First FDA Draft Guidance on the Nonclinical Development of Oligonucleotides
The FDA has released its first draft guidance on the nonclinical development of oligo-based therapeutics, including ASOs, siRNAs, mRNA, and gRNAs. This document provides crucial recommendations for IND-enabling studies and beyond.
- The term "surrogate" is mentioned 22 times, highlighting the FDA's interest in investigating on-target/exaggerated toxicity in various toxicological assessments, including reproductive and carcinogenicity studies.
- The term "class" is used approximately 24 times, indicating opportunities for companies to use the oligo platform approach for expedited IND filing.
However, there's an important catch: nonclinical safety data must be (1) publicly available in the literature or otherwise considered generally accepted scientific knowledge, (2) owned by the sponsor, or (3) available by right of reference.
For determining the first human starting dose, sponsors can use the NOAEL from:
1. Relevant species: pharmacologically active species (monkey is the most common).
2. More sensitive species: in the absence of pharmacologically active toxic species.
The guidance provides a roadmap for off-target assessments, starting with in silico analysis, then assessing hits in cells, and finally monitoring in animals and humans. Paper justification may be accepted.
There is a strong emphasis on establishing the PK/PD relationship early on for pharmacology, toxicology, and clinical studies.
New chemical modifications (backbone, sugar, or base) are considered new chemical entities and warrant investigation to understand their metabolism (and possibly excretion). Unfortunately, the guidance does not provide sufficient details on this topic.
We will start compiling a list of questions and comments to submit to the FDA. Please share your comments below.
