Inflammation and immunogenicity limit the utility of the rabbit as a nonclinical species for ocular biologic therapeutics.
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.
Safety Assessment, Genentech, Inc., South San Francisco, CA, United States. Electronic address: cdezafra@amgen.com.
Christina L Zuch
CLZ
de Zafra
Preclinical Safety, Novartis Institutes for BioMedical Research, Cambridge, MA, United States.
Vito G
VG
Sasseville
Nonclinical and Translational Sciences, Allergan, Irvine, CA, United States.
Steven
S
Matsumoto
Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland.
Christian
C
Freichel
Drug Metabolism and Pharmacokinetics, Novartis Institutes for BioMedical Research, Cambridge, MA, United States.
Mark
M
Milton
Preclinical Safety, Novartis Institutes for BioMedical Research, Cambridge, MA, United States.
Timothy K
TK
MacLachlan
Safety Assessment, Genentech, Inc., South San Francisco, CA, United States.
Cindy
C
Farman
Nonclinical and Translational Sciences, Allergan, Irvine, CA, United States.
Iona
I
Raymond
Nonclinical and Translational Sciences, Allergan, Irvine, CA, United States.
Swati
S
Gupta
Preclinical Safety, Novartis Institutes for BioMedical Research, Cambridge, MA, United States.
Ronald
R
Newton
Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland.
Elke-Astrid
EA
Atzpodien
Safety Assessment, Genentech, Inc., South San Francisco, CA, United States.
Evan A
EA
Thackaberry
D000818:Animals; D001688:Biological Products / Q000009:adverse effects*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005123:Eye / Q000276:immunology; D005128:Eye Diseases / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D011817:Rabbits; D013045:Species Specificity
D001688:Biological Products
3Rs; Anti-drug antibody; Biologic; Inflammation; Ocular; Ophthalmic; Rabbit