Advanced Therapy Medicinal Products (ATMPs) are human medicines based on cells, genes, or tissues and are seen as pioneering new opportunities for the treatment of a range of diseases. Currently, 22 ATMPs have been approved by the FDA, and the field of interest is growing rapidly. In traditional drug development, pharmacokinetic (PK) studies are necessary to use medicines under the best conditions of efficacy and safety.

For ATMPs, investigations of PK are also essential aspects as delineated in EMA’s guide on ATMPs, including flowcharts and checklists. However, there could be significant differences compared to traditional ADME (Absorption, Distribution, Metabolism, and Excretion) studies, and special considerations unique to the respective ATMPs are required. This is because ATMPs may not follow the common principles of ADME or exhibit a classical dose-response relationship. For example, in the case of cell therapies, clinical PK studies may consider body distribution/migration, cells growth, viability, differentiation/proliferation, and/or phenotype, depending on what is relevant to the specific ATMP.

Among 22 ATMPs approved by the FDA, five are chimeric antigen receptors (CAR) T-cell therapies: tisagenlecleucel (Kymriah™), lisocabtagene maraleucel (Breyanzi®), axicabtagene ciloleucel (Yescarta ™), idecabtagene vicleucel (Abecma®), and brexucabtagene autoleucel (Tecartus™). In this blog, we shed light on CAR-T therapy as an example case for ATMP drug development.

ATMP: CAR-T Cells Distribution, Expansion, and Persistence

CAR-T therapy involves genetically engineering and expanding autologous (or, in the future, potentially allogeneic) T-cells, after which the modified T-cells are administered to the patient. The genetically engineered CAR-T cells are adapted to target tumour cells using the CAR, which binds to specific antigens on tumour cells. After infusion, the concentration of CAR-T cells observed in the blood declines as the CAR-T cells distribute into the tissues. Upon interaction with the tumour target, the CAR-T cells become activated and rapidly expand, which can be measured as a rise to maximum concentrations in the blood (1-2 weeks after infusion). After this peak, the concentrations slowly decline, reflecting the death of the CAR-T cells (e.g. due to a decrease in tumour burden). However, CAR-T cell concentrations may continue to be observed for years and can even increase again when available target tumour cells increase. Since the engineered CAR gene is directly related to the expansion and persistence of CAR-T cells, PK studies are necessary in the development of these ATMPs.

Therefore, unlike most ATMP products, the PK of CAR-T cells involves the evaluation of traditional ADME PK parameters, but these need to be interpreted in the context of cellular kinetic parameters indicative of expansion (C_max) and persistence (AUC, t_last). At Venn Life Sciences, our team of experienced consultants and data analysts has the expertise to support and manage PK analyses for new therapies like ATMPs.

Practical Aspects for PK for ATMP: CAR-T Cells as an Example

The PK profiles of CAR-T cells do not always reflect a traditional PK profile, and therefore the following practical aspects need to be taken into account:

• The resulting CAR-T concentrations can vary greatly between subjects due to multiple factors (such as prior therapy, disease type, presence of target, production of the CAR-T cells, etc.). A high tumour burden will potentially result in higher concentrations as more target is available, which drives CAR-T expansion. Therefore, the concentrations of the CAR-T cells may not be directly linked to the dose provided.
• It is expected that fluctuations will be observed, with concentrations below the LLOQ followed by increases back to measurable levels; therefore, all these concentrations are expected to be included in the description of the PK profile
• Multiple peaks can be expected (due to re-activation), which may be related to expansion in response to increased target presence.
• Since blood concentrations are related to the expansion phase of CAR-T cells, it can be expected that in cases where there is no activation (e.g. when the CAR-target specific antigen is not present on the tumour), no increase in concentrations will be detected after dosing.

Concluding Remarks

• There is no standard approach for PK studies of ATMPs, as the required PK assessments depend on the unique design of each ATMP
• In some cases, traditional PK assessments can be applied; however, practical aspects must be considered, as the PK of such ATMPs needs to be interpreted in the context of the biological design of the ATMPs, and standard approaches for conventional products may not be applicable
• Venn Life Sciences has over twenty years of PK consultancy and data analysis experience covering a diverse range of therapeutic areas and different classes of drugs, including ATMPs. We are capable of Adequately Tailoring & Managing Pharmacokinetic Studies for ATMPs and are happy to collaborate with clients, applying our expertise to ensure the best possible approach is aligned with their goals.

If you are interested in learning more about how we can support you with PK in ATMPs, please contact Venn Life Sciences at BD@vennlifesciences.com. We would welcome the opportunity to discuss PK in ATMPs and other related aspects.