IGF-1 tripeptide analog · Rett syndrome
An oral medicine for Rett syndrome, a rare neurodevelopmental disorder caused by changes in the MECP2 gene. Trofinetide is a small synthetic analog of GPE, the tripeptide (glycine, proline, glutamate) normally cut away from the growth factor IGF-1. It is taken by mouth as a liquid, or as a powder dissolved in water.
The FDA label states that the mechanism behind trofinetide's effect in Rett syndrome is unknown1. Rett syndrome results from loss of MeCP2, a DNA-binding protein that regulates gene activity, and that loss disrupts how neurons mature and adapt3. Trofinetide is a longer-lasting relative of GPE, the tripeptide released when IGF-1 is broken down6. Because GPE contains glutamate and glycine, researchers think trofinetide modulates NMDA-type glutamate receptors and helps normalize neuronal activity and survival6. That remains a hypothesis, not a mechanism demonstrated in patients1,6. Unlike IGF-1 itself, a full-length protein, trofinetide is a small molecule and is taken by mouth1.
The main evidence is from people with Rett syndrome. LAVENDER, a 12-week phase 3 trial in 187 girls and young women aged 5 to 20, found modest but statistically significant gains over placebo on a caregiver symptom questionnaire (RSBQ change -4.9 vs -1.7) and on clinician-rated global improvement (3.5 vs 3.8)1,2. Diarrhea affected 80.6% on trofinetide versus 19.1% on placebo2.
In LILAC, a 40-week open-label extension with no placebo group, questionnaire scores kept improving among 154 participants, but 21.4% withdrew because of diarrhea4. A 2024 review notes the benefit was concentrated in some symptom areas, such as mood and repetitive face movements, with no shown effect on seizures, heart or bone problems6. Earlier, a 28-day phase 2 trial in 72 adolescent and adult males with fragile X syndrome reported a signal at the higher dose that met prespecified criteria5; trofinetide is not approved for fragile X.
FDA-approved in March 2023 as Daybue (Acadia Pharmaceuticals) for Rett syndrome in adults and children 2 years and older; a powder form, Daybue Stix, was approved in December 2025.
Per the FDA label, diarrhea is very common (85% of patients in the main and long-term studies) and persisted or came back in about half; vomiting is the other most common effect. Warnings cover dehydration from diarrhea, weight loss (more than 7% of body weight in 12% of treated patients versus 4% on placebo), and aspiration or aspiration pneumonia after vomiting. In the pivotal trial, 19% of treated patients stopped because of side effects, most often diarrhea.
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