Vabysmo

“She agreed, as the Applicant proposed, that the monkey alone should be used in the planned 6-month chronic toxicity study.”

“The monkey was selected as the most relevant species based on 100% sequence homology (VEGF) and binding affinity (Ang-2) comparable to humans.”

“Faricimab (RO6867461) bound to full length Ang 2 with high affinity across species including human, cynomolgus monkey, rabbit, and mouse, measured by Surface Plasmon Resonance (SPR).”

“Repeat-dose toxicity studies of up to 2 weeks in rabbits and up to 6 months in cynomolgus monkeys have been conducted.”

“A pre- and postnatal development study could not be conducted in cynomolgus monkeys due to ADA formation and exposure loss observed in general toxicology studies preventing sufficient systemic exposure with faricimab in such a study.”

“No standard rodent carcinogenicity studies have been conducted as faricimab showed no relevant binding to mouse or rat VEGF-A.”

“In summary, no target-related toxicological changes were observed up to the highest doses tested with faricimab including the evaluation of repeat-dose toxicity, male and female fertility, and embryofetal development using cynomolgus monkeys, the only feasible species cross-reactive to faricimab.”

“The 26-week IVT monkey study (report # 1057630) was submitted in draft form on 3/24/2015 (SD # 21), and in final form on 7/27/2015 (SD # 24).”

“Study # 1053361, 2-Month Toxicity and Toxicokinetic Study with RO6867461 Following Intravitreous and Intravenous Administration in Cynomolgus Monkeys with a 4-Week Recovery Phase”

“Safety pharmacology endpoints were included as part of the 2-month cynomolgus monkey study (neurological exam, respiration rate, body temperature) following IVT (1.5 to 6 mg/eye, once monthly, one eye dosed) and IV dosing (5 mg/kg once monthly)”

“In accordance with ICH S6(R1) guidance, standard genotoxicity studies were not conducted with faricimab.”

“No standard rodent carcinogenicity studies have been conducted as faricimab showed no relevant binding to mouse or rat VEGF-A.”

“An embryofetal development (EFD) study in cynomolgus monkeys showed an increase incidence of abortions in faricimab treated monkeys at IV doses of 1 or 3 mg/kg administered weekly on gestation days 20 to 48.”

“Stand-alone safety pharmacology studies were not performed.”

“In accordance with ICH S6(R1) guidance, standard genotoxicity studies were not conducted with faricimab.”

“In accordance with ICH S6(R1) guidance, standard genotoxicity studies were not conducted with faricimab.”

“In accordance with ICH S6(R1) guidance, standard genotoxicity studies were not conducted with faricimab.”

“No standard rodent carcinogenicity studies have been conducted as faricimab showed no relevant binding to mouse or rat VEGF-A.”

“No standard rodent carcinogenicity studies have been conducted as faricimab is not fully cross-reactive in rodents. The intended anti-angiogenic effects of faricimab and the weight of evidence do not suggest a carcinogenic potential of faricimab.”

“In both studies, heart rate and ECG endpoints, including QT and QTc, were comparable between control and faricimab-dosed groups.”

“The proposed clinical starting dose of 0.5 mg/eye is supported by the nonclinical data but the high dose of 6.0 mg/eye is not.”

“For ocular toxicity, the NOAEL was 0.5 mg/eye (the low dose). The LOAEL was 1.5 mg/eye (the mid-dose), due to ocular inflammation (observed by ophthalmology and confirmed by histopathology).”

“These data support that the ocular findings were primarily related to ADA formation and not a direct pro-inflammatory effect of faricimab.”

“Bioavailability was 2.2% in the rabbit and 13% in the cynomolgus monkey.”

“The main adverse findings identified in the nonclinical studies were ocular inflammation and various findings in the heart in both rabbits and monkeys.”

“A correlation between ADA development and reduced systemic exposure was observed in both 2- and 6-month GLP toxicology studies; this did not compromise the overall readout of the studies because there was still sufficient exposure in ADA-positive animals.”

“In the nAMD, DME, and RVO studies, the pre-treatment incidence of anti-faricimab antibodies was approximately 0.8 to 1.8%. After initiation of dosing, the incidence of anti-faricimab antibodies was approximately 8% to 10.4% in patients treated with VABYSMO across studies.”

“The following studies were reviewed under the initial IND by Dr Lansita (9-23- 2013).  Study # 1053361, 2-Month Toxicity and Toxicokinetic Study with RO6867461 following Intravitreous and Intravenous Administration in Cynomolgus Monkeys with a 4-Week Recovery Phase”

“The proposed clinical starting dose of 0.5 mg/eye is supported by the nonclinical data but the high dose of 6.0 mg/eye is not.”

“Study # 8292406, 26-Week Partial Ascending-Dose Toxicity and Toxicokinetic Study Following Once Monthly Intravitreous Injections in Cynomolgus Monkeys with a 13-Week Recovery”

“Study # 1053361, 2-Month Toxicity and Toxicokinetic Study with RO6867461 Following Intravitreous and Intravenous Administration in Cynomolgus Monkeys with a 4-Week Recovery Phase”

“A pre- and postnatal development study could not be conducted in cynomolgus monkeys due to ADA formation and exposure loss observed in general toxicology studies preventing sufficient systemic exposure with faricimab in such a study.”

“An embryofetal development (EFD) study in cynomolgus monkeys showed an increase incidence of abortions in faricimab treated monkeys at IV doses of 1 or 3 mg/kg administered weekly on gestation days 20 to 48.”

“A pre- and postnatal development study could not be conducted in cynomolgus monkeys due to ADA formation and exposure loss observed in general toxicology studies preventing sufficient systemic exposure with faricimab in such a study.”

“No standard rodent carcinogenicity studies have been conducted as faricimab showed no relevant binding to mouse or rat VEGF-A.”

“No standard rodent carcinogenicity studies have been conducted as faricimab showed no relevant binding to mouse or rat VEGF-A.”

“No standard rodent carcinogenicity studies have been conducted as faricimab is not fully cross-reactive in rodents. The intended anti-angiogenic effects of faricimab and the weight of evidence do not suggest a carcinogenic potential of faricimab.”

“the exposure margin at the NOAEL of 0.5 mg/eye/dose (based on the animal immune mediated ocular effects in the 6 month monkey study) with mean AUC(0-72h) = 20200 ng•hr/mL and a mean Cmax = 220 ng/mL on Day 141, is only around 1 when compared to values of human exposure”

“For ocular toxicity, the NOAEL was 0.5 mg/eye (the low dose). The LOAEL was 1.5 mg/eye (the mid-dose), due to ocular inflammation (observed by ophthalmology and confirmed by histopathology).”

“In a laser-induced model of choroidal neovascularization (CNV) in cynomolgus monkeys, faricimab reduced the formation of CNV and subsequent injury to the retina due to lesion formation to a significantly greater degree compared to anti-VEGF-A monoclonal antibody (mAb) alone.”

“An alternative rodent model for DME was not tested because the antibody in question reacts with human VEGF-A antigen and not with rodent, so classical animal models of diabetes could not work according to the applicant.”

“The CHMP noted that the Applicant presented the in vivo experimental model only for nAMD and not for DME, in contrast with the intended indications of faricimab.”