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Three residues, one methyl group: adding a methyl to the proline of GPE gave a tripeptide stable enough to become the first approved drug for Rett syndrome.
Also known as: NNZ-2566 · ACP-2566 · Daybue · glycyl-2-methyl-L-prolyl-L-glutamic acid
Part of the Neuropeptides & signaling cluster
Overview
Trofinetide (Daybue, NNZ-2566) is a synthetic analogue of glycine-proline-glutamate, the N-terminal tripeptide cleaved from insulin-like growth factor 1, in which the proline carries a 2-methyl group that lengthens its half-life. Taken orally twice daily, it became the first FDA-approved treatment for Rett syndrome in March 2023 after the phase 3 LAVENDER trial; diarrhoea is its dominant side effect.
Source & context
Biological / chemical source: Synthetic modified tripeptide (Neuren Pharmaceuticals / Acadia Pharmaceuticals)
Primary research or clinical context: Approved (US FDA, March 2023) as the first treatment for Rett syndrome in patients aged 2 and older; earlier studied in fragile X syndrome and traumatic brain injury
What trofinetide is
Trofinetide is a synthetic tripeptide: glycine, a methylated proline and glutamate. It is an analogue of GPE (glycine-proline-glutamate, sometimes called Glypromate), the three-residue fragment cleaved from the N-terminus of insulin-like growth factor 1 in the brain. GPE itself has neuroprotective activity but is degraded too quickly to be a drug; the single α-methyl group on trofinetide's proline solves that. Developed by Neuren Pharmaceuticals as NNZ-2566 and licensed to Acadia, it was approved by the US FDA in March 2023 as Daybue — the first treatment for Rett syndrome, for patients aged two years and older (Keam, Drugs 2023).
The smallest peptide drug on this site
With a molecular formula of C13H21N3O6 and a mass of about 315 Da, trofinetide is smaller than many non-peptide drugs, which is why the approval literature calls it a small molecule despite its peptide backbone. The IUPHAR one-letter record is GXE, with X standing for 2-methyl-L-proline; the chip display above uses the same convention. Its size and oral bioavailability set it apart from the injected peptides that dominate this directory: it is given as an oral solution twice daily.
Mechanism and rationale
Rett syndrome is an X-linked neurodevelopmental disorder, almost always caused by mutations in MECP2, that affects girls after an initial period of normal development. Endogenous GPE is present in the brain, and in Mecp2-deficient mice — the standard model of Rett — it partially reversed core symptoms, which motivated a stabilised analogue. Trofinetide was originally developed as a neuroprotective agent for neurodegenerative disease and traumatic brain injury and was evaluated in Rett syndrome, fragile X syndrome and brain injury before the Rett programme succeeded (IUPHAR record). The precise molecular target of GPE-class peptides is not settled in the evidence available for this profile.
LAVENDER: the phase 3 trial
LAVENDER randomised 187 females with Rett syndrome to twice-daily oral trofinetide (n = 93) or placebo (n = 94) for 12 weeks. On the co-primary endpoints, the least-squares mean change in the Rett Syndrome Behaviour Questionnaire was −4.9 with trofinetide versus −1.7 with placebo (P = 0.0175; effect size 0.37), and the Clinical Global Impression–Improvement score also favoured trofinetide (Neul et al., Nature Medicine 2023). Those results supported the March 2023 approval.
| Endpoint | Trofinetide (n = 93) | Placebo (n = 94) |
|---|---|---|
| Rett Syndrome Behaviour Questionnaire, LS mean change | −4.9 | −1.7 |
| Effect size (Cohen's d) | 0.37 | — |
Long-term extension and tolerability
LILAC, the 40-week open-label extension, treated 154 participants aged 5–21. The most common adverse events were diarrhoea (74.7%), vomiting (28.6%) and COVID-19 (11.0%); diarrhoea was the leading reason for withdrawal (21.4%). Behaviour Questionnaire scores continued to improve from the LAVENDER baseline — mean change −7.3 for those originally on trofinetide and −7.0 for those originally on placebo — and the safety profile matched the pivotal trial (Percy et al., Med 2024). Diarrhoea is therefore the clinically defining side effect of the drug.
