Trofinetide

Origin and structure

Trofinetide is built on GPE (glycine-proline-glutamate, also called glypromate), the three amino acids at the very start of IGF-1 (insulin-like growth factor 1). GPE occurs naturally in the brain, where it is cut from IGF-1. In mice with a faulty Mecp2 gene, a common animal model of Rett syndrome, GPE partly restored the connections between nerve cells, improved movement and breathing and extended survival. As a drug it was impractical: in rats its half-life in the blood was under two minutes, so steady levels would have needed a continuous infusion.

Neuren Pharmaceuticals first developed GPE itself, as glypromate, to protect the brain during heart surgery, and stopped in December 2008 when it failed to show a meaningful effect. Margaret Brimble's chemistry group made stabilised versions of GPE, and one of them became Neuren's trofinetide (NNZ-2566): GPE with an extra methyl group on the proline, chemically glycyl-L-2-methylprolyl-L-glutamic acid. That small change was designed to make it last longer in the blood and to let it be taken by mouth. Its formula is C13H21N3O6 and its molar mass 315.32 g/mol.

Neuren tested trofinetide intravenously in traumatic brain injury and by mouth in Rett syndrome and fragile X syndrome. Acadia Pharmaceuticals licensed the North American rights in August 2018 and the rights for the rest of the world in July 2023, ran the phase 3 programme and holds the authorisations for Daybue in the US and Daybu in the EU. The licensed medicine is a strawberry-flavoured oral solution of 200 mg/mL that can be swallowed or given through a stomach tube.

How it is thought to work

Nobody knows exactly how trofinetide works: both the EU and the US product information say its mechanism in Rett syndrome is unknown. Rett syndrome is a rare disorder of brain development that mainly affects girls, about 1 in 10,000 live-born girls. In 96 to 98% of classic cases it is caused by a mutation in the MECP2 gene on the X chromosome, which is thought to leave nerve cells with immature connections. Development looks normal for about six months, then milestones stall and a period of regression follows, most often between 6 and 30 months of age, in which children lose the purposeful use of their hands and spoken language. After that the disorder enters a more stable plateau phase. The EMA notes that IGF-1 levels in the brain are lower than normal in Rett syndrome, and trofinetide was meant to reproduce GPE's effects on those connections.

The supporting evidence comes from animals. In mice missing part of the Mecp2 gene, five weeks of injected trofinetide improved long-term potentiation in brain slices, a laboratory measure of how connections between nerve cells strengthen, and lengthened dendrites. In a second group of these mice it extended median survival from 13.5 to 15.5 weeks, although tremor scores rose. In rodent models of brain injury and stroke it dampened inflammation by microglia and astrocytes, the brain's immune and support cells. The EMA called the cell-culture evidence for nerve protection 'not convincing'.

Despite its origin, trofinetide does not act like IGF-1. In tests submitted to the EMA it did not bind the IGF-1 receptor at any concentration up to 1 mM, and it had no effect on IGF-binding proteins or growth hormone. Taken by mouth, at least 84% is absorbed, less than 6% binds to plasma proteins and more than 80% leaves the body unchanged in the urine. Blood levels fall quickly at first, with a half-life of 1.5 hours, and then slowly, with a terminal half-life of about 30 hours.

Is trofinetide approved?

Yes, as a prescription medicine for Rett syndrome: in the US since March 2023 and in the EU since August 2026. The two approvals cover different age groups and differently worded indications. Acadia's annual report for 2025 also lists approvals in Canada and Israel.

Trofinetide sold as a research chemical is not Daybue or Daybu. It has no marketing authorisation, is not made under a medicines licence and may not be used in people.

• EU: the EMA received Acadia's application in December 2024, for Rett syndrome from 2 years of age. The first assessment was led by the Dutch member of the CHMP, Peter Mol of the CBG, as rapporteur. On 26 February 2026 the CHMP advised against approval: it judged the 12-week differences too small to be clinically relevant, noted that key symptoms such as seizures were not measured, and doubted whether results in girls past the regression phase could be applied to younger children. Acadia asked for a re-examination, which new rapporteurs led, and narrowed the indication to neurobehavioural symptoms from 5 years of age. The CHMP then recommended approval on 25 June 2026, and the European Commission authorised Daybu on 20 August 2026, the first medicine approved in the EU specifically for Rett syndrome. It is an orphan medicine (designated in 2015) and is under additional monitoring.
• Netherlands: the EU authorisation applies here too, as a prescription-only medicine, and the authorisation holder is Acadia Pharmaceuticals (Netherlands) B.V. in Amsterdam. Reimbursement needs a separate decision by the health minister, advised by Zorginstituut Nederland. The institute's Horizonscan, last updated on 4 June 2026, counts just over 250 known girls with Rett syndrome in the Netherlands and, based on the US price, estimates the cost at about €377,000 to €906,000 per patient per year.
• US: the FDA approved Daybue on 10 March 2023, after a priority review, for Rett syndrome in adults and children from 2 years of age. Daybue Stix, packets of powder to be dissolved in water or a water-based drink, was added in December 2025.

