093: Trends in First-in-Human Trials of Intrathecal Antisense Oligonucleotide Therapies: Insights into Dose Selection, Dose Escalation & Early Clinical Development

Statement of Purpose, Innovation or Hypothesis: First-in-Human (FIH) studies represent a critical milestone in the development of intrathecal antisense oligonucleotide (ASO-IT) treatments. For CNS disorders, ASOs are often delivered directly into cerebrospinal fluid via intrathecal administration. Despite increasing interest in ASO-IT therapies, there remains a need for comprehensive analysis of FIH study designs, specifically dose selection and escalation strategies. This review aims to address this gap by analyzing ASO-IT FIH trial data to provide insights into early clinical development of ASO-IT therapies.

Description of Methods & Materials: A literature review was conducted using clinicaltrials.gov, PubMed, Citeline Trialtrove, and an internal database. The search, from 2010 to 2023, included “ASO”, “IT”, and “FIH”, as core search terms. Identified studies were evaluated for study design, dose selection and escalation scheme, safety margin estimates, and expected pharmacologic activity. Descriptive statistics were used to summarize various study parameters.

Data & Results: The review identified 25 FIH studies for ASO-IT therapies. Among these studies, 18, 12, and 9 included the dose escalation scheme, safety margin estimates, and pharmacologic activity projections, respectively. The ASO-IT products investigated in these trials targeted neuromuscular, neurodegenerative, and neurodevelopmental disorders. Most trials included adult patients and were conducted as a randomized controlled trial, however, over 30% were an open-label design. Pediatrics often followed a staged approach, beginning with adults or older children before moving to younger children. Over 60% of trials adopted a direct-to-multiple ascending dose approach, especially for rare diseases. A NOAEL-based approach and pharmacologically active dose (PAD) approach were often used together for FIH dose selection. Safety margins are generally estimated based on human-equivalent-dose (HED) using NOAEL multiplied by a scaling factor (commonly 10x) and the median safety margin for the starting and top dose was 32x and 2.65x, respectively. Blood exposure (C_max and AUC) was also used for margin estimation, generally resulting in higher values than those derived from HED. The median pharmacologic activity, predicted based on data from transgenic mice, non-human primates, and/or PBPK modeling, was 22% and 72% for the starting and top dose respectively. Typical dose escalation design included 4 cohorts (range 3 to 6) with a median dose range of 10x (range 3.75 to 24x). Median dose escalation was 3x between the first 2 cohorts, then escalation decreased gradually in later cohorts (Figure 1). Adaptive dose escalations based on emerging safety and PK data were common.

Interpretation, Conclusion or Significance: The analysis of ASO-IT FIH trials revealed variability in the trial design elements, however, these studies are typically done in patients. A typical approach for starting dose selection balanced safety (NOAEL/HED) and efficacy (PAD) to ensure a safety margin of at least 10x, with some pharmacologic activity. When selecting a top dose, a safety margin of at least 1x and high pharmacologic activity is generally recommended. The typical escalation scheme involved 4 cohorts, with a median dose range of 10x. Larger escalation occurred at earlier cohorts and smaller increments at later cohorts. Overall, these findings provide valuable insights into the early clinical development of ASO-IT therapies and inform future FIH study design in this rapidly evolving field.

Disclosures: No funding was received for this work. The views expressed are those of the authors and not necessarily those of Biogen.

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