072: Population Pharmacokinetic Modelling to Confirm Weight-Based Banded Dosing & Exposure-Response Efficacy Analyses to Support Trofinetide Treatment in Rett Syndrome

Statement of Purpose: Trofinetide is the first approved treatment for Rett syndrome (RTT) and was recently shown to be efficacious and well tolerated in the phase 3 LAVENDER study (NCT04181723). Weight-based dosing to achieve target exposure in LAVENDER was based on population pharmacokinetic (popPK) modeling using data from 13 studies. These exposure-response (E-R) analyses of LAVENDER results explored the relationship between exposure and efficacy endpoints.

Description of Methods & Materials: A previous popPK model was refined using pooled PK data from 13 studies (N=442) including LAVENDER. E-R models were developed using data from LAVENDER and two phase 2 studies and included the coprimary (Rett Syndrome Behaviour Questionnaire [RSBQ], Clinical Global Impression-Improvement [CGI-I]) and key secondary (Communication and Symbolic Behaviour Scales-Developmental Profile™ Infant-Toddler Checklist [CSBS-DP-IT] Social Composite score) efficacy endpoints, and a secondary efficacy endpoint related to nonverbal communication (RTT-Clinician Rating of Ability to Communicate Choices [RTT-COMC] scores) from LAVENDER that demonstrated benefit with trofinetide vs placebo.

Data & Results: After weight-based banded dosing in LAVENDER, median and individual area under the concentration-time curve from 0–12 hours at steady-state fell within the target exposure range (800–1,200 μg*h/mL). The E-R relationship was significant and higher trofinetide exposure was associated with improved RSBQ, CSBS-DP-IT Social Composite and RTT-COMC scores.

Interpretation, Conclusion or Significance: The proposed weight-based banded dosing regimen in the LAVENDER study achieved the targeted trofinetide exposure range. The E-R relationship was significant and demonstrated that higher trofinetide exposures are associated with improved efficacy outcomes.

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