RPB

GPE and Trofinetide

GPE: Gly-Pro-Glu, IGF-1(1–3), glypromate. Trofinetide: NNZ-2566, glycyl-L-2-methylprolyl-L-glutamic acid, Daybue (US, Canada), Daybu (EU)

Cognitive & neuro
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Note on this profile. Trofinetide is an approved prescription medicine for Rett syndrome in the United States (2023), Canada (2024) and the European Union (2026). GPE, the natural tripeptide it is based on, is not approved anywhere and has no established human use. This page explains the published science for both; use of trofinetide outside its licence, or of GPE at all, is unapproved.

1What it is

When IGF-1 is produced in the brain, an enzyme snips off its first three amino acids, glycine-proline-glutamate. For decades this fragment was considered waste. In the 1980s researchers in Sweden and later in Auckland found that GPE itself had effects on neurons independent of the IGF-1 receptor — it protected brain cells in injury models and modulated glutamate signalling (Sara 1989; Guan 1999). The problem was that it lasts only minutes in blood.

Trofinetide is GPE with one small change — a methyl group on the proline — which makes it resistant to the peptidases that destroy GPE, allowing oral dosing. It was developed by a New Zealand company originally for traumatic brain injury, then for fragile X syndrome and Rett syndrome. It became the first approved treatment for Rett syndrome, a rare genetic neurodevelopmental disorder affecting mostly girls, in March 2023 in the US.

2How it's thought to work

Not an IGF-1 mimic. GPE and trofinetide do not bind the IGF-1 receptor meaningfully. The receptor is unknown; glutamate-receptor interactions and effects on microglia have been proposed.
Rett models. in Mecp2-knockout mice, trofinetide improved survival, breathing, motor function and dendritic spine density, and normalised markers of neuroinflammation (Tropea 2009 — IGF-1 fragment; Deacon 2015, Neuropharmacology — trofinetide).
Anti-inflammatory and anti-apoptotic. reduces microglial activation and caspase activity after brain injury in rodents.
Synaptic maturation. increases expression of synaptic proteins in immature synapses, which is why neurodevelopmental disorders were chosen.
A synthetic analogue of glycine-proline-glutamate, the tripeptide cleaved from the end of IGF-1. It acts on astrocytes and microglia to settle inflammatory signalling rather than driving growth, and is approved for Rett syndrome.Schematic — not to scale

3What the research shows

Rett syndrome (trofinetide)

LAVENDER (Phase 3, n=187 girls and women aged 5–20, 12 weeks, randomised, double-blind, placebo-controlled): trofinetide improved both co-primary endpoints — the caregiver-rated Rett Syndrome Behaviour Questionnaire (RSBQ) and the clinician-rated Clinical Global Impression–Improvement (CGI-I) — versus placebo (Neul 2023, Nat Med). Effect sizes were modest but statistically robust. Open-label extensions (LILAC, LILAC-2) reported maintained improvement over up to ~2–3 years; the DAFFODIL study extended dosing to children aged 2–4 (Percy 2024). Earlier Phase 2 trials in adolescents/adults and in children had supported the dose (Glaze 2017, 2019, Neurology). [5][6][7]
Graded B (negative)

Fragile X syndrome

A Phase 2 trial in adolescents and adults with fragile X (Berry-Kravis 2020, J Neurodev Disord) showed signals on some exploratory scales at the higher dose but did not lead to development. [8]
Graded A (negative)

Traumatic brain injury (IV trofinetide)

The INTREPID trial of intravenous NNZ-2566 after moderate-to-severe TBI did not meet its primary endpoint †.

GPE in stroke, hypoxia-ischaemia, Parkinson models

Rat studies showed neuroprotection after hypoxic-ischaemic injury and 6-OHDA lesions (Guan 1999; Alexi 1999; Krishnamurthi 2004). No human trials of GPE itself. [2]

Community use of GPE

GPE is occasionally sold as a research peptide and discussed for "neuroprotection" or as an IGF-1 fragment. No published human data of any kind. Given its minutes-long , meaningful systemic effect from injection is doubtful.

