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. Elimika Pfuma Fletcher and Dr. Qin Sun, Policy Leads in the Center for Drug Evaluation and Research (CDER), Office of Clinical Pharmacology. They will be sharing some thoughts with us on the newly published final guidance titled Drug-Drug Interaction Assessment for Therapeutic Proteins. Welcome, Dr. Pfuma Fletcher and Dr. Sun! Thank you for speaking with us today.
Dr. Sun, for listeners less familiar with this area, can you provide a little background on therapeutic proteins?
Therapeutic proteins are large, complex amino acid-based molecules derived from living cells. Currently FDA defines the term “protein” as any alpha amino acid polymer with a specific, defined sequence that is over 40 amino acids in size. Therapeutic proteins include purified monoclonal antibodies, cytokines, enzymes, and other novel proteins. They are usually administered through intravenous, subcutaneous, or intramuscular injection.
Therapeutic proteins are a subgroup of biological products regulated by the Center for Drug Evaluation and Research (CDER) of the FDA. Other biological products, such as vaccines, allergenic products, cellular and gene therapy products, are regulated by the Center for Biologics Evaluation and Research (CBER) of the FDA. Although this guidance applies to therapeutic proteins, many of the general principles may be applicable to other biological products, such as novel products regulated by CBER.
Dr. Pfuma Fletcher, can you explain to the audience why it is important to evaluate drug-drug interactions involving therapeutic proteins and provide some of the reasons that FDA issued this guidance?
Sure, taking multiple drugs concomitantly can lead to drug-drug interactions (commonly referred to as DDIs), which can potentially result in either a loss of efficacy or an increase in adverse events for some drugs. So, it is important for drug developers to identify DDI risk, quantify extent of interaction when one exists, and develop appropriate mitigation strategies to facilitate safe and effective use of the investigational drug with concomitant medications.
Because of the importance of evaluating DDIs, FDA has issued multiple guidance documents on DDI assessment. For evaluating DDIs involving therapeutic proteins, this guidance supplements two published FDA guidances, which provide foundational principles for DDI assessment. These guidances are focused on small molecule DDI assessment for In Vitro and Clinical Drug Interaction Studies for Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions. This current guidance covers DDI assessment of therapeutic proteins, but details of DDI assessment for antibody-drug conjugates (which have a therapeutic protein component and a small molecule payload) can be found in an FDA guidance titled Clinical Pharmacology Considerations for Antibody-Drug Conjugates.
In recent years, there has been an increase in the development of novel therapeutic proteins, and they represent a growing proportion of new drugs approved by the agency. For example, over 40% of novel drugs approved by CDER in 2022 were therapeutic proteins. Although FDA has published several guidances laying out the expectations for drug interactions mediated through the hepatic enzymes and transporters, the considerations outlined in those guidance documents do not directly apply to therapeutic proteins, which do require some unique considerations.
Therapeutic proteins differ from small molecule drugs in how the body eliminates them. Small molecule drug elimination involves phase 1/2 metabolizing enzymes and transporters with liver and kidney commonly involved in elimination. In contrast, therapeutic proteins generally undergo nonspecific catabolism and can also undergo target-mediated drug disposition (TMDD). In addition, therapeutic proteins may have risks for immunogenicity, which is not a concern for small molecule drugs. These differences in elimination and immunogenicity mean the mechanisms for DDI differ. Therefore, it is important to have this dedicated guidance, which considers the unique DDI mechanisms for therapeutic proteins and offers a systematic and risk-based approach for evaluation of DDI.
Dr. Sun, when should sponsors consider conducting drug interaction studies for therapeutic proteins?
This is a very important question, and the guidance lays out a risk-based approach on it. When evaluating DDI risks for therapeutic proteins, several aspects should be considered, including DDI mechanisms, disease type and severity if DDI mechanism is related to the disease condition, product type (e.g., cytokine or not), clearance pathways, and co-administered drugs in targeted patient populations. The guidance also includes a decision tree that summarizes the main concepts of the risk-based approach for different DDI scenarios.
