A Phase I/II, First-In-Human Trial to Evaluate the Safety, Tolerability, and Pharmacokinetic Activity to Prevent or Treat Neuropsychiatric Symptoms in Pediatric Subjects With Timothy Syndrome

Timothy Syndrome Type 1 (TS1) is an ultra-rare, life-threatening autosomal dominant disorder caused by a pathogenic gain-of-function variant (p.G406R) in exon 8A of the CACNA1C gene, which encodes the CaV1.2 L-type calcium channel. The condition is characterized by multisystem involvement, including cardiac arrhythmias (long QT syndrome), syndactyly, hypoglycemia, and a high prevalence of neurodevelopmental and neuropsychiatric manifestations such as autism spectrum disorder, epilepsy, and global developmental delay. While advances in cardiac management have improved survival, there are currently no disease-modifying therapies targeting the neurologic and developmental features of TS1, representing a critical unmet medical need.

This first-in-human Phase I/II study evaluates TS1-ASO, an investigational antisense oligonucleotide designed to modulate pre-Messenger RNA (mRNA) splicing of CACNA1C by reducing inclusion of exon 8A and promoting expression of exon 8. This targeted approach aims to correct the underlying molecular mechanism driving abnormal calcium signaling. Preclinical studies in human induced pluripotent stem cell-derived neural organoids, assembloids, and in vivo transplantation models have demonstrated that TS1-ASO achieves target engagement, normalizes calcium channel function, and rescues disease-relevant cellular phenotypes. Toxicology studies in rodents and juvenile nonhuman primates support a favorable safety profile with no dose-limiting toxicities observed at clinically relevant exposures.

The study employs a non-randomized, open-label, sequential dose-escalation design in a small cohort of pediatric participants with genetically confirmed TS1. Dosing is administered intrathecally via lumbar puncture to achieve direct central nervous system exposure, consistent with established delivery approaches for antisense oligonucleotide therapies in neurologic disorders. Dose selection and escalation are guided by cerebrospinal fluid (CSF) volume-based scaling from nonclinical models, incorporating a conservative, stepwise approach to achieve pharmacologically active Central Nervous System (CNS) concentrations while maintaining safety margins.

Participants undergo intensive safety monitoring, including continuous cardiac telemetry during dosing periods, serial electrocardiograms, neurologic assessments, and comprehensive laboratory evaluations. Pharmacokinetic sampling in CSF and plasma is conducted to characterize drug distribution and exposure. Pharmacodynamic assessments include measurement of CACNA1C exon 8/8A splicing in CSF as a marker of target engagement. Clinical outcome assessments span multiple domains of neurodevelopment and function, including adaptive behavior, motor skills, communication, seizure frequency (where applicable), and caregiver- and clinician-reported measures.

Given the ultra-rare nature of TS1 and limited patient population, the study is designed to generate descriptive safety, pharmacokinetic, and exploratory efficacy data to inform future development. The study includes a staged enrollment approach with interim safety reviews to ensure appropriate risk mitigation. Longitudinal follow-up allows for assessment of durability of response and continued safety evaluation over time.

This trial represents a precision medicine approach targeting the molecular basis of TS1 and is intended to establish foundational clinical data for a novel therapeutic strategy addressing neurodevelopmental disease in this population.

Inclusion criteria

• Confirmed CACNA1C c.1216 G>A, p.G406R variant in exon 8A (TS1) on exome or genome testing.
• Age > 2 months. Given that neurodevelopmental symptoms start early in TS1 and treatment is predicted to more effectively prevent rather than rescue developmental delay, ASD, and epilepsy, the Sponsor proposes that early treatment is most likely to yield clinical benefit.

Exclusion criteria

• Critical illness including cardiac arrhythmia that is unstable, invasive ventilatory support, sustained hypoglycemia, or active infection.
• Diagnosis of a secondary genetic disorder in addition to TS1.
• Hypoxic-ischemic injury to >25% of the brain from prior cardiac arrest.
• Age > 5 years old with absence of any neurologic, developmental, or psychiatric diagnoses, or symptoms on physical exam and intake assessment scales as there would unlikely be a benefit to treatment in the setting of normal cognition and development and lack of epilepsy or other neuropsychiatric diagnoses.
• Inability to complete required procedures including anesthesia, magnetic resonance imaging brain, and lumbar puncture (LP).
• Participation in another investigational trial within the 90 days prior to first dose, including any gene therapy within the participant's lifetime.