4Reported side effects and interactions

Literature-reported

Literature (trofinetide, LAVENDER and extensions). diarrhoea in ~80% of treated participants (vs ~19% placebo), often requiring dose adjustment or anti-diarrhoeal medication; vomiting ~27%; weight loss; fever; seizures were reported at similar rates to placebo. Discontinuation for adverse events ~17%. The label advises monitoring hydration and weight and stopping if severe diarrhoea develops.

Community-reported

Community-reported (GPE). essentially none documented.

Theoretical. none specific beyond the class.

Interactions. trofinetide is a weak inhibitor of CYP3A4 and OATP1B1/1B3 ; label advises caution with sensitive CYP3A4 substrates and certain statins †. No interaction data for GPE.

Markers researchers commonly monitor

Following the trofinetide label and trial protocols:

MarkerWhy it's watched
Body weight and hydration statusdiarrhoea and weight loss are the main adverse effects; weight is checked at each visit.
Electrolytes (sodium, potassium) and creatinineif diarrhoea is persistent.
RSBQ and CGI-I scalesthe trial outcomes, completed by caregivers and clinicians.
Seizure diaryRett syndrome includes seizures; no increase was seen but tracking is standard care.
For GPE: no compound-specific markers; IGF-1 is not changed by GPE and is not a marker of its effect

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Daybue is a ready-made strawberry-flavoured oral solution (200 mg/mL), given by mouth or gastrostomy tube with a measured syringe; large volumes (up to 60 mL twice daily) are needed at adult doses. GPE research material is ; with only in a laboratory context — no human handling protocol exists. (GPE research use only)

6Commonly studied alongside

IGF-1 and mecasermin (the parent protein; mecasermin was itself trialled in Rett with mixed results), Cerebrolysin and Semax (community "neuro" peptides with no combined evidence), ketogenic diet and anti-seizure medicines in Rett clinical care.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

RegionStatus (checked —)
United StatesFDA-approved March 2023 (Daybue) for Rett syndrome in adults and children aged 2 and older; GPE not approved and not permitted for compounding
European UnionEuropean Commission approval 2026 (Daybu) for neurobehavioural symptoms of Rett syndrome aged 5 and older †
United KingdomNot yet licensed by MHRA as of review date †
AustraliaNot approved; may be accessible via Special Access Scheme †
South AfricaNot registered
SportNot specifically listed by WADA; GPE marketed as an IGF-1 fragment could fall under S2 interpretation †

8Open questions

  • The receptor or binding partner for GPE and trofinetide remains unidentified.
  • Long-term functional outcomes in Rett beyond caregiver and clinician rating scales.
  • Whether trofinetide helps other neurodevelopmental disorders (fragile X was disappointing).
  • Whether GPE has any systemic activity in humans — never tested.

9References

  1. 1Sara VR et al. (1989). Identification of Gly-Pro-Glu (GPE), the aminoterminal tripeptide of insulin-like growth factor 1 which is truncated in brain, as a novel neuroactive peptide. Biochem Biophys Res Commun. PubMed · DOI
  2. 2Guan J et al. (1999). N-terminal tripeptide of IGF-1 (GPE) prevents the loss of TH positive neurons after 6-OHDA induced nigral lesion in rats. Brain Res. PubMed · DOI
  3. 3Tropea D et al. (2009). Partial reversal of Rett syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci USA. PubMed · DOI
  4. 4Deacon RMJ et al. (2015). NNZ-2566, a novel analog of (1–3) IGF-1, as a potential therapeutic agent for fragile X syndrome. Neuromolecular Med [verify journal]. PubMed · DOI
  5. 5Glaze DG et al. (2019). Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome. Neurology. PubMed · DOI
  6. 6Neul JL et al. (2023). Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study (LAVENDER). Nat Med. PubMed · DOI
  7. 7Percy AK et al. (2024). Trofinetide for the treatment of Rett syndrome: long-term safety and efficacy results of the open-label LILAC and LILAC-2 studies [verify]. Med. PubMed
  8. 8Berry-Kravis E et al. (2020). A double-blind, randomized, placebo-controlled clinical study of trofinetide in the treatment of fragile X syndrome. Pediatr Neurol. PubMed · DOI
  9. 9FDA (2023). Daybue (trofinetide) prescribing information. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

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11Page history

31 Oct 2026Profile published — awaiting medical review

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