AI Article Synopsis
- - Trofinetide was recently approved for treating Rett syndrome based on positive results from the phase 3 LAVENDER study, which allowed for a weight-based dosing approach.
- - Efficacy endpoints like the Rett Syndrome Behaviour Questionnaire (RSBQ) and Communication and Symbolic Behavior Scales (CSBS-DP-IT) showed significant improvement correlating with higher trofinetide drug exposure.
- - The analysis confirmed that higher drug exposure within the target range significantly improved symptoms in patients, supporting the established dosing regimen for trofinetide.
Article Abstract
Introduction: Trofinetide was recently approved for the treatment of Rett syndrome (RTT) on the basis of the efficacy and safety findings of the phase 3 LAVENDER study, which used a body weight-based dosing regimen. Exposure-response (E-R) efficacy modeling was used to characterize relationships between trofinetide exposure measures (maximum drug concentration and area under the concentration-time curve for the dosing interval of 0-12 h [AUC]) and efficacy endpoints in RTT clinical studies to support the trofinetide dosing regimen.
Methods: Efficacy endpoints were modeled using trofinetide exposure measures predicted from the population pharmacokinetic model and Bayesian estimates. The analysis population for each E-R model comprised individuals receiving placebo or trofinetide who had available trofinetide exposure measures. Efficacy endpoints were scores from the Rett Syndrome Behaviour Questionnaire (RSBQ), the Clinical Global Impression-Improvement, the Communication and Symbolic Behavior Scales Developmental Profile™ Infant-Toddler Checklist (CSBS-DP-IT) Social Composite, and the Rett Syndrome Clinician Rating of Ability to Communicate Choices (RTT-COMC).
Results: Higher trofinetide exposure was associated with improvements in RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Assuming target trofinetide AUC values of 800-1200 μg·h/mL, the reductions in RSBQ total scores at week 12 were approximately five- to seven-fold greater with trofinetide (range 3.55-4.94) versus placebo (0.76). Significant E-R relationships were also found for the CSBS-DP-IT Social Composite and RTT-COMC scores.
Conclusion: E-R efficacy modeling demonstrated significant relationships between trofinetide exposure and RSBQ, CSBS-DP-IT Social Composite, and RTT-COMC scores. Trofinetide is efficacious within the target exposure range, supporting the approved dosing regimen for trofinetide.
Trial Registration: NCT01703533, NCT02715115, NCT04181723.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10960884 | PMC |
| http://dx.doi.org/10.1007/s12325-024-02796-y | DOI Listing |
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