Trofinetide (NNZ-2566): the GPE analogue and its research record
Prepared by: Research Desk. Sources are linked for verification.
Published 1 November 2026
At a glance
- What it is: trofinetide, also coded NNZ-2566, is a synthetic analogue of glycine-proline-glutamate (GPE), the N-terminal tripeptide cleaved from insulin-like growth factor 1 (IGF-1), with an added methyl group on the proline (Bickerdike et al., 2009, PubMed)
- Main research areas: rodent models of traumatic brain injury, mouse models of Rett syndrome, and clinical trials in Rett syndrome and fragile X syndrome
- Regulatory record: the US FDA approved it in March 2023 under the brand name Daybue, and the European Commission authorised it in August 2026 under the name Daybu
- Mechanism: the FDA's nonclinical review states that its mechanism of action is unknown (FDA pharmacology review)
From GPE to trofinetide
IGF-1 is cleaved in the brain to release the tripeptide Gly-Pro-Glu, which had been studied for its own effects on neurons. Natural GPE is broken down quickly in plasma. Neuren Pharmaceuticals added a methyl group to the alpha carbon of proline, giving Gly-(α-methyl)Pro-Glu. The change was designed to slow enzymatic breakdown and extend the half-life (Bickerdike et al., 2009). A 2023 review summarises the chemistry and the development history (PubMed).
Rodent brain-injury studies
Most early work tested NNZ-2566 in a rat model called penetrating ballistic-like brain injury, at the Walter Reed Army Institute of Research, with the compound given after the injury:
- Inflammation markers: NNZ-2566 reduced the injury-induced rise in pro-inflammatory cytokines such as IL-1β, TNF-α and IFN-γ in the injured brain (Wei et al., 2009, PubMed)
- Proposed pathway: a follow-up study reported higher levels of ATF3, a transcription factor that represses inflammatory cytokines, in several brain cell types (Cartagena et al., 2013, PubMed)
No human brain-injury trial results were found when we searched.
The Rett syndrome mouse work
Rett syndrome is a neurodevelopmental disorder mostly caused by mutations in the MECP2 gene, and it mainly affects girls. A 2009 PNAS study gave the parent tripeptide, rather than trofinetide, to Mecp2-mutant mice and reported improvements in survival, activity and synaptic measures (Tropea et al., 2009, PubMed).
The FDA's review of trofinetide itself describes a study in Mecp2-null mice. Long-term potentiation, a measure of synaptic strengthening, increased, and median survival rose from 13.5 to 15.5 weeks. Motor and breathing measures did not improve. The same review notes that binding to the IGF-1 receptor was not assessed (FDA pharmacology review).
Clinical trials in Rett syndrome
- Phase 2, adolescents and adults: 56 participants; mainly a safety study with exploratory efficacy measures (Glaze et al., 2017, PubMed; NCT01703533)
- Phase 2, children aged 5 to 15: 82 participants; the arm with the highest exposure differed from placebo on caregiver and investigator rating scales (Glaze et al., 2019, PubMed; NCT02715115)
- LAVENDER, phase 3: 187 girls and young women aged 5 to 20 were randomised to trofinetide (93) or placebo (94) for 12 weeks (Neul et al., 2023, Nature Medicine, PubMed; NCT04181723)
- LILAC and LILAC-2: open-label extensions of LAVENDER, with 154 participants over 40 weeks and 77 participants respectively (PubMed; PubMed)
- DAFFODIL: an open-label study in 15 girls aged 2 to 4 (PubMed)
In LAVENDER, the co-primary end points were a caregiver rating scale (the Rett Syndrome Behaviour Questionnaire, RSBQ) and an investigator's global impression of improvement (CGI-I). RSBQ scores changed by −4.9 with trofinetide and −1.7 with placebo (p=0.0175). Mean CGI-I scores were 3.5 and 3.8 (p=0.0030), where lower is better and 4 means no change (Neul et al., 2023).
Gastrointestinal effects were common in the trial. Diarrhoea was reported in 80.6% of the trofinetide group against 19.1% with placebo, and vomiting in 26.9% against 9.6%. Withdrawal because of adverse events was 17.2% against 2.1%.
Fragile X syndrome
A double-blind, placebo-controlled phase 2 trial in 72 adolescent and adult males with fragile X syndrome was published in 2020 (Berry-Kravis et al., 2020, PubMed). We found no phase 3 fragile X results when we searched on 1 November 2026.
Regulatory record
The FDA approved trofinetide (Daybue) on 10 March 2023 for Rett syndrome in people aged 2 and over. In the EU, the Committee for Medicinal Products for Human Use gave a negative opinion in February 2026, then a positive opinion after re-examination on 25 June 2026. The European Commission granted marketing authorisation for Daybu on 20 August 2026, for neurobehavioural symptoms of Rett syndrome in people aged 5 and over (EMA EPAR page). This page reports that record only and does not cover clinical use.
