Trofinetide

A synthetic, orally bioavailable analog of the IGF-1 N-terminal tripeptide glycine-proline-glutamate, FDA approved in March 2023 as Daybue, the first treatment for Rett syndrome, after earlier programs in traumatic brain injury and fragile X syndrome did not progress.

Also referenced as: NNZ-2566, NNZ2566, Daybue, Daybu, Glycyl-2-methylprolyl-glutamate, Glycyl-L-2-methylprolyl-L-glutamic acid, Daybue Stix

Also appears in: Cognitive

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What is Trofinetide?

Trofinetide is a synthetic tripeptide, glycyl-2-methylprolyl-glutamate (C13H21N3O6, molecular weight 315.33), built on the sequence glycine-proline-glutamate (GPE) that is cleaved from the N-terminus of insulin-like growth factor 1 in the brain. The single structural change, an alpha-methyl group on the proline, slows enzymatic breakdown and improves the elimination half-life and oral bioavailability over the parent peptide (Bickerdike et al., Journal of the Neurological Sciences, 2009;278(1–2):85–90); native GPE has a plasma half-life of under five minutes and needs intravenous infusion to hold a neuroprotective concentration (reviewed in Kennedy et al., Frontiers in Pharmacology, 2023;14:1341746). It was developed by Neuren Pharmaceuticals under the code NNZ-2566, licensed for North America to Acadia Pharmaceuticals in 2018, and Acadia bought the ex-North American rights in July 2023, so one company now holds the drug worldwide.

It is one of the few short peptides to reach full regulatory approval: the US Food and Drug Administration approved it on March 10, 2023 under the brand name Daybue (NDA 217026) as the first treatment for Rett syndrome, a rare neurodevelopmental disorder caused by mutations in MECP2. Where trofinetide appears in reagent catalogs, it is on the strength of that approval and of its IGF-1 lineage, although the clinical product is an oral solution dispensed through specialty pharmacies and the weight-based doses used in Rett syndrome are measured in grams, not milligrams.

How it works

The FDA label states that the mechanism by which trofinetide produces its effect in Rett syndrome is unknown. The preclinical literature points to several overlapping candidate mechanisms:

• Restoration of IGF-1-pathway signaling in synaptic maturation. The parent tripeptide, delivered systemically to Mecp2-mutant mice, extended life span, improved locomotor and breathing measures, and partially restored dendritic spine density, PSD-95 levels, and synaptic amplitude in motor cortex, framing Rett syndrome as a disorder of delayed synapse maturation that IGF-1-derived peptides can partly correct (Tropea et al., Proceedings of the National Academy of Sciences, 2009;106(6):2029–2034). Trofinetide is the stabilized, orally active version of that fragment.
• Attenuation of neuroinflammation and apoptosis after injury. In a rat penetrating ballistic-like brain injury model at the Walter Reed Army Institute of Research, NNZ-2566 improved balance-beam recovery, reversed the injury-induced rise in Bax and fall in Bcl-2, and reduced neutrophil infiltration and activated microglia without changing lesion volume (Lu et al., Journal of Neurotrauma, 2009;26(1):141–154). A companion study in the same model showed reduced TNF-alpha, IFN-gamma, and IL-6 expression (Wei et al., Journal of Neuroinflammation, 2009;6:19), and follow-up work tied the anti-inflammatory effect to upregulation of the immunomodulatory transcription factor ATF3 across microglia, astrocytes, natural killer cells, and neurons (Cartagena et al., NeuroMolecular Medicine, 2013;15(3):504–514).
• Anti-apoptotic neuroprotection in stroke. NNZ-2566 reduced infarct area when a four-hour infusion was started three hours after endothelin-induced middle cerebral artery constriction in rats, was also active orally as a microemulsion, and attenuated apoptotic death in primary striatal cultures (Bickerdike et al., Journal of the Neurological Sciences, 2009).
• Normalization of overactive ERK and Akt signaling. In Fmr1-knockout mice, NNZ-2566 corrected learning and memory deficits, hyperactivity, and social behavior while normalizing dendritic spine density and overactive ERK/Akt signaling (Deacon et al., NeuroMolecular Medicine, 2015;17(1):71–82).