What the research shows

The approval rests on one placebo-controlled phase 3 trial of 12 weeks, supported by two phase 2 trials and by open-label extensions without a control group. Neuren or Acadia sponsored every trial described here. The main results:

• Phase 2 in adolescents and women (RETT-001): 56 participants received one of two doses or placebo for up to four weeks. Because the trial was small, it counted p < 0.2 as a signal of benefit, and on that lenient threshold the higher dose did better than placebo on three core measures.
• Phase 2 in girls aged 5 to 15 (RETT-002, Neurology 2019): 82 participants received one of three doses or placebo for six weeks. The highest dose beat placebo on the caregiver questionnaire (RSBQ), the clinician's global impression (CGI-I) and a clinician symptom scale, but the EMA noted that there was no correction for multiple testing and that the middle dose did worse than the lowest.
• LAVENDER (phase 3, Nature Medicine 2023, NCT04181723): 187 girls and women aged 5 to 20 with classic Rett syndrome, all past the regression phase, received trofinetide (93) or placebo (94) for 12 weeks. The RSBQ, scored from 0 to 90, fell by 4.9 points against 1.7 on placebo (p = 0.0175), and the mean CGI-I was 3.5 against 3.8 on a seven-point scale where lower is better (p = 0.0030). On the key secondary endpoint, a score for non-verbal communication held steady on trofinetide (−0.1) but fell on placebo (−1.1).
• How large is that effect? No minimal clinically important difference has been established for the RSBQ. Acadia's own estimates of the smallest meaningful change ranged from 3 to 7 points, so the observed difference of about 3 points sits at the bottom of that range. Most of the experts advising the EMA warned that diarrhoea, which affected most children on trofinetide, may have revealed who was on the drug, and that more drop-outs on trofinetide could have inflated the result. Of eight other secondary outcomes only one differed nominally from placebo, and quality of life did not.
• LILAC and LILAC-2 (open-label extensions, Med 2024): 154 participants continued on trofinetide for 40 weeks, of whom 54% completed; 77 then entered LILAC-2, planned for up to 32 months. RSBQ scores kept falling: compared with the start of LAVENDER, by 7.3 points after 40 weeks in those on trofinetide from the start (7.0 in those switched from placebo) and by 11.8 points at week 104 of LILAC-2, but without a placebo group and with many drop-outs these figures cannot show what the drug added.
• Girls aged 2 to 4 (open-label, 15 participants): 12 had diarrhoea and 8 vomited, and most left the study when Acadia ended it after the US approval. The US label covers this age group; the EU label does not, because children this young may still be in the regression phase and the main trial did not include them.
• Fragile X syndrome (phase 2, Pediatric Neurology 2020): 72 adolescent and adult males received one of two doses or placebo for 28 days. The higher dose met prespecified exploratory criteria, with a 4.5% probability that this was a false positive, but trofinetide has not been approved for fragile X.
• Traumatic brain injury: in a placebo-controlled phase 2 trial with 251 participants, Neuren gave trofinetide as a 72-hour intravenous infusion, according to the EMA's assessment report. It has not been approved for brain injury.

Side effects and warnings

Diarrhoea dominates. In LAVENDER it affected 80.6% of participants on trofinetide, against 19.1% on placebo, starting after a mean of 7 days and lasting a mean of 51 days; 52% of cases were mild, 45% moderate and 3% severe. Vomiting affected 26.9%, against 9.6% on placebo. Within the 12 weeks, 17% stopped because of side effects, against 2% on placebo, and across the trial and its extensions of up to 144 weeks 43% stopped, most often because of diarrhoea (26%).

