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. Qin Sun, Biologics Lead, and Dr. Sarah Ridge, Policy Analyst, in the Center for Drug Evaluation and Research’s (CDER), Office of Clinical Pharmacology. They will be sharing some thoughts with us on the newly published final guidance titled, “Clinical Pharmacology Considerations for Antibody-Drug Conjugates.” Welcome, Dr. Sun and Dr. Ridge. Thank you for speaking with us today.

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Dr. Sun, for listeners less familiar with this topic, what is an antibody-drug conjugate and why did FDA issue this guidance?

Sure, an antibody-drug conjugate (or ADC) is generally composed of a small molecule drug, also known as a payload, and an antibody or antibody fragment, conjugated together by a chemical linker. As such, an ADC has multiple constituent parts. An ADC is designed to target specific cells, such as cancer cells, while minimizing effects on non-targeted cells. When the antibody binds to its target antigen on the cell surface, the ADC is internalized, and the cytotoxic payload is released to kill the tumor cells.

ADCs are distinct from both biologics and small molecule drugs. There are special clinical pharmacology considerations for ADCs due to their unique structure and mechanism of action. FDA has accumulated decades of experience and has approved 11 ADCs for oncology as of January 2024. Hence, FDA developed and issued this guidance document to provide a comprehensive clinical pharmacology recommendations for ADCs. The topics covered include dosing strategies, bioanalytical approach, intrinsic factors, drug-drug interactions (or DDIs), and more to support the growing number of ADCs under development.

Dr. Ridge, what are the key considerations for ADC dosing strategies?

When it comes to the selection of dosing strategies for ADCs, careful consideration is needed due to ADC’s unique structure. The ADC’s constituent parts, such as the antibody and the cytotoxic payload, can independently impact safety and efficacy. Therefore, it is important to consider the pharmacokinetics (also called PK) and pharmacodynamics (also called PD) of not only the ADC as a whole but also the relevant constituent parts. The FDA recommends exploring a wide dosage range early in development to understand how the ADC and its active constituent parts contribute to the safety and efficacy of the treatment. This early evaluation aids in making informed decisions for dosing strategies in later stages of development.

Dr. Sun, what are some unique considerations for the bioanalytical approach in ADC development?

This is really an important question. First, the assay needs to be validated as recommended in ICH M10 guidance bioanalytical method validation and study sample analysis. Second, if the antibody’s target is shed into systemic circulation, the assay needs to distinguish the target-bound vs. target-unbound ADC. Third, under certain scenarios, measuring some analytes may not be necessary. For example, if the antibody constituent only acts as a carrier, and the total antibody concentrations highly correlates to the ADC, measuring the total antibody may not be necessary at later stages. In addition, the guidance provides recommendations regarding which analytes should be measured in various dedicated clinical pharmacology studies, such as organ impairment, QTc, DDI, and PK comparability studies. More details on this can be found in the guidance.

Dr. Ridge, are there any special considerations for dose- or exposure-response analyses for ADCs?

Yes, there are special considerations for dose- and exposure-response analyses given the selectivity of the antibody and the potency of the cytotoxic payload. And so, it is important to understand the exposure-response relationship of each constituent part of the ADC and the ADC as a whole. Dose- and exposure-response analyses can be used to support dose selection of the ADC to achieve an optimal balance between safety and efficacy. Conducting these studies early in ADC development can help support decision making in later development.

Dr. Sun, what intrinsic patient factors need to be evaluated for ADCs?

Thank you for this challenging but great question. Any intrinsic patient factor that has the potential to affect exposure of ADC or its constituent parts should be evaluated. For example, organ impairment, pharmacogenomics, body weight, age, gender, etc. These intrinsic factors can be evaluated through population PK analysis or in dedicated studies.

The guidance provides some special considerations for organ impairment and pharmacogenomics assessments.

For organ impairment, first, the impact of renal and hepatic impairment on PK of the unconjugated payload should be evaluated according to the principles outlined for small molecule drugs. Second, renal impairment may increase the exposure of the ADC if its molecular weight is less than 69 KDa, and hepatic impairment has been reported to decrease the exposure for certain ADCs. Third, multiple factors need to be considered for choosing a population PK analysis vs. a dedicated study. For example, is there a potential for a significant exposure change of the unconjugated payload in patients with organ impairment? Is the exposure-response relationship steep for safety? Although dosage adjustment is challenging for ADCs, the assessment of organ impairment is essential to inform labeling strategy, and sometimes can recommend avoiding dosing in a specific population with identified risks.

For pharmacogenomics, the guidance provides some examples where evaluating its impact may be relevant. For example, genetic variants of metabolic enzymes and transporters may impact the PK of the unconjugated payload, such as UGT1A1, CYP2D6, or BCRP. In addition, genetic variants of the antibody target or Fc-gamma receptors can affect ADC response.

Dr. Ridge, how should drug-drug interactions be evaluated in ADC development programs?

Thank you for this question, evaluation of drug-drug interactions (also called DDIs) should begin with an in vitro assessment for risk associated with drug metabolizing enzymes and transporters. This should include an assessment of the unconjugated payload and the relevant ADC constituent parts as an inhibitor, inducer, or substrate. Based on the outcomes of the in vitro characterization, a clinical DDI study may or may not be needed.

Although the systemic exposure of the unconjugated payload can be relatively low, characterizing the systemic exposure is important to determine its potential as an inhibitor or inducer in vivo. However, assessment of the unconjugated payload as a substrate can be recommended even if systemic exposure is low, as a relatively small increase in systemic exposure of the cytotoxic payload could have an impact on safety.

In addition to the unconjugated payload, the DDI potential of the antibody component should also be considered. An understanding of the medications commonly used by the target patient population can be helpful when designing these DDI assessments and developing DDI-based risk mitigation strategies.

Dr. Sun, are QTc and immunogenicity assessments needed for ADCs?

Yes, both QTc and immunogenicity assessments are recommended for all ADC development programs.

For QTc assessment, the antibody component of an ADC typically has a low likelihood of affecting QTc directly, so the focus of the assessment is often on the effect of the unconjugated payload, linker, and relevant metabolites. The principles for characterization of QT prolongation risk are similar to those for small-molecule drugs.

For immunogenicity assessment, ADCs can trigger immune responses against the antibody, the conjugated payload, or the linker. It is important to evaluate the immunogenicity to ADCs and the impact on PK, safety, and efficacy. The FDA recommends a multi-tiered immunogenicity testing approach. In addition, multiple assays may be needed to evaluate where the anti-drug antibodies bind.

Dr. Ridge, for our final question, what are a couple of key items from the guidance that you especially want listeners to remember?

We hope listeners gain an appreciation for the unique nature of the ADC. We also hope they remember that a thorough understanding of the PK and PD of the ADC and its constituent parts early in development is crucial to inform dosing strategies later in development.

Other items to note include the special considerations for intrinsic factors such as organ impairment and how study outcomes can affect labeling recommendations. Due to the safety concern of the cytotoxic payload in circulation, it is essential to determine the DDI potential of the unconjugated payload as a substrate even if its systemic exposure is relatively low.

And just to wrap up, we are very excited for this guidance publication. Our recommendations are based on decades of experience regulating ADCs, and we hope that it is informative for the drug development community.

Dr. Sun and Dr. Ridge, thank you for taking the time to share your thoughts on the final guidance on common issues in clinical pharmacology considerations for antibody-drug conjugate drug development. We all have learned so much from 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.