Status as of September 2026
Trofinetide is an approved prescription medicine in the United States for Rett syndrome. ClinicalTrials.gov lists completed and terminated open-label extension studies, a study of cognitive function during treatment, and an open-label study in girls aged two to five. Reviews of the Rett treatment landscape place it as the first disease-specific therapy after decades in which only symptomatic care existed (Percy et al., CNS Drugs 2024; Gold et al., Nature Reviews Disease Primers 2024).
Relation to other peptides on this site
Trofinetide belongs to the IGF-1 story: the IGF-1 profile describes the 70-residue growth factor from which GPE is cleaved, and the growth cluster covers the GH–IGF axis. Its nearest relatives in size are the site's other tripeptides — GHK-Cu and KPV — though those have no approved indication. It is a supervised paediatric neurological medicine; nothing here is guidance on its use.
Sequence
One-letter sequence commonly cited for Trofinetide (educational; isoforms and modifications may differ):
GXE
X = 2-methyl-L-proline (the proline of GPE with an added α-methyl group). X marks a non-canonical residue — see the structure block below. (Plotted as alanine on the wheel.)
Residues plotted ~100° apart around an α-helix — clustering of one color reveals an amphipathic face.
Structure & chemistry
Molecular identity & reference confidence
Source-supported reference
Reference values are taken from the cited molecular record or curated profile. A database match is not independent laboratory verification; modifications, counter-ions, and formulations can change the measured mass.
- Molecular form
- Glycine–(2-methyl)proline–glutamate: the IGF-1 N-terminal tripeptide GPE with a methylated proline
- Species
- Not established by this molecular identity audit
- Termini (N / C)
- Not specified / Not specified
Average reference mass
Reference policy updated: 2026-10-05
- IUPHAR/BPS source snapshot · 2026-10-01
- PubChem molecular record · 2026-10-01
- Molecular formula
- C13H21N3O6
- Average reference mass
- ≈ 315.32
- Backbone
- Glycine–(2-methyl)proline–glutamate: the IGF-1 N-terminal tripeptide GPE with a methylated proline
- Status
- Approved: US FDA, March 2023 (Rett syndrome, age ≥ 2). First drug approved for the condition
The α-methyl group on proline confers resistance to enzymatic degradation and a longer half-life than endogenous GPE (IUPHAR record).
- PubChem CID: 11318905
- IUPHAR ligand: 12482
- ChEMBL: CHEMBL197084
- DrugBank: DB06045
- CAS RN: 853400-76-7
- UNII: Z2ME8F52QL
Chemistry values: curated profile, PubChem, IUPHAR/BPS Guide to Pharmacology · fetched 2026-10-01.
Clinical development snapshot
ClinicalTrials.gov lists 14 registered studies with “Trofinetide” as an intervention (snapshot 2026-09-07). A registry footprint is not evidence of efficacy or approval.
| NCT | Title | Phase | Status | Updated |
|---|---|---|---|---|
| NCT07730112 | Adapting a Psychosocial Support Intervention for the Rett Syndrome Community | Not applicable | not yet recruiting | 2026-07-28 |
| NCT06705816 | Cognitive Function in Rett Syndrome During Trofinetide Treatment | — | recruiting | 2026-06-18 |
| NCT04776746 | Open-Label Extension Study of Trofinetide for Rett Syndrome | Phase 3 | terminated | 2024-09-27 |
| NCT04988867 | An Open-Label Study of Trofinetide for the Treatment of Girls Two to Five Years of Age Who Have Rett Syndrome | Phase 3 | terminated | 2024-09-24 |
| NCT04279314 | Open-Label Extension Study of Trofinetide for the Treatment of Girls and Women With Rett Syndrome | Phase 3 | completed | 2024-04-11 |
| NCT04181723 | Study of Trofinetide for the Treatment of Girls and Women With Rett Syndrome (LAVENDER™) | Phase 3 | completed | 2024-04-08 |
Trofinetide — reconstitution calculator
Enter how much peptide is in the vial and how much diluent (e.g. bacteriostatic water) is added. The tool returns the resulting solution concentration — and, for any amount you type, the volume it corresponds to. This is educational arithmetic, not a dosing recommendation.
