A Phase 1, Open-Label Study to Evaluate the Effects of Food and Evening Dosing on the Pharmacokinetics of Oral Trofinetide in Healthy Adult Subjects

Darwish, Mona; Youakim, James M.; Harlick, Jim; DeKarske, Daryl; Stankovic, S.

doi:10.1007/s40261-022-01156-4

Cited by 11 publications

(7 citation statements)

References 20 publications

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“…RTT is a severe burden on patients and their family members because it affects all aspects of the quality of life of RTT patients and requires lifelong medical care and support [14,34,40]. Therefore, the USFDA approval of Trofinetide is one of the important milestones for RTT therapy.…”

Section: Discussionmentioning

confidence: 99%

“…One Phase I study evaluated the influence of food and the evening oral dosing of Trofinetide (60 mL solution, 12 g Trofinetide) on its pharmacokinetic behavior [40]. This study in healthy individuals demonstrated that the bioavailability of Trofinetide was unaffected by diet, showed no diurnal change, and was primarily excreted through urine.…”

Section: Clinical Studiesmentioning

confidence: 99%

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Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need

Hudu

El-Migdadi

Al-Qtaitat

et al. 2023

JCM

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Rett syndrome (RTT) is a rare disability causing female-oriented pediatric neurodevelopmental unmet medical need. RTT was recognized in 1966. However, over the past 56 years, the United States Food and Drug Administration (USFDA) has authorized no effective treatment for RTT. Recently, Trofinetide was approved by the USFDA on 10 March 2023 as the first RTT treatment. This article underlines the pharmaceutical advancement, patent literature, and prospects of Trofinetide. The data for this study were gathered from the PubMed database, authentic websites (Acadia Pharmaceuticals, Neuren Pharmaceuticals, and USFDA), and free patent databases. Trofinetide was first disclosed by Neuren Pharmaceuticals in 2000 as a methyl group containing analog of the naturally occurring neuroprotective tripeptide called glycine-proline-glutamate (GPE). The joint efforts of Acadia Pharmaceuticals and Neuren Pharmaceuticals have developed Trofinetide. The mechanism of action of Trofinetide is not yet well established. However, it is supposed to improve neuronal morphology and synaptic functioning. The patent literature revealed a handful of inventions related to Trofinetide, providing excellent and unexplored broad research possibilities with Trofinetide. The development of innovative Trofinetide-based molecules, combinations of Trofinetide, patient-compliant drug formulations, and precise MECP2-mutation-related personalized medicines are foreseeable. Trofinetide is in clinical trials for some neurodevelopmental disorders (NDDs), including treating Fragile X syndrome (FXS). It is expected that Trofinetide may be approved for treating FXS in the future. The USFDA-approval of Trofinetide is one of the important milestones for RTT therapy and is the beginning of a new era for the therapy of RTT, FXS, autism spectrum disorder (ASD), brain injury, stroke, and other NDDs.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Studiesmentioning

confidence: 99%

Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need

Hudu

El-Migdadi

Al-Qtaitat

et al. 2023

JCM

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“…The E–R efficacy analyses used predicted trofinetide exposure measures based on individual PK parameters estimated from the previously developed popPK model [ 9 ] that included 13 trofinetide clinical studies: eight phase 1 studies in healthy participants (including a food effect study [ 15 ] and mass balance study [ 16 ]), two phase 2 studies in participants with RTT (Neu-2566-Rett-001 [ 4 ] and Rett-002 [ 5 ]), one phase 2 study in fragile X syndrome [ 17 ], one phase 2 study in traumatic brain injury, and the phase 3 LAVENDER study [ 7 ]. Exposure measures for each participant and the efficacy endpoints were combined with demographics and covariates in a time-ordered sequence to create the analysis-ready datasets.…”

Section: Methodsmentioning

confidence: 99%

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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“…By tailoring dosages to different weight categories, researchers can assess how variations in body weight influence drug responses and potential side effects. This approach helps identify appropriate dosage ranges for further investigation, aiming to establish a more personalized and effective treatment strategy for a broad spectrum of individuals within the target population 21 .…”

Section: New Treatmentsmentioning

confidence: 99%

Trofinetide receives FDA approval as first drug for Rett syndrome

Mughal,

Ahmed,

Rangwala

et al. 2024

Annals of Medicine &Amp; Surgery

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A Phase 1, Open-Label Study to Evaluate the Effects of Food and Evening Dosing on the Pharmacokinetics of Oral Trofinetide in Healthy Adult Subjects

Cited by 11 publications

References 20 publications

Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need

Trofinetide for Rett Syndrome: Highlights on the Development and Related Inventions of the First USFDA-Approved Treatment for Rare Pediatric Unmet Medical Need

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

Trofinetide receives FDA approval as first drug for Rett syndrome

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