Traditionally, the selection of relevant species for non-clinical studies, as part of the preclinical drug development phase, has been a fairly straightforward process. This consists of new drugs assessed in two species, typically the rat and dog. However, with the introduction of biologics, preclinical species selection has become much more of a case by case process, and as a result target-specific pharmacology plays a critical role, for both biologics and increasingly small molecule drugs.
With this in mind, it’s important you consider preclinical species selection as early as possible in the drug development process, to ensure you’re prepared to provide regulators with justification as to why the chosen species is the most suitable for your therapeutic.
Here, we take a look at the necessary considerations you need to be aware of where species selection is concerned, for both biologics and small molecule drugs.
Species selection for biologics: what you need to know
The goal of performing non-clinical safety assessment in one rodent and one non-rodent species remains relevant, however, for Biologics the most important consideration when selecting species is pharmacological relevance.
It’s well accepted that dose-limiting effects associated with biologics are linked to exaggerated pharmacology rather than the kind of off-target toxicity generally associated with xenobiotic. The products themselves are generally relatively well tolerated. As a result, it’s important you perform non-clinical safety assessment in species in which the intended pharmacology is present, and ideally, closely resembles the effects anticipated, following dose administration to humans.
Therefore, when selecting the species, you should always base this on the knowledge of the drug-specific pharmacology, and confirmation that this is replicated in the selected non-clinical species.
At this stage, be sure to have a good understanding of any differences in the level of expression of the target, or cell populations and biological pathways affected by target ligation. It’s also imperative that you compare the results in the candidate non-clinical species to those in human samples.
Where this comparative data is not already available, you may have to perform in vitro assays measuring the relevant pharmacology to confirm whether a species is relevant. Simply comparing homology of the target at the amino acid sequence level, or even confirming binding to the target may not be sufficiently informative to select a species, as this may not lead to induction of the intended pharmacology.
What do the regulators expect?
The importance of this data cannot be over-emphasized; regulators won’t want to see studies performed in non-relevant species and confirming the intended biology is therefore crucial. In fact, it determines whether a standard two species approach or a single species program should be performed.
Where only a single pharmacologically relevant species is identified, non-clinical safety assessment studies can be justified in this species alone and there are many precedents for this approach, particularly for the assessment of monoclonal antibodies.
There is often a misconception that biologics safety will need to be assessed in a non-human primate, simply because other products in this class have been assessed in this species.
This isn’t strictly true, and as discussed above, biologics should only be assessed in pharmacologically relevant species. Often this is the non-human primate, however, you shouldn’t consider this a default, there are many examples where other species are relevant. You will also need to provide data confirming both the lack of relevance of other species such as the dog and mini-pig as well as the primate’s relevance to be able to carry out studies in this species.
Additional considerations such as hypersensitivity or immunogenicity can also be relevant, although again, you will need evidence to confirm the other species is unsuitable to support your studies in the non-human primate.
Have a product which falls between a large and small molecule classification?
If you’re developing therapeutics which fall between large and small molecule classification such as, oligonucleotides and chemically synthesized peptides, you should also consider approaching these with a hybrid NCE/Biologics strategy. For these products, the regulators are likely to request that you undertake an NCE-style safety assessment program in two species, one rodent and one non-rodent.
Although these products are chemically synthesized, the way in which they mediate their effects in vivo is completely dependent on appropriate pharmacology, as they require both specific target sequences and downstream biology. In this instance, assessment in at least one pharmacologically relevant species should be conducted.
Where you can only identify one pharmacologically relevant species, you may find that the regulators want two species to be used, and a surrogate molecule generated to enable on-target pharmacology to be assessed in the otherwise non-relevant species. Alternatively, they may request assessment in a second species using the clinical product, even though it might be non-relevant in order to assess the off-target toxicity traditionally observed with small molecule drugs. If you are working with a product such as this, you should engage in discussion with the regulators at an early stage so you can be confident your non-clinical safety program will generate a data set that will fulfil their requirements.
Selection of appropriate species for assessment of the safety of novel drugs is a critical step for ensuring you are successful in progressing to the clinic —and it’s not a default process!
Not sure where to start?
Take a stepwise approach and be sure to have a thorough understanding of your product and where relevant, its pharmacology. It will be critical in selecting those species which will enable generation of the most appropriate data set and will ultimately inform the safety profile of your product.
Additionally, seeking advice from a contract research organization that has extensive experience of interacting with the regulators will help you navigate your species selection strategy.
Species selection is just one of the areas to consider early on in the drug development phase. Learn more about some of the other considerations in our ‘How to plan and conquer the drug development process in the early stages’ article.