Topics to be discussed include:
- Different types of nucleic acid-based drugs
- Mechanisms of actions and non-specific effects
- Current approaches to address non-specific and potentially toxic effects
- 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
- Summarize our current understanding of the origins of non-specific and potentially toxic effects
- Provide direction on how to minimize the potential toxic effects of nucleic acids drugs
- Provide an overview of DMPK considerations from a safety evaluation perspective
SHORT COURSE PRESENTATIONS:
Nonclinical Considerations for the Development of Oligonucleotide Therapeutics
Sarah Lamore, PhD, DABT, Senior Director, Toxicology, PepGen
This presentation will review some of the common toxicities associated with oligonucleotide administration, discuss the regulatory expectations for the nonclinical safety evaluation of oligonucleotide therapeutics in the context of the applicable guidance documents, and present case studies based on recently approved products.
Further Considerations for the Development of Complex Oligonucleotide-Based Therapeutics
Kristy Szretter, PhD, Scientific Director, Takeda Pharmaceutical
This presentation will build on the regulatory expectations for the nonclinical development of ASOs and GalNAc-siRNAs, and address the additional considerations for more complex oligonucleotide-based modalities (e.g., lipid nanoparticles, antibody-oligo conjugates, circular RNAs). Relevant guidance documents and case studies will be used to highlight the similarities and unique aspects of each nonclinical package.
Application of In Vitro Toxicity Assays in Preclinical Safety Assessment of Systemically and Intrathecally Administered Antisense Oligonucleotides (ASOs)
Fengjiao Zhang, PhD, 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.
ADME and PK/PD Considerations for Preclinical Development of Antisense Oligonucleotides (ASOs)
Xiao Shelley Hu, PhD, President and Founder, Translational Consulting LLC
ASOs 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 ASOs.