Cell and gene therapies are changing the face of modern medicine – But how to find the right dose?

Diane Seimetz

by Diane Seimetz

Transition from nonclinical to clinical stage is an important step in drug development. Finding the right dose for the first in human study can be a challenging undertaking for biopharmaceuticals. For cell and gene therapy products (commonly referred to as ATMPs), this is even more challenging, as candidates of this product category rarely follow common principles such absorption, distribution, metabolization and excretion. Even Paracelsus’ toxicology principle “only the dose makes the poison” is in question, which was applicable for more than five centuries.

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A classical dose-response relationship typically does not apply for ATMPs. For example, cell-based products can proliferate, differentiate and even persist life-long in a different phenotype than initially administered. An example of CD-19 targeted CAR-T pharmacokinetic profile is shown in the following:

Figure 1: Pharmacokinetic profile of a CD-19 targeted CAR-T // Mueller KT et al., Blood Journal 2017


Figure 1: Pharmacokinetic profile of a CD-19 targeted CAR-T // Mueller KT et al., Blood Journal 2017

Furthermore, virus-based ATMPs such as oncolytic viruses can replicate in target tissues.

As the “acting dose” can be very different from the administered dose the dose finding exercise for ATMPs is often about finding answers to the question: How to dose a living drug?

While working on multiple ATMP projects, we have identified a set of key questions guiding a tailored dose-finding exercise. As an example, guiding questions for a genetically modified hematopoietic stem cell product is provided in the following:

  • What is the minimum number of cells typically needed for reconstitution?

  • Would the genetic modification require a different lower threshold?

  • What is the level of target protein needed to be expressed by the genetically modified cells?

  • What can we learn from animal studies incl. limitations thereof?

  • Would there be a concern with a high dose, if so, what would be the concern?

  • What is known from related cases, either in advanced development or approved?

  • Are there limits in terms of manufacturability?

Diane was presenting on dose finding strategies for ATMPs including selected case studies during the 26th Annual Congress of the European Society for Gene and Cell Therapy (ESGCT).

Biopharma Excellence has comprehensive expertise and a proven track record in the field of ATMPs. For examples of recent projects, please see the list on our website.

Interested in learning more about how YOUR cell and gene therapy projects can benefit from our expertise? Get in contact with us.

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