Module 9 2024

03/09/2024

Nonclinical testing of biologics Step 1 – Selection of relevant animal species

• IMPORTANT : Toxicology studies on NBEs should ONLY be conducted in species which are pharmacologically relevant “Toxicity studies in non -relevant species may be misleading and are discouraged. ” (ICH S6, R1)

• This is a key difference between NBEs and NCEs….

• Species selection is a carefully considered and proactive decision

• Use of 2 species is still the default position but ONLY if both are pharmacologically relevant - If the target has evolved significantly over time, it will often discount more common species such as rodents and dogs as they are too distal to the human on the evolutionary tree • Immunogenicity of biologics in rodents, dogs and mini-pigs is also a concern, as high levels of immunogenicity would also prevent their use in chronic studies • If NO relevant species, alternative models can be considered e.g. surrogate biologic, use of humanised transgenic mice…. → Considered case-by-case and must be justified – Scientific Advice useful

• Species selection must also be justified to external Ethics at CROs and to Health Authorities receiving CTAs/INDs

The Organisation for Professionals in Regulatory Affairs

Preclinical Testing of Biologicals – Sept 2024

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Prior H et al (2020). Justification for species selection for pharmaceutical toxicity studies. Tox Res. 9:758-770.

Nonclinical testing of biologics Step 1 (cont’d) – Selection of relevant animal species

How can we demonstrate that the tox species is pharmacologically relevant?

Key Criteria :

1. High target sequence homology to human → e.g. Gene and Protein Atlas 2. Similar target binding affinity to human → e.g. BIAcore, ELISA, Cell-based assays

3. Similar target expression and distribution to human 4. Achievable target occupancy and target kinetics

5. Functional equivalence of pharmacodynamic effects in vitro and/or in vivo (IC 50 /EC 50 ) → Much more than just demonstrating binding to target – need to show the pharmacology/biology is the same/similar and, if not, understand the gaps Also important to have sufficient knowledge of MoA to understand if nonclinical species should react similarly and thus be able to predict potential human toxicities • TGN1412 FIH Trial led to catastrophic effects in Healthy Volunteers → - Relative potency differed markedly between humans & primates - Primate immune pathway was significantly different from human, particularly for this target, CD28 - Difference between humans and primates not well understood before entering clinical study

The Organisation for Professionals in Regulatory Affairs

Preclinical Testing of Biologicals – Sept 2024

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