Repatha: which tox species, and why?

“The Applicant identified the hamster and monkey as pharmacologically relevant species for toxicology testing with evolocumab; both species express PCSK9, to which evolocumab binds with high affinity.”

“Evolocumab binds to human, cynomolgus monkey and hamster PCSK9 with high affinity (KD = 16, 8 and 14 pM, respectively; see Table 2).”

“Evolocumab is pharmacological active in human, Cynomolgous monkey and hamster. The latter two were used in toxicology studies, where also the pharmacodynamics parameters were measured.”

“The primary nonclinical toxicity studies of evolocumab were conducted in hamsters for up to 3 months and monkeys for up to 6 months duration with once weekly subcutaneous dosing.”

“The nonclinical reproductive and developmental safety profile of evolocumab was informed by three studies: (1) an enhanced pre-postnatal development study in cynomolgus monkeys, (2) a fertility and early embryonic development study in hamsters and (3) assessment of male and female fertility endpoints in the 6 month cynomolgus monkey study.”

“Evolocumab did not cause any drug-related tumors when administered to hamsters for up to 2 years in a lifetime carcinogenicity assay at doses administered once every other week that provide a 38-, 15- and 6.6-fold safety margin for evolocumab at the recommended human doses of 140 mg Q2W, 420 mg QM and 420 mg Q2W administered subcutaneously.”

“The Applicant identified the hamster and monkey as pharmacologically relevant species for toxicology testing with evolocumab; both species express PCSK9, to which evolocumab binds with high affinity.”