Oligonucleotides: FDA drafts clinical pharmacology guidance

Regulatory NewsRegulatory News | 27 June 2022 |  By 

The US Food and Drug Administration (FDA) last week issued draft guidance spelling out its expectations for the types of clinical pharmacology assessments that should be conducted during the development of oligonucleotide therapies. The agency notes that several oligonucleotide therapies have been approved for rare diseases in recent years and that such treatments are now in development for common chronic diseases.
While the synthetically modified ribonucleic acid (RNA) or hybrid RNA/deoxyribonucleic acid (DNA) treatments hold promise for wide range of indications, the agency says they may also have potentially unwanted long-lasting effects even after the drug has been expelled from the body.
On 24 June, the FDA published a draft guidance titled Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics. It explicitly lays out the agency’s expectations on types of pharmacodynamic, pharmacokinetic and safety assessments that should be conducted during the development of such products.
“Oligonucleotide therapeutics are an emerging therapeutic modality with increasing numbers of drugs in development,” the agency said. “Antisense and small interfering RNA (siRNA) oligonucleotide therapeutics have been FDA-approved in recent years to treat rare diseases; in addition, many oligonucleotide therapeutics are currently in development to treat common chronic diseases.”
FDA notes that while oligonucleotide drugs are typically cleared rapidly from systemic circulation, they may stay in tissue for a longer time and have long pharmacodynamic half-lives. With that in mind, regulators want sponsors to consider certain studies to better understand the pharmacological effects of the drugs.
In general, the sponsor should characterize the plasma pharmacokinetics of an oligonucleotide therapeutic following single and multiple doses early in drug development. However, for some treatments, regulators note that plasma pharmacokinetics might not reflect the target tissue distribution, pharmacodynamics, safety, or efficacy.
With that in mind, they note that in multiple-dose studies, sponsors should include an assessment of appropriate pharmacodynamic biomarkers such as target mRNA, target protein, or a downstream biomarker that reflects modulation of the target protein.
“Such assessments are important in situations where pharmacodynamic changes are independent of plasma pharmacokinetic changes,” said FDA. “The selection of the pharmacodynamic endpoints should be discussed with the appropriate FDA review staff, especially in cases where the pharmacodynamic endpoints might not directly reflect target knockdown (e.g., cerebrospinal fluid for central nervous system targets).”
Oligonucleotide treatments are relatively novel. With that in mind regulators list a number of steps they would like sponsors to take to show the product is safe and effective including cardiac repolarization delay studies and immunogenicity risk assessments.
“An unwanted immune response to an oligonucleotide therapeutic can be generated to the carrier, backbone, oligonucleotide sequence, or any novel epitopes created from the whole drug (carrier plus oligonucleotide),” said FDA. “The development of oligonucleotide therapeutics is rapidly evolving, and new chemistries, modifications etc. can significantly affect the immunogenicity risk and clinical immunogenicity assessment of a particular product.”
FDA said immunogenicity risk assessments should be risk-based and include product factors, pharmacology of the product and patient characteristics.­ The guidance also looks at specific assessments to determine potential drug interactions that may have a significant effect on how the drug works.


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