094: Analyzing First-in-Human Trial Designs of Antisense Oligonucleotides: A Preliminary Review Across Subcutaneous, Intravenous & Intrathecal Routes of Administration

Statement of Purpose, Innovation or Hypothesis: Antisense oligonucleotides (ASOs) are emerging as significant players in modern therapeutic modalities. Despite numerous products in development, only 12 ASOs secured regulatory approval by 2023. The design of the first-in-human (FIH) trial represents a unique challenge. This review aims to summarize insights from previously conducted FIH trials of ASOs from various routes of administration, including subcutaneous (SC), intravenous (IV) and intrathecal (IT).

Description of Methods & Materials: A review of FIH ASO trials from 2010 – 2023 was conducted using four main data sources: PubMed, clinicaltrial.gov, CITELINE TrialTrove and an internal database. Retrieved trials were subdivided based on the route of administration (SC, IV and IT). The parameters of interest were summarized by descriptive statistics.

Data & Results: A total of 71 trials were analyzed involving 24, 22 and 25 ASOs to be administered by SC, IV and IT routes, respectively. SC ASOs primarily targeted cardiovascular diseases and metabolic/endocrinology. Notably, almost all (23/24, 95.8%) SC trials followed a randomized, placebo-controlled trial (RCT) design with a non-oncology indication and a 3:1 active-to-placebo randomization ratio (52.2%, 12/23). Only 1 oncology trial utilized an open-label (OL) design. 87% (20/23) of the non-oncology SC trials followed a single ascending dose (SAD) approach, while 13% followed a direct-to-multiple ascending dose (MAD) approach. Moreover, 91.3% (21/23) of these trials were conducted in healthy volunteers, while 2 trials included either patients only or both healthy volunteers and patients. The only 1 oncology trial followed a direct-to-MAD approach in patients only. Most IV ASOs were investigated for oncology (45%) and muscular dystrophy (41%). In non-oncology IV ASOs trials (n=12), 75% were conducted as RCT and 25% as OL trials. In contrast to SC ASOs studies, 33.3% (4/12) followed a SAD approach, while 66.7% followed a direct-to-MAD approach. The randomization ratio was highly variable within this category, with a 2:1 active-to-placebo randomization ratio being the most common. Typically, these trials were conducted in patients (75%, 9/12). On the other hand, 90% (9/10) of oncology IV trials were conducted as OL in patients and utilized a direct-to-MAD approach. IT ASOs primarily targeted neuromuscular diseases. 64% (16/25) of IT trials were conducted as RCT, with a 3:1 active-to-placebo randomization ratio (56%, 9/16), while 36% were OL trials. Similar to IV ASOs trials, 32% (8/25) of IT trials followed a SAD approach while 56% (14/25) followed a direct-to-MAD approach and the rest (12%, n=3) were conducted in a single patient with intra-patient dose escalation. In most cases (96%, 24/25), the trials were conducted in patients. In all routes of administration, the median number of dose levels ranged 4-5, typically the median dose escalation ratio was 2-3 between the first and second cohorts and decreased gradually in the later cohorts (Table 1).

Interpretation, Conclusion or Significance: Our analysis highlights the diverse approaches and characteristics of FIH trials of ASOs administered by SC, IV and IT routes. Understanding the nuances in trial design, dose strategies, and therapeutic targets across different routes of administration and therapeutic areas is crucial for optimizing the design of future FIH trials and advancing the clinical development of ASO therapies.

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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