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Trofinetide: treating Rett syndrome, and its side effects

Clinical review pending

What the pivotal trial of trofinetide showed, how the drug is used and which gastrointestinal risks matter most.

What is trofinetide?

Trofinetide, sold as DAYBUE and DAYBUE Stix, is a synthetic analog of glycine-proline-glutamate (GPE). This three-amino-acid fragment is naturally cleaved from insulin-like growth factor 1 (IGF-1) in the brain. Trofinetide is the first drug approved specifically for Rett syndrome. This rare genetic disorder affects girls almost exclusively and leads to problems that include loss of skills already acquired, movement difficulties and impaired communication. US approval came in 2023. Source

How does trofinetide work?

The exact mechanism of action in Rett syndrome is not fully understood, as the prescribing information also points out. Preclinical work suggests that the drug could influence several processes that are disrupted in the disorder:

  • Reducing inflammatory responses in the nervous system by acting on microglia and astrocytes.

  • Supporting the formation and maturation of synapses and dendrites.

  • Normalizing IGF-1-related signaling pathways in the central nervous system.

The aim is to improve the function of brain networks impaired by the loss of MECP2 function that causes Rett syndrome.

Benefit is judged with behavioral scales and the clinician’s overall impression, not with a single biomarker. Before trofinetide, there was no drug treatment approved specifically for Rett syndrome. In the phase 3 LAVENDER trial, trofinetide significantly improved both the caregiver-completed Rett Syndrome Behaviour Questionnaire and the clinician’s global rating compared with placebo 1. The trial randomized 187 female participants over 12 weeks. For the difference in questionnaire score, P = 0.0175. The table shows the changes.

The most common side effects of trofinetide involve the gastrointestinal tract.

Is trofinetide FDA-approved?

Yes. The FDA approved trofinetide as DAYBUE in 2023 to treat Rett syndrome in adults and in children aged 2 and older 2. It was the first approved treatment for this condition. DAYBUE Stix, a powder for preparing a solution, is listed in the prescribing information revised in December 2025 3.

What is trofinetide prescribed for?

Trofinetide is used for Rett syndrome from age 2. Because diarrhea is common, any other medicines taken at the same time that can worsen diarrhea or dehydration need especially careful review. Source

What side effects have been reported?

According to the prescribing information, common side effects include:

  • Diarrhea, which occurs in most people treated.

  • Vomiting.

  • Fever.

  • Decreased appetite and fatigue.

  • Anxiety.

  • Seizures.

  • Cold symptoms. Source

The more serious risks, and the measures they call for, include:

  • Diarrhea and dehydration, which may require adjusting fluid intake and other medications.

  • Severe vomiting, in which stomach contents can enter the airways (aspiration) 3.

  • Significant weight loss; weight is therefore monitored.

Studies at a glance

Treatment group Randomized female participants Change in questionnaire score
Trofinetide 93 Decrease of 4.9 points 1
Placebo 94 Decrease of 1.7 points

Source

References provided in the source article

Sources: FDA prescribing information for DAYBUE; the LAVENDER trial (Neul et al., Nature Medicine, 2023, DOI: 10.1038/s41591-023-02398-1 1 ), indexed on PubMed.

Provenance and editorial review status

Adapted for Nutrient Desk from the source article. The claims and source attributions in the original text still require clinical review. This draft has not been cleared for indexing.