Nucleic acid therapeutics continue to expand beyond established antisense oligonucleotides and siRNAs to include increasingly complex modalities such as antibody-oligo conjugates, circular RNA, and gene editing therapies. Although these approaches share a nucleic acid component, their mechanisms of action, delivery strategies, chemical modifications, and potential safety liabilities can differ significantly. This short course will examine current nonclinical and regulatory considerations, common class effects, predictive toxicity assays, and ADME and PK/PD strategies to support the safe development of both established and next-generation nucleic acid therapeutics.
Topics to be discussed:
• Different types of nucleic acid-based drugs
• Mechanisms of actions and non-specific effects
• Current approaches to address non-specific effects and potential liabilities
• Findings secondary to class-effect of oligonucleotides
Aimed at both novice and advanced nucleic drug developers, the course will:
• Introduce and explain the differences between various types of nucleic acid drugs including antisense oligonucleotides, siRNAs, antibody-oligo conjugates, circular RNA and gene editing therapies
• Summarize our current understanding of the origins of non-specific effects and potential liabilities
• Provide direction on regulatory expectations and how to minimize the potential liabilities of nucleic acids drugs
• Provide an overview of DMPK considerations from a safety evaluation perspective
8:00 AM Welcome Remarks by Conference Director and Short Course Chair:
Sarah Lamore, PhD, Senior Director, Toxicology, Wave Life Sciences
8:05 AM Nonclinical Considerations for the Development of Oligonucleotide Therapeutics
Sarah Lamore, PhD, Senior Director, Toxicology, Wave Life Sciences
This presentation will review some of the common toxicities associated with oligonucleotide administration with a focus in antisense oligonucleotides (ASO) and siRNAs, discuss the regulatory expectations for the nonclinical safety evaluation of oligonucleotide therapeutics in the context of the applicable guidance documents, and present case studies highlighting some of the common class effects associated with siRNA and ASO administration.
8:30 AM Nonclinical Development of Next-Generation Oligonucleotide Therapies
Kristy Szretter, PhD, DABT, Scientific Director, Takeda Pharmaceutical
This presentation will review evolving regulatory and nonclinical considerations for oligonucleotide-based therapeutics, building on established approaches for antisense oligonucleotides and GalNAc-siRNAs. Using GalNAc-siRNA as a foundation, it will explore how common elements and modality-specific challenges influence the design of safety packages for more complex modalities, including antibody-oligo conjugates, circular RNA and gene editing therapies. Key considerations will include impact of delivery approaches, chemical modifications, on- and off-target effects, and long-term safety.
8:55 AM Networking Break
9:05 AM Application of in vitro Toxicity Assays in Preclinical Safety Assessment of Systemically and Intrathecally Administered Antisense Oligonucleotides (ASOs)
Fengjiao Zhang, PhD, DABT, Director, Toxicology, Preclinical & Clinical Discovery & Development Team, Wave Life Sciences
Preclinical safety assessment is a crucial phase of drug development and helps ensure patient safety by determining a safe starting clinical dose, screening out liability molecules, and by defining parameters for clinical monitoring. Preclinical safety assessment of ASOs include application of in vitro toxicity assays for throughput screening of potential toxicity, providing an early indication of hazardous properties prior to animal studies, and for understanding the mechanism of toxicity. Class effects that are observed following systemic or intrathecal administration of ASOs could include immune stimulation, complement system activation, clotting time prolongation, thrombocytopenia, and organ toxicities observed at supraclinical doses. Common histopathology findings include dose- and duration dependent infiltration of vacuolated macrophages and mononuclear inflammatory cells (could be non-dose-dependent) in multiple organs with systemic dosing, and predominantly in CNS with IT dosing. These effects are screened out and managed using efficiently designed in vitro and in vivo toxicity studies. We will discuss mechanisms of such effects along with the clinical relevance and use of predictive in vitro assays.
9:30 AM ADME and PK/PD Considerations for Preclinical Development of Antisense Oligonucleotides (ASOs)
Xiao Shelley Hu, PhD, President and Founder, Translational Consulting LLC
Olignonucleotides (ONs), including ASOs, siRNA and conjugated ONs are an emerging class of medicines for unmet medical needs. The ADME and PK/PD entail specific considerations to support effective preclinical development. This talk will focus on factors relevant to preclinical development of these ONs.