Trends in First‐in‐Human Studies for Intrathecal Antisense Oligonucleotides: Insights From 2010 to 2024

Abstract Advancements in antisense oligonucleotide (ASO) therapies have expanded their application to neurological disorders through intrathecal (ASO‐IT) delivery into cerebrospinal fluid (CSF). To examine study designs and practices in ASO‐IT first‐in‐human (FIH) trials, we analyzed 29 trials between 2010 and 2024 via a comprehensive review. Most trials targeted rare neurological disorders, with increasing numbers of ASO‐ITs advancing to clinical testing over time. Patient populations were predominantly used over healthy participants, with over 50% trials employing randomized controlled designs (3:1 active‐to‐placebo) while others were open label. Trials commonly start in adults or older children before expanding to younger cohorts. Recent trends reveal increased uses of direct‐to‐multiple ascending dose strategies and single‐patient trials, particularly for rare diseases. Dose escalations typically spanned four cohorts over a 10× dose range, with early escalations up to 4× between adjacent cohorts and smaller increments (1.25‐1.5×) in later cohorts. Human dose selection often integrates translational modeling and human equivalent dose approach, scaled by CSF or central nervous system (CNS) tissue volumes. Starting doses prioritized robust safety margins (median 30×) with limited pharmacological activity, while top doses aimed therapeutic benefit with high activity and safety margins ≥1×, with the goal to achieve ≥70%‐80% target engagement (e.g., mRNA knockdown) during dose escalation. Dosing intervals, typically 2‐4 weeks (up to 12 weeks), reflected ASO‐ITs’ prolonged CNS half‐life. Adaptive designs enabled real‐time dose adjustments upon emerging safety and pharmacokinetics/pharmacodynamic data. This analysis highlights the importance of flexible, personalized, innovative FIH designs, such as single‐patient studies, and model‐informed strategies to advance ASO‐IT development for rare neurological diseases.