Trofinetide

Summary

Trofinetide (brand name Daybue) is the first FDA-approved treatment for Rett syndrome in adults and pediatric patients 2 years of age and older. It is a synthetic analogue of the naturally occurring brain peptide GPE (glycine-proline-glutamate), designed with enhanced metabolic stability compared to endogenous GPE. It was approved in March 2023 based on the LAVENDER Phase 3 clinical trial.

Mechanism of Action

Synthetic analogue of the N-terminal tripeptide of IGF-1 (glycine-proline-glutamate, GPE). Acts to suppress neuroinflammation and restore synaptic function by modulating microglial activity, reducing pro-inflammatory cytokine production, and supporting glutamatergic neurotransmission. Also thought to normalize dendritic spine density and morphology in neurons.

Routes of Administration

Goals & Uses

• Fragile X syndromeNeurological DisorderLow
• Improvement of synaptic functionNeuroscienceModerate
• Treatment of Rett syndromeNeurodevelopmental DisorderHigh
• Traumatic brain injuryNeuroprotectionLow
• Reduction of neuroinflammationNeurologyModerate

Contraindications

• Hypersensitivity to trofinetide or excipientsAllergic/immunologicHigh
• Severe renal impairmentOrganModerateKidney function concerns

Adverse Effects

• Weight loss / decreased appetiteMetabolicCommon
• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• FatigueGeneralUncommonLow energy or tiredness
• VomitingGastrointestinalCommonForceful expulsion of stomach contents
• DiarrheaGastrointestinalCommonLoose or frequent stools
• DehydrationFluid BalanceUncommonLoss of body water or inadequate hydration

Drug Interactions

• Oral contraceptivesModerateDelayed gastric emptying may affect absorption timing
• CYP3A4 substrates (sensitive)Moderate

Population Constraints

• PregnancyReproductive SafetyRelative
• Children under 2 years of agePediatricAbsolute
• BreastfeedingReproductiveRelative
• Severe renal impairment (eGFR <30 mL/min)RenalRelative

Regulatory Status

• European UnionInvestigationalAs of 2024, not yet approved in the EU; regulatory pathway being explored.
• United StatesApprovedApproved: Rett syndrome in adults and pediatric patients 2 years of age and olderApproved March 10, 2023 by FDA. Received Breakthrough Therapy, Orphan Drug, and Rare Pediatric Disease designations. NDA 216353.
• United KingdomUnknownNo confirmed MHRA approval as of early 2024; regulatory review status uncertain.

FDA approved on March 10, 2023 for Rett syndrome (adults and children ≥2 years). Received Breakthrough Therapy, Orphan Drug, and Rare Pediatric Disease designations. Marketed by Acadia Pharmaceuticals.

Evidence & Sources

No sources recorded yet.