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USFDA Guidance: Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics

The US Food and Drug Administration (FDA) released the final guidance yesterday (14 June 2024) titled "Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics". This guidance aims to provide drug developers with critical insights and recommendations to optimize the development of oligonucleotide-based therapies, ensuring their safety and efficacy for patients.


Oligonucleotide Therapeutics are short, synthetic strands of nucleic acids designed to modulate gene expression or protein function. They hold significant potential for treating various genetic, infectious, and chronic diseases.


Oligonucleotide therapeutics are an emerging therapeutic modality with increasing numbers of drugs in development. They include a wide variety of synthetically modified RNA or RNA/DNA hybrids designed to bind to a target RNA sequence to alter RNA expression and/or downstream protein expression.


This guidance represents the FDA’s recommendations for certain evaluations during the development of oligonucleotide therapeutics, including:

  1. Characterizing the potential for QTc interval prolongation.

  2. Performing immunogenicity risk assessment.

  3. Characterizing the impact of hepatic and renal impairment.

  4. Assessing the potential for drug-drug interactions.


The guidance aims to assist sponsors in designing robust clinical pharmacology studies for oligonucleotide therapeutics, addressing unique challenges posed by these novel agents. Sponsors should provide detailed descriptions of how their therapeutic oligonucleotides interact with target genes or proteins.


The guidance emphasizes the importance of characterizing the pharmacokinetics (PK) and pharmacodynamics (PD) of oligonucleotide therapeutics. This includes absorption, distribution, metabolism, and excretion (ADME) profiles, as well as the therapeutic and toxic effects related to the drug's concentration and exposure.


By adhering to these recommendations, sponsors can enhance the efficiency and success of their drug development programs, ultimately bringing safe and effective oligonucleotide therapeutics to patients in need.

For detailed information, refer to the full guidance document available on the FDA website: Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics.

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