058: Population Pharmacokinetic Modelling to Predict Trofinetide Exposure & Exposure-Response Safety Analyses in Girls With Rett Syndrome Aged 2–4 Years

Statement of Purpose: Trofinetide is the first approved treatment for Rett syndrome (RTT). Previous trofinetide population pharmacokinetic (popPK) modeling confirmed weight-based banded dosing in the phase 3 placebo-controlled LAVENDER study in females with RTT aged 5-20 years would achieve target therapeutic exposure range (area under curve 0-12 hours at steady-state [AUC_0-12,ss] = 800−1,200 µg*h/mL). This study aims to confirm weight-based banded dosing in girls with RTT aged 2–4 years.

Description of Methods & Materials: A previous popPK model (n=13 studies) was updated with the Phase 2/3 DAFFODIL study (NCT04988867) in females with RTT aged 2-4 years receiving weight-based open-label trofinetide dosing (≥9-12 kg = 5 g BID; ≥12-20 kg = 6 g BID). Individual trofinetide exposure parameters were estimated to confirm target exposure achievement in DAFFODIL. Exposure values versus select treatment-emergent adverse events (TEAEs) in DAFFODIL were compared with two Phase 2 studies and LAVENDER.

Data & Results: Exposure parameters (AUC_0-12,ss) in DAFFODIL were within target range and similar to LAVENDER (Figure). TEAEs of diarrhea and vomiting were exposure dependent in LAVENDER. Exposure ranges with TEAEs in DAFFODIL were within those observed in the previous studies.

Interpretation, Conclusion or Significance: Weight-based banded trofinetide dosing for females with RTT aged 2–4 years achieved targeted exposure as evaluated in LAVENDER and there were no additional safety concerns.

Disclosures: MD, HB, KMB are employees of Acadia Pharmaceuticals Inc; KM, HB are employees of Cognigen Division Simulations Plus Inc.