Guidance Recap Podcast | Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics
Thank you for joining us for another episode of the Guidance Recap Podcast. The Guidance Recap Podcast provides highlights for FDA guidance documents straight from the authors. My name is Kylie Haskins, and I am the host for today’s podcast. In today’s episode, I am excited to be talking with Dr. Anuradha Ramamoorthy, Master Scientist and Policy Lead, and Dr. Hobart Rogers, Clinical Pharmacologist, both in the Office of Clinical Pharmacology located within the Office of Translational Sciences in the Center for Drug Evaluation and Research. They will be sharing some thoughts with us on the newly published final guidance titled, “Clinical Pharmacology Considerations for the Development of Oligonucleotide Therapeutics.” Welcome, Dr. Ramamoorthy and Dr. Rogers! Thank you for speaking with us today.
Dr. Rogers, for those less familiar with this topic, what are oligonucleotide therapeutics?
Oligonucleotide therapeutics encompass a wide variety of synthetically modified RNA or RNA/DNA hybrids that are specifically designed to bind to a target RNA sequence via Watson-Crick base pairing to alter RNA and subsequent downstream protein expression. Oligonucleotide therapeutics are chemically modified to avoid immune recognition, increase binding potency, and to avoid or slow degradation by endogenous nucleases.
It is important to note that oligonucleotide therapeutics are a diverse class of therapeutics that can differ in several ways, including sequence, mechanism of action, chemical modifications, conjugation, and route of administration amongst others. RNA Oligonucleotides have distinct characteristics compared to small molecules and biologics that may cause unique regulatory considerations. Of importance, they are an emerging therapeutic modality with increasing numbers of drug applications submitted to the FDA for review. To date, the FDA has approved 17 RNA oligonucleotide therapeutics including six siRNAs or small-interfering RNAs and eleven antisense oligonucleotides.
Unlike small molecule drugs, the pharmacokinetic half-life of an oligonucleotide therapeutic is typically short, but the pharmacodynamic half-life is generally long. The pharmacodynamic half-life usually drives the dosing interval and dose selection for these products. Because the pharmacodynamic half-life is so long, these medicines can sometimes be dosed every six months to a year. However, this all varies by chemistry, and chemistry-specific variations should be considered in the clinical pharmacology evaluation of these products.
Dr. Ramamoorthy, why did FDA issue this guidance?
Oligonucleotide therapeutics are distinct from both small molecule drugs and large biologics. There are some specific clinical pharmacology considerations for oligonucleotide therapeutics because of their unique mechanism of action, structure, size, etc. FDA is issuing this guidance to provide consistent recommendations to sponsors focused on four key areas for which we frequently receive questions from drug developers:
- Characterizing QTc interval prolongation and proarrhythmic potential.
- Performing immunogenicity risk assessments.
- Characterizing the impact of hepatic and renal impairment on pharmacokinetics, pharmacodynamics, and safety.
- Assessing drug-drug interaction liability.
The recommendations in this guidance provide general best practices intended for oligonucleotide therapeutics that bind to a target RNA sequence to alter RNA expression and/or downstream protein expression.
The recommendations provided in this guidance were informed by experiential knowledge gained from FDA’s review of these products during development, approval, and in post marketing stages. It is also informed by regulatory research that was performed and stakeholder input submitted to a Federal Register notice that the FDA issued in 2019 to collect comments from stakeholders on the application of clinical pharmacology during development of oligonucleotide therapeutics. FDA then published a draft guidance in 2022 and received comments on the draft guidance, which were considered in drafting this final guidance.
We are continuing to deepen and broaden our regulatory experience for this emergent therapeutic modality and will be planning to provide additional recommendations in the future. For now, we encourage the sponsors to contact FDA with their questions if the guidance does not address their particular question.
Dr. Rogers, can you elaborate on the unique characteristics of oligonucleotide therapeutics on QT interval?