Limitations
- Small effect sizes: the LAVENDER differences from placebo were modest on both scales
- Short controlled period: the only phase 3 placebo comparison lasted 12 weeks; the extensions were open label, with no placebo group
- Sponsor: the trials were funded by Neuren or Acadia Pharmaceuticals
- Unknown mechanism: the link between GPE biology, the mouse findings and the clinical effects has not been established
- Animal data: rodent injury and Mecp2 findings do not establish effects in people
Key terms
- GPE: glycine-proline-glutamate, a tripeptide released when IGF-1 is cleaved
- IGF-1: insulin-like growth factor 1, a hormone involved in growth and brain development
- MECP2: the gene most often mutated in Rett syndrome
- RSBQ: the Rett Syndrome Behaviour Questionnaire, a caregiver-completed rating scale
- CGI-I: the Clinical Global Impression of Improvement, a 7-point investigator rating where 4 means no change
- Open-label extension: a follow-on study where everyone receives the study drug and knows it
Supplier
Purita is a store that sells peptides for laboratory research use only. When we checked on 1 November 2026 it did not have a trofinetide product page, and we have not checked whether trofinetide appears anywhere else in its catalogue. The link below goes to its neurological research category.
Affiliate disclosure: this is a paid link. CognitivePepti earns a commission if a purchase is made through it, at no extra cost to the buyer. A listing is not an endorsement or a statement about product quality. See the affiliate disclosure.
Related pages
More from CognitivePepti
Cognition-related peptides in research: Semax, Selank and DSIP
A side-by-side research reference on Semax, Selank and DSIP: where they came from, their sequences, the studies on record, proposed mechanisms and FDA status.
Selank: the tuftsin analogue and its research record
Selank is a synthetic heptapeptide built on the tuftsin sequence. This page summarises its origins, published preclinical work, regulatory record and remaining gaps.
DSIP (delta sleep-inducing peptide): fifty years of open questions
DSIP was isolated from rabbit brain in 1977, yet its receptor and mechanism remain unresolved. A summary of the early studies, open questions and the 2026 FDA advisory agenda.
Semax: the ACTH(4-7)-Pro-Gly-Pro peptide and its research record
Semax is a synthetic heptapeptide built from an ACTH fragment and a Pro-Gly-Pro tail. This overview covers its design, the rodent BDNF and ischaemia studies, and FDA's July 2026 briefing document.
Epithalon (Ala-Glu-Asp-Gly): the pineal tetrapeptide in research
Epithalon (AEDG) is a synthetic tetrapeptide modelled on bovine pineal extract. This overview covers its sequence, cell and rodent studies, and its place on FDA's July 2026 advisory agenda.
Peptides and the blood–brain barrier: how research measures entry
Can peptides cross the blood–brain barrier? Transport studies describe three main routes, selective carriers and efflux, and why stability matters for Semax, Selank and DSIP.
Dihexa: the angiotensin IV analogue and the 2025 retractions
Dihexa is an angiotensin IV-derived molecule studied in rodent memory models. Its proposed HGF/c-Met mechanism rests partly on a 2014 paper retracted in 2025.
Cerebrolysin: the porcine brain peptide mixture and its research record
Cerebrolysin is a peptide mixture made by digesting pig brain protein. What its composition analysis, Cochrane reviews and retracted mouse studies show.
P21 (P021): the CNTF-derived peptide and its research record
P21, or P021, is a small adamantylated peptide derived from ciliary neurotrophic factor. What its design is, what the rat and mouse studies report, and what has not been tested.
Davunetide (NAP): the ADNP-derived peptide and its research record
Davunetide, the eight-amino-acid NAP fragment of ADNP, went from mouse tau studies to a 313-person phase 2/3 trial in PSP. Here is what the record shows.
Humanin: the mitochondrial-derived peptide and its research record
Humanin is a 24-amino-acid peptide encoded in mitochondrial DNA. Its 2001 discovery, proposed partners such as Bax and IGFBP-3, mouse cognition studies, the P3S variant and the gaps in the evidence.
Nerinetide (NA-1): the PSD-95 inhibitor peptide and its stroke trial record
Nerinetide (NA-1) is a Tat-linked peptide that disrupts NMDA receptor–PSD-95 coupling. Its rat and primate stroke studies, the ESCAPE-NA1, ESCAPE-NEXT and FRONTIER trials and a 2025 post-hoc analysis.
Pinealon (Glu-Asp-Arg): the EDR tripeptide and its research record
Pinealon (Glu-Asp-Arg, EDR) is a synthetic tripeptide from the St Petersburg bioregulator group. This overview covers its cell and rodent studies, the proposed DNA-binding mechanism and the thin human record.