FDA proposes guidance for nonclinical safety assessment of oligonucleotide-based drugs

The US Food and Drug Administration (FDA) has published draft guidance on nonclinical safety assessments of oligonucleotide-based therapeutics (ONT). The guidance outlines the agency’s expectations for pharmacology and pharmacokinetic characteristics and conducting different toxicity studies.

FDA noted that while the proposed guidance specifically addresses ONTs, other guidances may also apply broadly to such drugs.

“ONTs present unique challenges for nonclinical safety evaluations,” said FDA. “Although current guidance for small molecule drugs and therapeutic proteins may mention ONTs, this guidance provides detailed recommendations specific to nonclinical assessment of ONTs that have been developed based on experience to date with this category of products.”

“These recommendations address ONT characteristics that differ from small molecule drugs and therapeutic proteins,” the agency added.

The guidance specifically outlines FDA’s thinking on single-stranded or double-stranded ONTs. These may be created synthetically or derived naturally, with native or modified backbone or nucleoside structures that increase or decrease protein expression and/or function.

FDA notes that the guidance may address ONTs that are antisense, small interfering RNA, microRNA, transfer RNA, decoys, and aptamers. However, immune stimulatory oligonucleotides, such as CpG motifs acting via Toll-like receptors, and CBER-regulated products such as DNA/RNA vaccines, virally delivered ONTs, messenger RNA and RNA used for gene editing, are not covered under the guidance.

ONTs that are part of other types of molecules may be covered under the guidance depending on the characteristics of the oligonucleotide portion of the drug, the agency said.

Generally, sponsors are asked to conduct certain safety assessments of their ONTs and to consider their modes of activity. FDA notes that ONTs may use several modes of activity to achieve the same pharmacological effect. However, the agency notes that most often, they contain nucleotide base sequences complementary to a targeted sequence of an intracellular nucleic acid.

The guidance focuses on two types of general safety assessments. The first addresses on-target effects, also called exaggerated pharmacology, safety issues due to adverse pharmacologic effects at the target of interest. FDA says the potential effect for safety issues related to on-target effects should be characterized and generally assessed in at least one test species when one or more test species are available that are pharmacologically responsive to the drug in development.

“For some ONTs, it may not be practical to experimentally assess exaggerated pharmacology in toxicology studies,” said FDA. “In these cases, a literature-based weight-of-evidence (WoE) assessment of the potential adverse effects resulting from exaggerated pharmacology should be provided (e.g., data from genetically modified animal models or data from known human diseases).”

The other general safety assessment to consider is for off-target hybridization-dependent effects.

“Given their ability to form Watson-Crick-Franklin base pairs, ONTs have the potential to bind to nontargeted RNA or DNA sequences that share partial or complete complementarity with the base sequence present in the ONT, which can lead to adverse effects in humans that might not be detected in toxicology studies,” said FDA. “Therefore, sequence-dependent off-target assessments should be conducted for ONTs using appropriate in silico and in vitro methodologies to identify potential off-target hybridization.”

The agency lists several factors to consider when conducting sequence-dependent off-target assessments, such as the ONT's risk factor and sensitivity, elements of the ONT and its predicted metabolites, potential hybridization to the transcriptome and nuclear and mitochondrial genome, and more.

The guidance further addresses issues such as pharmacology and pharmacokinetics of the ONTs. It also delves into toxicity, carcinogenicity, and reproductive and developmental studies.

In June, FDA finalized a guidance on clinical pharmacology assessments sponsors should consider during the development of ONTs. The agency has also scheduled a 4 December virtual meeting to discuss clinical pharmacology considerations when developing novel therapeutic modalities where it intends to delve into the final guidance. (RELATED: This Week at FDA: Tarver named CDRH chief, GOP report critical of HHS’ COVID vaccine promotion, Regulatory Focus 25 October 2024)

Stakeholders can comment on the draft guidance on www.regulations.gov under docket FDA-2024-D-4624 until 14 January 2025.

Draft Guidance

FDA proposes guidance for nonclinical safety assessment of oligonucleotide-based drugs

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