Weight loss of more than 7% occurred in 12.9% on trofinetide, against 4.7% on placebo, and the EMA warns that this could affect the growth of young patients. Fever, decreased appetite, fatigue, anxiety, irritability and seizures (8.6% against 6.4%) were also more common than on placebo. Seizures are part of Rett syndrome itself, but the EMA lists them as a side effect because of that imbalance. Serious adverse events were equally rare in both groups (3%). Since approval, aspiration and aspiration pneumonia have been reported after vomiting, two risks people with Rett syndrome already face.

The product information asks for laxatives to be stopped before treatment and for weight and hydration to be watched. Trofinetide weakly inhibits the enzyme CYP3A4 and the transporter P-gp: it raised exposure to loperamide, a common antidiarrhoeal, 1.7-fold, and the EU label asks for close monitoring with sensitive drugs such as ciclosporin and digoxin. The labels lower the dose in moderate kidney impairment and advise against use in severe impairment. There are no data in pregnancy, and the EU label advises effective contraception. A 26-week study in genetically modified mice found no increase in tumours, but a two-year cancer study in rats was still running when the EU product information was written, so the long-term carcinogenic potential is unknown.

Trofinetide, IGF-1 and IGF-1 DES

Because trofinetide comes from IGF-1, it is sometimes grouped with IGF-1 products, but the EMA's assessment shows that it does not act through the IGF-1 receptor. IGF-1 itself has been tried in Rett syndrome: in a 2018 placebo-controlled crossover trial, 30 girls received mecasermin (recombinant IGF-1) and placebo for 20 weeks each. It improved none of the main outcomes, and some measures, including a severity scale and the EEG, got worse.

IGF-1 DES is the other half of the same split: IGF-1 without its first three amino acids, which still acts on the IGF-1 receptor. Trofinetide is a stabilised version of the three amino acids that are removed. The human studies listed in the EMA's assessment were done in healthy volunteers and in people with Rett syndrome, fragile X syndrome or traumatic brain injury.

Frequently asked questions

Is trofinetide (Daybu) available in the Netherlands?

Daybu has been authorised throughout the EU, the Netherlands included, since 20 August 2026, for neurobehavioural symptoms of Rett syndrome from 5 years of age. It is a prescription-only medicine, and the authorisation holder is Acadia's Dutch subsidiary in Amsterdam. Authorisation does not mean reimbursement: that takes a separate decision by the health minister, advised by Zorginstituut Nederland. Trofinetide sold as a research chemical is not Daybu and may not be used in people.

What is the difference between Daybue and Daybu?

They contain the same active substance in a strawberry-flavoured oral solution of 200 mg/mL, sold under a US and an EU brand name. The US label (Daybue) covers Rett syndrome from 2 years of age and also includes Daybue Stix, a powder dissolved in water. The EU label (Daybu) is narrower: neurobehavioural symptoms of Rett syndrome from 5 years, because the main trial only included girls and women aged 5 to 20 who were past the regression phase.

Does trofinetide cure Rett syndrome?

No. It does not repair the MECP2 mutation that causes the disorder, and how it works is unknown. In LAVENDER the caregiver questionnaire improved by about 3 points more than on placebo, on a scale from 0 to 90, and the EMA called the improvements small but relevant for a rare and serious disorder. The trial lasted 12 weeks and did not measure seizures; longer data come from open-label extensions without a placebo group.

How common is diarrhoea with trofinetide?

Very common. In LAVENDER 80.6% of participants on trofinetide had diarrhoea, against 19.1% on placebo, mostly mild or moderate and starting after about a week on average. It is the main reason people stop: across the trial and its extensions of up to 144 weeks, 26% stopped because of diarrhoea. The product information asks for laxatives to be stopped before the start and for hydration and weight to be watched.

Is trofinetide the same as IGF-1?

No. It is a modified version of only the first three amino acids of IGF-1, and in tests for the EMA it did not bind the IGF-1 receptor or affect growth hormone or IGF-binding proteins. IGF-1 itself, as the medicine mecasermin, was tested in 30 girls with Rett syndrome in a 2018 crossover trial and improved none of the main outcomes. IGF-1 DES, the IGF-1 that lacks those three amino acids, is a different compound again.

Is trofinetide banned in sport?

Trofinetide is not named on WADA's Prohibited List for 2026, nor on the 2027 list that applies from 1 January 2027. The catch-all class S0 does not cover it, because S0 is limited to substances without a current approval for human use anywhere. The list does not say whether the open-ended growth-factor clause in class S2.3 could apply to it. The Dutch Dopingautoriteit uses the same list.

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.

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