We are still gaining experience in this area. Overall, we ask sponsors to assess the QT prolongation risk and submit a proposed QT assessment plan as outlined in the FDA guidances E14, E14 Q&A, and S7B that are focused on the clinical and non-clinical evaluation of QT/QTc Interval. Sometimes sponsors think that they don’t need to conduct QT studies because the chemistry is the same or similar to a previous product. However, we are still learning with each chemistry and recommend the standard battery of nonclinical and clinical QT studies.
Dr. Rogers, how should immunogenicity risk assessments be performed for oligonucleotide therapeutics?
1See guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs (October 2012), guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs Questions and Answers (R3) (June 2017), guidance for industry E14 and S7B Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential--Questions and Answers (August 2022).
Typically, these compounds are thought to be low immunogenicity risk, however changes in the chemistry and conjugation can certainly modify this assessment. We do see anti-drug antibody (or ADA) positivity in these products and some of it is transient meaning that the immune system sees it and does not mount a continued response. So far, ADA positivity has not been associated with meaningful differences in efficacy and safety. However, there has been a single instance of increased Ctrough – which is the concentration reached by a drug immediately before the next dose is administered – associated with ADA positivity.
We should note that conjugation to other components, such as lipid nanoparticles, or monoclonal antibodies can change the immunogenicity risk assessment.
We ask sponsors to assess immunogenicity because we want to understand the ADA level at baseline and the level in the proceeding months given the long duration of action and subsequent dosing intervals for these therapeutics. We do not typically assess neutralizing antibodies given the intercellular mechanisms of action of oligonucleotides, though in certain circumstances, it may be recommended.
We recommend that for clinical immunogenicity assessments, where feasible, immunogenicity sample collection should coincide with pharmacokinetic and pharmacodynamic sampling time points. This will allow for us to evaluate whether ADAs impact the pharmacokinetics or pharmacodynamics of the oligonucleotide therapeutic.
We encourage the sponsors to communicate with appropriate review divisions when they need further clarification specific to their products.
Dr. Ramamoorthy, what considerations are there for the impact of hepatic and renal impairment with oligonucleotide therapeutics?
It is important to evaluate early in drug development, whether the liver or kidneys play a role in the disposition or elimination of the oligonucleotide therapeutic. Typically, this is done during preclinical and early Phase 1 clinical studies. If these early assessments indicate the liver and/or kidneys are involved, then further clinical evaluation of effect of liver and kidney impairment should be performed to obtain meaningful data on the safety and efficacy of the product in these patient populations.
There are generally three scenarios we commonly see:
- The first scenario is that early assessments indicate the liver and kidneys are not involved in the disposition and elimination of the oligonucleotide therapeutic. In this scenario, enrolling patients with a wide range of kidney and liver function in late phase clinical studies is important to help generate clinical experience in these patient populations. In general, the sponsor should provide justification when patients with some degree of kidney or liver impairment are excluded, especially when the liver and kidneys are not involved in either the disposition of the drug or when it is not anticipated that impairment has any impact on response. Sponsors can refer to the FDA guidance Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs for best practices on clinical trial enrollment.
- The second scenario is that early assessment studies indicate the kidneys play a role in clearing the oligonucleotide therapeutic. In this scenario, we recommend further characterization of the effect of renal impairment. This can be done through different strategies, including a reduced study design to assess the impact of severe renal impairment or kidney failure not receiving dialysis on the pharmacokinetics, pharmacodynamics, tolerability, and safety of the oligonucleotide therapeutic. Additional details can be found in the FDA guidance Pharmacokinetics in Patients with Impaired Renal Function — Study Design, Data Analysis, and Impact on Dosing and Labeling. Performing these characterizations early in drug development is important to inform inclusion/exclusion criteria for late-stage clinical trials.
