Inflammation and immunogenicity limit the utility of the rabbit as a nonclinical species for ocular biologic therapeutics

- Toxicology studies of novel medicines are typically conducted in both rodents and non-rodents.
- Rabbits are often used as a second species for the safety evaluation of ocular biologic drugs.
- Confounding factors preclude the interpretation of safety in these rabbit toxicology studies.
- Support for Phase I clinical trials is thus based primarily on non-human primate toxicology data.
- Toxicology studies of ocular biologic drug candidates in rabbits should not be conducted.

The nonclinical safety evaluation of therapeutic drug candidates is commonly conducted in two species (rodent and non-rodent) in keeping with international health authority guidance. Biologic drugs typically have restricted species cross-reactivity, necessitating the evaluation of safety in non-human primates and thus limiting the utility of lower order species. Safety studies of cross-reactive ocular biologic drug candidates have been conducted in rabbits as a second toxicology species, despite the fact that rabbits are not a rodent species. Such studies are often confounded by the development of anti-drug antibodies and severe ocular inflammation, the latter requiring studies to be terminated prematurely for animal welfare reasons. Notably, these confounding factors preclude the interpretation of safety. Nonclinical toxicology programs should be designed with consideration of ethical animal use and 3Rs principles (Replacement, Reduction and Refinement). The experience of several pharmaceutical sponsors, demonstrating that toxicology studies of ocular (intravitreal and topical ocular) biologic drug candidates in the rabbit are of limited interpretive value, calls into question the utility of such studies in this species and indicates that such studies should not be conducted.