Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study

Neul, Jeffrey L.; Percy, Alan K.; Benke, Tim A.; Berry‐Kravis, Elizabeth; Glaze, Daniel G.; Marsh, Eric D.; Lin, Tim; Stankovic, S.; Bishop, Kathie M.; Youakim, James M.

doi:10.1038/s41591-023-02398-1

Cited by 82 publications

(44 citation statements)

References 40 publications

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“…These factors alone, namely the steady decline with increasing age and the impact of the specific genetic variant, could require careful consideration of the timing of future gene replacement trials. The recent FDA approval of trofinetide (Daybue) deserves mention as these natural history data stand as an important benchmark against which to assess the future efficacy of this and future therapeutic agents 15 …”

Section: Discussionmentioning

confidence: 99%

Distribution of hand function by age in individuals with Rett syndrome

Neul,

Benke,

Marsh

et al. 2023

Annals of the Child Neurology Society

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ObjectiveWe aimed to determine the longitudinal distribution of hand function skills in individuals with classic Rett syndrome (RTT), an X‐linked dominant neurodevelopmental disorder, and correlate with MECP2 variants.MethodWe conducted a longitudinal study of 946 girls and young women with typical RTT seen between 2006 and 2021 in the US Natural History Study (NHS) featuring a structured clinical evaluation to assess the level of hand function skills. The specific focus of this study was to assess longitudinal variation of hand skills from age 2 through age 18 years in relation to specific MECP2 variant groups.ResultsFollowing the initial regression period, hand function continues to decline across the age spectrum in individuals with RTT. Specific differences are noted with steeper declines in hand function among those with milder variants (Group A: R133C, R294X, R306C, and C‐terminal truncations) compared with groups composed of individuals with more severe variants.ConclusionsThese temporal variations in hand use represent specific considerations that could influence the design of clinical trials that test therapies aiming to ameliorate specific functional limitations in individuals with RTT. Furthermore, the distinct impact of specific MECP2 variants on clinical severity, especially related to hand use, should be considered in such interventional trials.

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Section: Discussionmentioning

confidence: 99%

Distribution of hand function by age in individuals with Rett syndrome

Neul,

Benke,

Marsh

et al. 2023

Annals of the Child Neurology Society

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“…Efficacy data from three studies in females ≥ 5 years of age with RTT were pooled for the E–R analyses: Neu-2566-Rett-001 (NCT01703533) [ 4 ], Neu-2566-Rett-002 (NCT02715115) [ 5 ], and LAVENDER (NCT04181723) [ 7 ]. The results presented in this manuscript are based on published studies.…”

Section: Methodsmentioning

confidence: 99%

“…Trofinetide was given BID orally or by gastrostomy tube at 30 mL (6 g) for participants weighing ≥ 12 to < 20 kg, 40 mL (8 g) for participants weighing ≥ 20 to < 35 kg, 50 mL (10 g) for participants weighing ≥ 35 to < 50 kg, or 60 mL (12 g) for participants weighing ≥ 50 kg. Change from baseline to week 12 in RSBQ total score (− 4.9 vs − 1.7) and CGI-I score at week 12 (3.5 vs 3.8), the coprimary endpoints, and change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile™ Infant–Toddler Checklist (CSBS-DP-IT) Social Composite score (− 0.1 vs − 1.1), the key secondary endpoint, were statistically significantly improved with trofinetide treatment versus placebo, respectively [ 7 ]. An additional secondary endpoint that measured nonverbal communication (Rett Syndrome Clinician Rating of Ability to Communicate Choices [RTT-COMC]) by assessing the ability of participants to select pictures or objects using modalities such as eye contact or gestures was also significantly improved with trofinetide (− 0.4) over placebo (0.0) on the basis of the change from baseline to week 12 [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…An updated popPK model [ 9 ] using data from 13 clinical studies, including three studies in individuals with RTT (two phase 2 studies [ 4 , 5 ] and the phase 3 LAVENDER study [ 7 ]), was conducted. This analysis was used to estimate the individual systemic exposure of participants with RTT in the LAVENDER study and confirmed that applying the recommended body weight-banded dosing regimens achieved the steady state target exposure range (AUC 0–12,ss = 800–1200 μg·h/mL).…”

Section: Introductionmentioning

confidence: 99%

“…The objectives of these E–R efficacy analyses were to update the previous E–R model that was developed using data from the phase 2 studies [ 4 , 5 ] with additional efficacy data from the phase 3 LAVENDER study [ 7 ] to characterize the relationship between trofinetide exposure and the coprimary efficacy endpoints in LAVENDER (RSBQ and CGI-I), and to develop E–R models to characterize the relationships between trofinetide exposure and the key secondary efficacy endpoint (CSBS-DP-IT Social Composite) and another secondary efficacy endpoint (RTT-COMC) in the LAVENDER study.…”

Section: Introductionmentioning

confidence: 99%

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

Darwish,

Passarell,

Youakim

et al. 2024

Adv Ther

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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.

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Clinical trials for Lennox–Gastaut syndrome: Challenges and priorities

Knowles,

Warren,

Mohamed

et al. 2024

Ann Clin Transl Neurol

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Objective: Lennox‐Gastaut syndrome (LGS) is a severe, childhood‐onset epilepsy that is typically refractory to treatment. We surveyed the current landscape of LGS treatment, aiming to identify challenges to the development of efficacious therapies, and to articulate corresponding priorities toward clinical trials that improve outcomes. Methods: The LGS Special Interest Group of the Pediatric Epilepsy Research Consortium integrated evidence from the literature and expert opinion, into a narrative review. Results: We provide an overview of approved and emerging medical, dietary, surgical and neuromodulation approaches for LGS. We note that quality of care could be improved by standardizing LGS treatment based on expert consensus and empirical data. Whereas LGS natural history is incompletely understood, prospective studies and use of large retrospective datasets to understand LGS across the lifespan would enable clinical trials that address these dynamics. Recent discoveries related to LGS pathophysiology should enable development of disease‐modifying therapies, which are currently lacking. Finally, clinical trials have focused chiefly on seizures involving “drops,” but should incorporate additional patient‐centered outcomes, using emerging measures adapted to people with LGS. Interpretation: Clinicians and researchers should enact these priorities, with the goal of patient‐centered clinical trials that are tailored to LGS pathophysiology and natural history.

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Trofinetide for the treatment of Rett syndrome: a randomized phase 3 study

Cited by 82 publications

References 40 publications

Distribution of hand function by age in individuals with Rett syndrome

Distribution of hand function by age in individuals with Rett syndrome

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

Clinical trials for Lennox–Gastaut syndrome: Challenges and priorities

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