- The third scenario is that early assessment studies indicate the liver is the target of the oligonucleotide therapeutic or there is active targeting to the liver. In this scenario we recommend characterizing the impact of liver impairment. One strategy for this is to conduct sequential or adaptive enrollment of patients with hepatic impairment. Doing this early in drug development is important as it can help inform the study design of late phase clinical trials.
One challenge is that organ function impairment can result in pharmacodynamic changes that are not reflective of pharmacokinetic changes. Therefore, when possible, the sponsor can conduct pharmacodynamic assessments. Population pharmacokinetic-pharmacodynamic modeling may also be utilized to assess the correlation between organ impairment and pharmacodynamics, other biomarkers, safety, or efficacy data.
In general, the expectation is that a sufficient number of participants with a range of kidney and liver function should be enrolled across the oligonucleotide therapeutic development program to obtain meaningful data unless there is adequate justification not to enroll them such as presence of safety concerns.
Dr. Ramamoorthy, can you discuss considerations for assessing drug-drug interactions with oligonucleotide therapeutics?
When it comes to drug-drug interactions (also called DDIs), there are two broad types to be aware of: a pharmacokinetic-based interaction and a pharmacodynamic-based interaction.
I will discuss the pharmacokinetic-based interaction first. Typically, when we think of pharmacokinetic-based DDIs, we think of two situations:
- The first situation is when the new drug is a substrate of a drug metabolizing enzyme or transporter. Because oligonucleotide therapeutics are primarily metabolized by endonucleases and exonucleases and are chemically modified to resist degradation, this type of pharmacokinetic-based DDI is typically not expected. In addition, these products are typically not substrates of the common transporters. Therefore, even if the patient is taking concomitant medications that can induce or inhibit cytochrome P450 enzymes or modulate the transporters, we don’t anticipate that the disposition of the oligonucleotide therapeutic will be affected.
- Moving on to the second situation, which is that the oligonucleotide is an inducer or inhibitor of cytochrome P450 enzymes or transporters. Oligonucleotide therapeutics typically do not modulate or minimally modulate the major cytochrome P450 enzymes and drug transporters. However, some oligonucleotide therapeutics can interfere with cellular process that can indirectly modulate cytochrome P450 enzymes or transporters (for example some oligonucleotide therapeutics interfere with heme synthesis or cytokine modulation). Therefore, we typically recommend in vitro assessments to identify if there is a potential for the oligonucleotide therapeutic to act as inducer or inhibitor. If the in vitro assessments indicate a need for further evaluation, then we recommend conducting clinical DDI assessments.
Briefly touching on pharmacodynamic interactions - oligonucleotide therapeutics can exhibit pharmacodynamic interactions with a concomitant drug. Because such interactions may be unique to the individual therapeutic, the sponsor is encouraged to consult with the relevant review Division regarding assessment of pharmacodynamic drug interactions.
Dr. Rogers, for our final question, what are few key items from the guidance that you especially want listeners to remember?
First, we want to remind stakeholders that this guidance serves as a recommendation for oligonucleotide therapeutics that use an RNA-based mechanism of action. These recommendations are based on the collective knowledge the Agency has gained in regulating these novel products as well as the review of the scientific literature, public comments received to a federal register request on this topic, and public comments received for the original draft guidance. This guidance does not provide any chemistry-specific recommendations because we are continuing to gain experience with these.
As we gain more experience with this class of therapeutics, we will continue to refine our best practices and recommendations. We hope that stakeholders find this document useful. We encourage sponsors to contact the Agency with their questions on oligonucleotide therapeutics as this is an emerging area of drug development.
Dr. Ramamoorthy and Dr. Rogers, thank you for taking the time to share your thoughts on the final guidance on clinical pharmacology considerations for the development of oligonucleotide therapeutics. We all have learned so much from your insights on this document. We would also like to thank the guidance working group for writing and publishing this final guidance.
To the listeners, we hope you found this podcast useful. We encourage you to look at the snapshot and to read the guidance.