Aprepitant for the Treatment of CLIFAHDD

The sodium leak ion channel NALCN is responsible for a background sodium influx that contributes to the resting membrane potential and serves as a key regulator in neuronal and cell excitability. Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD; OMIM 616266) is a debilitating and ultra-rare neurodevelopmental disease with early infancy onset caused by a de novo autosomal dominant mutation in NALCN, often associated with NALCN gain-of-function (GOF). CLIFAHDD is associated with global neurodevelopmental delay, hyperkinetic movement disorders (e.g., dystonia, chorea, ataxia), seizures, apnea, constipation, insomnia, and increased risk of early childhood mortality. There are currently no drug treatments for CLIFAHDD. A multidisciplinary drug repurposing pipeline identified aprepitant as a promising lead candidate with converging functional, in silico, in vitro, and in vivo preclinical data support. The primary objective of this Phase 1 clinical trial is to determine the safety, tolerability and pharmacokinetics (PK) of chronic aprepitant use in individuals with CLIFAHDD. The hypothesis is that aprepitant will be safe, tolerable, and amendable to chronic use in patients with CLIFAHDD based on prior safety and PK data on aprepitant use in pediatric and adult populations, including off-label chronic use. The exploratory objectives are: (1) to identify potential pharmacodynamic biomarkers reflecting NALCN pathway modulation; (2) to assess preliminary signals of clinical efficacy and outcome measures for future trials. The study is designed as a single-center, Phase 1, open-label, dose-escalation study designed to evaluate the safety, tolerability, and PK of chronically administered oral aprepitant in individuals with CLIFAHDD (n=3-5, with protocol-defined criteria allowing expansion to a max n=5). Participants will undergo evaluations of disease severity and symptoms over a 90 day lead-in period. For the baseline visit and initiation of cycle 1, participants will travel to UTHSA for onsite clinical monitoring, collection of baseline clinical outcome assessments, and PK assessments. Following the initial dose, each participant's biological and pharmacokinetic response will be evaluated over a 72-hour period. PK sampling will include an 8-point plasma concentration-time profile followed by additional blood draws. After the initial PK assessment, participants will enter a structured dose escalation period, during which aprepitant will be increased in 1mg/kg every 4 weeks. PK analyses with an 8-point plasma concentration-time profile will be performed at the end of each 4-week cycle to establish steady state drug availability with chronic dosing. Safety evaluations, clinical outcome assessments, and pharmacodynamic biomarkers will be assessed at the end of each 4-week cycle. Safety data (rather than PK analyses) will be used to guide dose escalation and will be reviewed in real time by the study clinician and Principal Investigator, without a planned pause in study conduct. Escalation will continue until either a maximum tolerated dose (MTD) is established or the maximum FDA-approved dose is reached. At the maximum dose or end of Cycle 3, participants will undergo an 8-point plasma concentration-time profile to characterize dose-dependent PK changes and elimination. Participants will undergo details safety, clinical, and pharmacodynamic biomarker assessments. Remote safety monitoring will continue for 3 weeks