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New FDA Draft Guidance “Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics” – XenoTech’s perspective on in vitro DDI testing

The FDA has released a new draft guidance for industry titled “Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics.”

The document represents the agency’s current thinking on clinical pharmacology considerations during the evaluation of novel oligonucleotide therapeutics including:

  • characterizing the potential for QTc interval prolongation,
  • performing immunogenicity risk assessment,
  • characterizing the impact of hepatic and renal impairment, and
  • assessing the potential for drug-drug interactions (DDI).

We would like to bring to your attention several points made by the agency as they pertain to our field of expertise – an in vitro assessment of the DDI potential of new drug candidates.

The new draft guidance, in agreement with prevailing industry opinion, recognizes that oligonucleotide therapeutics are not typically metabolized by cytochrome P450 (CYP) enzymes nor are they substrates of nine major transporters of concern for evaluating perpetrator potential of small molecule drugs. This has been a position adopted by XenoTech Consulting in advising our clients’ concerns related to oligonucleotide drugs.

We share the agency view that, for the oligonucleotide therapeutics undergoing substantial renal active secretion as an unchanged drug, it could be important to evaluate whether it is a substrate of renal transporters in vitro.

This new FDA draft guidance document refers to the Guidance “In Vitro Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions” (January 2020) as a general framework for conducting in vitro experiments and interpreting data for therapeutic oligonucleotides and further states that an overall recommendation for specific types of oligonucleotide therapeutics (e.g., based on chemistry or delivery strategies) cannot be provided at this time.

The agency has referred to XenoTech’s publication on in vitro assessment of inhibition of cytochrome P450 enzymes, UDP-glucuronosyltransferases, and transporters by phosphodiester- or phosphorothioate-linked oligonucleotides, for careful selection of an appropriate test system for evaluating these molecules, generally pooled human hepatocytes. A need to conduct enzyme induction or inhibition studies with oligonucleotide can be considered in light of the agency position that, “based on current experience, oligonucleotide therapeutics either do not modulate or minimally modulate the major CYP enzymes and drug transporters”. Despite this statement, the agency expects the sponsor to provide adequate justification if in vitro assessments of oligonucleotide therapeutics as perpetrators of drug interactions are not conducted.

The draft guidance lists the possible mechanisms for interactions between oligonucleotide therapeutics and CYP enzyme or transporters as off-target hybridization with CYP enzyme or transporter mRNA transcripts or hybridization with mRNA transcripts of proteins affecting the synthesis or degradation of heme or by modulating cytokine expression. With the exception of the latter mechanism, which is recognized for potential interaction between immunomodulating biologics and small molecules drugs, these mechanisms are oligonucleotide-specific. The circumstances under which these possible mechanisms should be evaluated or the means to accomplish it, are not clarified.

Evaluating the therapeutic oligonucleotides’ DDI potential is an evolving field that will be shaped by advancing science. Multiple white papers illustrating common regulatory and industry views on this subject were published by the Oligonucleotide Safety Working Group and a recent FDA publication summarized in vitro DDI CYP or transporters studies performed for five approved oligonucleotide therapeutics Mipomersen (2013), Eteplirsen (2016), Nusinersen (2016), Patrisiran (2018), and Inotersen (2018) (Clin Transl Sci (2021) 14, 468–475).

The draft guidance is open for public comments till 09/26/2022.