Vabysmo
faricimab
Species
MonkeyRabbit
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Conducted Stated
Speciesopen answer page →
Species
Cynomolgus monkey only for pivotal tox (rabbit dropped after early studies)
“She agreed, as the Applicant proposed, that the monkey alone should be used in the planned 6-month chronic toxicity study.”
Why that species
100% VEGF sequence homology and comparable Ang-2 binding affinity in monkey; rabbit unsuitable (severe toxicity, ADA)
“The monkey was selected as the most relevant species based on 100% sequence homology (VEGF) and binding affinity (Ang-2) comparable to humans.”
Surrogate molecule
No surrogate; clinical molecule tested in monkey (and rabbit in early studies)
“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).”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“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).”
Pivotal GLP studies
GLP 2-month IVT/IV monkey study with 4-week recovery; 26-week monthly IVT monkey study with 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”
Route in tox
Intravitreal (monthly, one eye) plus IV arms; IV for EFD study
“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)”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“In accordance with ICH S6(R1) guidance, standard genotoxicity studies were not conducted with faricimab.”
Carcinogenicity
Not conducted (no rodent VEGF-A binding); weight-of-evidence carcinogenicity assessment document
“No standard rodent carcinogenicity studies have been conducted as faricimab showed no relevant binding to mouse or rat VEGF-A.”
Reproductive & developmental
Monkey EFD (IV, GD20-48): non-dose-dependent increase in abortions, no NOAEL; fertility via 6-month study organ histology
“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.”
Safety pharmacology
No stand-alone studies; endpoints in 2-month and 6-month monkey tox studies
“Stand-alone safety pharmacology studies were not performed.”
First doseopen answer page →
First-in-human starting dose
Starting dose 0.5 mg/eye IVT supported by monkey tox data (6 mg/eye high dose not initially supported; dose escalation gated)
“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.”
NOAEL / key findings
Ocular NOAEL 0.5 mg/eye (ADA-linked ocular inflammation at ≥1.5 mg/eye); systemic NOAEL 1.5 mg/eye; heart squamous cyst/plaque at high dose
“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).”
Risksopen answer page →
Immune & cytokine safety
ADA-driven immune-complex ocular inflammation in monkey; minimal in vitro cytokine release or complement activation
“These data support that the ocular findings were primarily related to ADA formation and not a direct pro-inflammatory effect of faricimab.”
Biodistribution & persistence
Low systemic bioavailability after IVT (2.2% rabbit, 13% monkey); faster clearance from FcRn-silenced Fc; vitreous cleared after recovery
“Bioavailability was 2.2% in the rabbit and 13% in the cynomolgus monkey.”
Modality-specific risk
Intraocular inflammation/immunogenicity and possible heart findings; anti-angiogenic reproductive risk
“The main adverse findings identified in the nonclinical studies were ocular inflammation and various findings in the heart in both rabbits and monkeys.”