The first scenario is when the therapeutic protein is a pro-inflammatory cytokine. It is well known that pro-inflammatory cytokines have the potential to suppress CYP enzyme expression, and thus may increase the exposure of various CYP substrates. Therefore, DDI studies are warranted for therapeutic proteins that are proinflammatory cytokines. One example for this scenario is peg-interferon.
The second scenario is when the therapeutic protein is a pro-inflammatory cytokine modulator. Change in cytokine levels has the potential to change CYP enzyme expression, resulting in altered systemic exposure of concomitantly administered CYP substrates. In this scenario, the DDI studies are typically conducted in patients, although the sponsor may have the choice of not doing a clinical DDI study. For example, blinatumomab has labeling language for DDI risk without clinical DDI study, while tocilizumab has clinical DDI study results described in the labeling.
The third scenario is for DDI mechanisms not related to cytokines. Some examples include DDI resulting from therapeutic protein-mediated changes in physiological processes, target-mediated drug disposition, neonatal Fc receptor (FcRn) binding, or immunogenicity of therapeutic proteins. One example is efgartigimod, which affects binding to FcRn of other mAbs or Fc-fusion proteins. The other example is methotrexate, which is an immunosuppressor and affects the immunogenicity and the exposure of some other therapeutic proteins, such as adalimumab.
The important take-home message is that the guidance provides a-risk-based approach for different scenarios where DDI should be evaluated for therapeutic proteins.
Dr. Pfuma Fletcher, what are some general considerations for designing studies to evaluate DDI potential for therapeutic proteins?
There are a few general considerations related to the DDI study design. For DDIs studies evaluating the effect of other drug(s) on the therapeutic protein, sponsors should consider using a parallel design when the therapeutic protein has a long half-life. When evaluating the effect of the therapeutic protein on the other drug(s), a single-sequence, crossover design can be used.
For cytokine modulators, the time course for cytokine modulation can guide the timing and duration of administration for the substrate and therapeutic protein. In addition, a cocktail approach, which involves evaluating multiple substrates simultaneously, can be considered to evaluate the interaction potential of cytokine modulators.
In addition, modeling and simulation approaches have been used and are applied for DDI evaluation. Population pharmacokinetic analyses can be used if prospectively designed and the necessary information related to timing of administration and concomitant medications are well-documented. In general, population pharmacokinetic analyses are used to evaluate the effect of other agents on the investigational therapeutic protein as investigational drug PK data are usually already being collected. However, PK collection can be planned for concomitant drugs to evaluate the effect of the therapeutic protein on the other drug. Other modeling approaches such as physiologically-based PK (PBPK) modeling are still evolving, and sponsors are encouraged to discuss with the FDA when such approaches are being applied to evaluate the DDI potential of therapeutic proteins.
Dr. Sun, for our last question, what are a couple of key items that you especially want listeners to remember?
We’d like listeners to remember that the DDI mechanisms for therapeutic proteins are very different compared to small molecules, and could also be unique to individual protein product, so it is important to know when and how to evaluate those DDI risks for different scenarios. Also, for pro-inflammatory cytokine modulators, there are multiple options to address the DDI risks, and it is possible to provide labeling language or justification without clinical DDI studies for those therapeutic proteins. We will continue to gain experience with various topics, including the impact of proinflammatory cytokines or their modulators on transporters. In addition, new modalities are in development and even newer ones continue to emerge. Therefore, FDA will continue to gather more information on DDI assessment for therapeutic proteins and will continue to share updates. We recommend that sponsors contact FDA to discuss specific questions for their products.
Dr. Pfuma Fletcher and Dr. Sun, thank you for taking the time to share your thoughts on the DDI Assessment for Therapeutic Proteins final guidance. We all have learned so much from your experience and insights in this area, and we appreciate the hard work that you have invested to inform safe and effective use of the drugs and biologics we regulate. We would also like to thank the guidance working group for writing and publishing this guidance.
To the listeners, we hope you found this podcast useful. We encourage you to take a look at the snapshot and to read the guidance.