Exposure–Response Efficacy Modeling to Support Trofinetide Dosing in Individuals with Rett Syndrome

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 0–12 ]) 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 0–12 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. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-024-02796-y.

Is trofinetide a future treatment for Rett syndrome? A comprehensive systematic review and meta-analysis of randomized controlled trials

“…Additionally, a study conducted by Neul et al showed that trofinetide exhibited a significant change compared to placebo in the communication ability measuring scales, the caregiver-rated Communication and Symbolic Behavior Scales Developmental Profile™ Infant–Toddler Checklist (CSBS-DP-IT) Social Composite score and the Rett syndrome clinician rating of ability to communicate choices (RTT-COMC) [ 21 ]. Furthermore, an exposure–response (E-R) efficacy model by Darwish et al [ 22 ] demonstrated that high trofinetide exposure improved the Rett Syndrome Behavior Questionnaire (RSBQ), CSBS-DP-IT, and RTT-COMC scores. Trofinetide was much better than placebo in reducing RSBQ total scores, with five to seven times greater reductions assuming target trofinetide with area under the concentration–time curve for the dosing interval 0 to 12 h (AUC 0–12 ) values of 800–1200 μg·h/mL [ 22 ].…”

“…Furthermore, an exposure–response (E-R) efficacy model by Darwish et al [ 22 ] demonstrated that high trofinetide exposure improved the Rett Syndrome Behavior Questionnaire (RSBQ), CSBS-DP-IT, and RTT-COMC scores. Trofinetide was much better than placebo in reducing RSBQ total scores, with five to seven times greater reductions assuming target trofinetide with area under the concentration–time curve for the dosing interval 0 to 12 h (AUC 0–12 ) values of 800–1200 μg·h/mL [ 22 ]. LILAC study by Percy et al [ 23 ], a phase III open-label extension study of Neul et al study [ 20 ], assessed the safety and efficacy of trofinetide after 40 weeks of treatment in 154 females with RTT, aged 5–21 years.…”