Case Study: Dose Escalation in Pediatric Rare Disease Trials
This case study describes a first‑in‑pediatrics, multicenter dose‑escalation trial for an oral small molecule intended to up‑regulate a deficient metabolic pathway in a rare autosomal recessive disorder. The syndrome manifests in neonates to early childhood with failure to thrive, intermittent hypoglycemia, and neurodevelopmental delay. An adult program does not exist; only preclinical juvenile toxicology and a small compassionate‑use set (n=6, mixed ages) inform risk. The primary objective is to identify a pediatric recommended Phase 2 dose (pRP2D) by balancing safety, pharmacokinetics (PK), and pharmacodynamic (PD) target engagement. Secondary objectives include characterization of exposure–response for safety (e.g., hypoglycemia, transaminase elevations) and early PD signal (a plasma metabolite ratio). Exploratory objectives track growth velocity and caregiver‑reported function.
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