Reference form: Glycine–(2-methyl)proline–glutamate: the IGF-1 N-terminal tripeptide GPE with a methylated prolineAverage reference mass: 315.32 Da
Enter an amount to see the volume it corresponds to.
Educational concentration mathematics only. This tool does not recommend a dose, amount, or protocol, and nothing here is medical advice. Many peptides are not authorized by Health Canada for human use — see our reconstitution and bacteriostatic-water guides for context.
Change log
Dated observations from the data pipeline (registry flags, trial footprints, identifiers) and editorial reviews of this profile.
- IdentifiersCross-linked to IUPHAR ligand 12482 and PubChem CID 11318905.
- TrialsClinicalTrials.gov snapshot added: 14 registered studies, highest phase 3.
- EditorialProfile content reviewed and updated by the editorial team.
FAQ about Trofinetide
What is Trofinetide?+
Trofinetide (Daybue, NNZ-2566) is a synthetic analogue of glycine-proline-glutamate, the N-terminal tripeptide cleaved from insulin-like growth factor 1, in which the proline carries a 2-methyl group that lengthens its half-life. Taken orally twice daily, it became the first FDA-approved treatment for Rett syndrome in March 2023 after the phase 3 LAVENDER trial; diarrhoea is its dominant side effect.
What Canadian product status is recorded for Trofinetide?+
Canadian product status for Trofinetide has not been verified in this profile. No verified record here does not mean no authorization exists. Status depends on the product, formulation and use; consult Health Canada's product records.
What is the typical length of Trofinetide?+
Trofinetide is commonly described as approximately 3 amino acids (IGF-1 N-terminal tripeptide analogue).
What is trofinetide?+
A synthetic analogue of glycine-proline-glutamate, the N-terminal tripeptide of IGF-1, with a methylated proline. Sold as Daybue, it was FDA-approved in March 2023 as the first treatment for Rett syndrome.
Is trofinetide a peptide?+
Yes — a three-residue peptide (Gly–2-methyl-Pro–Glu, about 315 Da), small enough that the approval literature also calls it a small molecule. It is taken orally.
What did the phase 3 trial show?+
In LAVENDER, the Rett Syndrome Behaviour Questionnaire improved by −4.9 with trofinetide versus −1.7 with placebo over 12 weeks (P = 0.0175).
What are trofinetide's side effects?+
Diarrhoea (74.7% in the 40-week extension) and vomiting (28.6%) are the most common; diarrhoea was the main reason for stopping treatment (21.4%).
Why does trofinetide have a methylated proline?+
Endogenous GPE is degraded too quickly to work as a drug; the α-methyl group on proline resists enzymatic breakdown and lengthens the half-life.
Related peptides
References & further reading
- 1.Neul JL et al. (2023). Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study. Nature Medicine
- 2.Percy AK et al. (2024). Trofinetide for the treatment of Rett syndrome: Results from the open-label extension LILAC study. Med
- 3.Keam SJ (2023). Trofinetide: First Approval. Drugs
- 4.Percy AK et al. (2024). Rett Syndrome: The Emerging Landscape of Treatment Strategies. CNS Drugs
- 5.Gold WA et al. (2024). Rett syndrome. Nature Reviews Disease Primers
- 6.PubChem — Trofinetide (CID 11318905)