None of these pathways has been confirmed as the operative one in humans, and the label’s “unknown mechanism” wording is the accurate summary of the approved indication.

Research status

Trofinetide has an unusually complete clinical record for a peptide, spanning two failed or shelved indications and one approval.

Traumatic brain injury (not progressed). The compound’s first clinical program was INTREPID, a Neuren-sponsored phase 2, randomized, placebo-controlled study of a 72-hour intravenous infusion of NNZ-2566 in moderate-to-severe TBI (ClinicalTrials.gov NCT00805818, with an exception-from-informed-consent companion record NCT01366820; 261 participants enrolled, completed January 2016). The registered primary endpoint was safety; efficacy on the Extended Glasgow Outcome Scale and the Mayo-Portland Adaptability Inventory, plus cognitive and neuropsychological testing, sat among the secondary measures. The sponsor’s 2016 summary, which was never peer reviewed, reported that the safety endpoint was met and that there was no significant separation from placebo on the functional outcome measures, with a favorable signal confined to exploratory cognitive testing. The registry carries no posted results, no efficacy publication from INTREPID has appeared on PubMed, and a parallel phase 2 study in concussion (NCT02100150) was terminated after 32 participants. No further brain-injury trial has been registered.

Fragile X syndrome (shelved). An exploratory phase 2 trial randomized 72 adolescent and adult males to 35 or 70 mg/kg twice daily or placebo for 28 days (NCT01894958). The authors reported that the 70 mg/kg arm met a prespecified composite success criterion with a permutation-test false-positive probability of 0.045 (Berry-Kravis et al., Pediatric Neurology, 2020;110:30–41). The result rested on a novel multi-domain analytic model in a four-week study, and no follow-on fragile X trial has been registered in the decade since the study completed in 2015.

Rett syndrome (approved). Two phase 2 studies preceded the pivotal trial. A dose-escalation study randomized 56 adolescent and adult females and reported efficacy at 70 mg/kg on prespecified criteria (Glaze et al., Pediatric Neurology, 2017;76:37–46; NCT01703533), and a dose-ranging study in 82 girls aged 5–15 found statistically significant improvement at 200 mg/kg twice daily on the Rett Syndrome Behaviour Questionnaire, a clinician visual-analog scale, and the Clinical Global Impression-Improvement scale (Glaze et al., Neurology, 2019;92(16):e1912–e1925; NCT02715115).

LAVENDER (NCT04181723) was the phase 3 trial: 187 females aged 5–20 randomized to weight-banded oral trofinetide (n=93) or placebo (n=94) for 12 weeks. Both co-primary endpoints were met, though with modest effect sizes: least-squares mean change on the Rett Syndrome Behaviour Questionnaire was −4.9 versus −1.7 (P=0.0175; Cohen’s d 0.37), and CGI-I at week 12 was 3.5 versus 3.8 (P=0.0030; d 0.47). The key secondary endpoint, the CSBS-DP-IT Social Composite, also separated from placebo (−0.1 versus −1.1; P=0.0064; d 0.43). Diarrhea occurred in 80.6% of the trofinetide arm versus 19.1% on placebo (Neul et al., Nature Medicine, 2023;29(6):1468–1475; communication endpoints in Neul et al., Pediatric Neurology, 2024;152:63–72). The trial design was prespecified in Neul et al., Contemporary Clinical Trials, 2022;114:106704.

Extension and pediatric data followed. LILAC (NCT04279314) treated 154 LAVENDER participants open-label for 40 weeks; diarrhea occurred in 74.7% and was the leading reason for withdrawal (21.4%), while RSBQ scores continued to improve in both former arms (Percy et al., Med, 2024;5(9):1178–1189). LILAC-2 (NCT04776746) carried 77 participants out to 32 months, with diarrhea in 53.2%, before the sponsor terminated it after approval to move patients to commercial supply (Percy et al., Med, 2024;5(10):1275–1281). DAFFODIL (NCT04988867), a 15-participant open-label phase 2/3 study in girls aged 2–4, supported the weight-based dosing used for the youngest approved age band; diarrhea occurred in 80% and vomiting in 53% (Percy et al., Med, 2025;6(6):100608).

