cutaneous dosing restored motor performance without altering dopamine loss and increased neuroblast proliferation. Oral administration prevented scopolamine‑induced memory loss, enhanced hippocampal synaptophysin, and acted as an M2 antagonist. Across models, the peptide showed neuroprotective, neurotrophic and cognitive benefits.

Reported Benefits

Human data suggest NNZ‑2591 may improve adaptive behavior, quality of life and core symptoms in Phelan‑McDermid syndrome, with caregiver‑reported gains in communication and socialisation. Animal studies consistently demonstrate reduced brain injury, better motor recovery after Parkinsonian lesions, enhanced neurogenesis, and protection against drug‑induced memory deficits. Together, these findings indicate potential for NNZ‑2591 to support neuroprotection, functional recovery and cognitive performance in diverse neurological contexts, though human evidence remains limited.

Limitations of the Evidence

The clinical evidence is confined to a single, uncontrolled, small‑sample trial of short duration, limiting conclusions about efficacy and durability. Pre‑clinical results come from rodent models that may not translate to humans. Dose‑response relationships, optimal treatment windows, and long‑term safety have not been established. Mechanistic pathways are inferred from biomarkers rather than definitive molecular targets, and no comparative or placebo‑controlled data are available.

Safety Considerations

In the PMS trial, treatment‑emergent adverse events were mostly mild to moderate, and no serious safety signals emerged. Pre‑clinical studies reported no overt toxicity at the administered doses. However, the limited sample size and short exposure period mean rare or delayed adverse effects cannot be ruled out. Caution is advised until larger, controlled studies confirm the safety profile.

How It Is Administered

NNZ‑2591 has been administered orally in humans, twice daily with dose titration from 4 mg/kg to 12 mg/kg over six weeks. In animal experiments the peptide was given by sub‑cutaneous injection, oral gavage, or intracerebroventricular infusion, demonstrating systemic bioavailability and brain penetration. Formulation details are not disclosed in the published abstracts.

Routes of Administration

Goals & Uses

• NeuroprotectionNeurologyModerate
• Cognitive and behavioral improvementNeurological / FunctionalLow
• Treatment of Phelan-McDermid syndromeNeurodevelopmental DisorderModerate
• Treatment of Pitt-Hopkins syndromeNeurodevelopmental DisorderModerate
• Treatment of Rett syndromeNeurodevelopmental DisorderModerate
• Treatment of Angelman syndromeNeurodevelopmental DisorderModerate

Contraindications

• Severe hepatic impairmentOrganModerateLiver function concerns
• Known hypersensitivity to NNZ-2591 or diketopiperazine componentsAllergyHigh

Adverse Effects

• HeadacheNeurologicUnknownPain in the head or upper neck
• Gastrointestinal discomfortGastrointestinalUnknown
• IrritabilityPsychiatricUnknownIncreased agitation or short temper
• SomnolenceNeurologicUnknownExcessive sleepiness

Drug Interactions

• IGF-1 / insulin pathway modulatorsModerate

Population Constraints

• PregnancyReproductive SafetyRelative
• Renal impairmentOrgan ImpairmentRelative
• Pediatric patients (primary population)AgeRelative

Regulatory Status

• European UnionUnknownNo known EU regulatory designation at this time
• United StatesInvestigationalFDA Orphan Drug Designation for Phelan-McDermid syndrome and Pitt-Hopkins syndrome; Phase 2 trials ongoing
• United KingdomUnknownNo known UK regulatory designation at this time

NNZ-2591 has received Orphan Drug Designation from the FDA for several rare neurodevelopmental conditions including Phelan-McDermid syndrome and Pitt-Hopkins syndrome. It is not yet approved in any jurisdiction. Phase 2 trials are ongoing in the US and Australia.

Evidence & Sources

• NNZ-2591 in Children and Adolescents With Phelan-McDermid Syndrome: Single-Group, Open-Label, Phase 2 Trial Results
  Journal ArticleLowNeumeyer AM, et al.2026-01-01T00:00:00.000000Z
• A novel diketopiperazine improves functional recovery given after the onset of 6-OHDA-induced motor deficit in rats
  Journal ArticleLowKrishnamurthi RV, et al.2009-01-01T00:00:00.000000Z
• Peripheral administration of a novel diketopiperazine, NNZ 2591, prevents brain injury and improves somatosensory-motor function following hypoxia-ischemia in adult rats
  Journal ArticleLowGuan J, et al.2007-01-01T00:00:00.000000Z
• NNZ-2591, a novel diketopiperazine, prevented scopolamine-induced acute memory impairment in the adult rat
  Journal ArticleLowGuan J, et al.2010-01-01T00:00:00.000000Z
• Insulin-like growth factor-1 and its derivatives: potential pharmaceutical application for treating neurological conditions
  Journal ArticleModerateGuan J, et al.2013-01-01T00:00:00.000000Z
• IGF-1 derived small neuropeptides and analogues: a novel strategy for the development of pharmaceuticals for neurological conditions
  Journal ArticleModerateGuan J, Gluckman PD2009-01-01T00:00:00.000000Z

Frequently Asked Questions