Post-approval. A FAERS disproportionality analysis covering the first quarter of 2023 through the fourth quarter of 2024 identified 2,824 patients with trofinetide as the primary suspect drug, found gastrointestinal disorders dominant, and placed most adverse events in the first 30 days (Yu et al., Frontiers in Pharmacology, 2026;17:1643906). The LOTUS real-world study (Cosand et al., Developmental Medicine & Child Neurology, 2026;68(3):407–417) and a 2026 case report of trofinetide-induced enterocolitis syndrome (Jones et al., Journal of Child Neurology, 2026;41(8):1190–1192) add to the tolerability picture. An observational cognitive-function cohort in adults on trofinetide at the University of Minnesota (NCT06705816) is recruiting. Regulatory coverage has widened: Health Canada approved Daybue in October 2024; the FDA approved the Daybue Stix powder formulation under a separate application (NDA 219884) in December 2025 on bioequivalence data (Darwish et al., Advances in Therapy, 2026;43(4):1536–1551); and in the EU, an initial negative CHMP opinion announced in March 2026 was reversed on re-examination, with a positive opinion on June 25, 2026 and marketing authorization as Daybu on August 20, 2026 for neurobehavioral symptoms of Rett syndrome in patients aged 5 years and older, narrower than the US age-2 label.

Common dosage forms

• Oral solution, 200 mg/mL (Daybue), a pink-to-red, strawberry-flavored liquid supplied in 450 mL multi-dose bottles and dosed by weight band in the gram range; the oral-solution format is what every Rett syndrome trial used.
• Powder for oral solution in single-dose packets of 5,000 mg, 6,000 mg, or 8,000 mg (Daybue Stix); its only inactive ingredients are natural strawberry flavor and sucralose, so unlike the liquid it carries no dye or paraben preservatives. Approved in the US in December 2025.
• Intravenous solution was used only in the traumatic brain injury program and has no marketed counterpart.
• Lyophilized powder or solution in vials — where it appears in reagent catalogs, it is under the names trofinetide or NNZ-2566. These presentations have no relationship to the clinical dose scale, which is measured in grams per dose, and injectable use has no basis in the human record outside the TBI studies.

Key considerations

• Approval is real but narrow, and the effect size is modest. The FDA Approved status reflects Daybue’s March 2023 approval for Rett syndrome in patients aged 2 and older, and the EU label starts at age 5 after a regulatory path that included a negative first opinion. LAVENDER’s co-primary endpoints were met with Cohen’s d values of 0.37 and 0.47 over 12 weeks on caregiver- and clinician-rated scales, not on an objective biomarker. The longer-term improvements come from open-label extensions without a placebo arm, and the pivotal and extension publications were authored or co-authored by sponsor employees and by investigators with disclosed consulting relationships to the sponsor.
• Gastrointestinal toxicity is the defining safety signal. Diarrhea affected roughly 80% of treated participants in LAVENDER and DAFFODIL and was the leading cause of discontinuation in LILAC; the label carries warnings for diarrhea, weight loss, and vomiting with aspiration risk, and post-marketing pharmacovigilance has added off-label signals for decreased appetite, weight decrease, and irritability concentrated in the first month.
• The neuroprotection and cognition claims did not survive controlled testing outside Rett syndrome. The TBI program, the compound’s original rationale, produced no peer-reviewed efficacy result and no separation from placebo on its functional outcome measures by the sponsor’s own account, and the fragile X signal came from a 28-day exploratory study that was never followed up. Research-market framing of trofinetide as a general neuroprotective or nootropic agent rests on rodent data and on exploratory endpoints, not on human efficacy.
• Mechanism is formally unknown. The label states the mechanism in Rett syndrome has not been established; the IGF-1 synaptic-maturation, anti-inflammatory ATF3, and ERK/Akt stories come from animal models and have not been confirmed in patients.
• Naming and identity. Trofinetide is the same molecule as NNZ-2566, and the EU brand name is Daybu rather than Daybue. It is distinct from the native tripeptide glycine-proline-glutamate (GPE, sometimes sold as “Glypromate” or “IGF-1 (1-3)”), from mecasermin (full-length recombinant IGF-1, which was also trialed in Rett syndrome), and from the synthetic IGF-1 variants LR3 and DES(1-3) found in the research market.