Bizengri
zenocutuzumab
Sources:FDA multi-discipline review ↗
Species
Monkey
Longest study
13 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“The cynomolgus monkey was utilized as the only pharmacologically relevant species for toxicity testing, in view of cross reactivity of MCLA-128 with the HER2/HER3 targets in this species.”
Why that species
Binds human and monkey HER2/HER3 (98-99% sequence identity); anti-HER2 Fab does not bind rodent HER2
“Together, these results support the use of cynomolgus monkeys as the pharmacologically relevant species for zenocutuzumab toxicity assessment.”
Surrogate molecule
No surrogate; clinical molecule (MCLA-128) tested in cynomolgus monkey
“Toxicokinetic (TK) characteristics of MCLA-128 (zenocutuzumab) were studied as part of single and repeated dose toxicity studies in cynomolgus monkeys, the pharmacologically relevant species.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“The Applicant evaluated the safety of zenocutuzumab in GLP-compliant 1-month and 13-week repeat-dose toxicology studies in cynomolgus monkeys with the intended IV route of administration.”
Pivotal GLP studies
GLP cynomolgus 1-month (5 weekly IV doses, 8-wk recovery) and 13-week (weekly IV, 6-wk recovery) studies; 10/30/101 mg/kg
“In the 13-week repeat-dose toxicology study in monkeys, zenocutuzumab was intravenously administered at 10, 30, and 101 mg/kg once weekly for 13 weeks, followed by a 6-week recovery period.”
Route in tox
IV infusion (1 h)
“Method of Administration: IV infusion (1 h) on Days 1, 8, 15, 22, and 29”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Standard genotoxicity studies are not considered appropriate for this class of biological product, in line with the ICH S6 (R1) guideline.”
Carcinogenicity
Not conducted (ICH S6(R1), ICH S9)
“Carcinogenicity studies have not been performed with MCLA-128 as they are not considered appropriate for this class of biological product, in line with the ICH S6 (R1) and ICH S9 guidelines.”
Reproductive & developmental
Not conducted; literature weight-of-evidence (HER2/HER3 essential for embryo-fetal development); boxed warning
“The Applicant did not conduct reproductive or embryo-fetal developmental toxicology studies with zenocutuzumab.”
Safety pharmacology
Incorporated into repeat-dose monkey studies (ECG, BP, respiration, temperature, CNS); no effects
“Stand-alone safety pharmacology studies were not conducted. Safety pharmacology was evaluated as part of the general toxicology studies performed with MCLA-128.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
NOAEL 100 mg/kg/wk (1-month) and 101 mg/kg/wk (13-week) per applicant; FDA noted 2 early deaths/moribund, immune-mediated infusion reaction, GI lesions, skin, adrenal
“The Applicant suggests that these findings were unrelated to zenocutuzumab as comparable findings were not observed in animals that showed higher zenocutuzumab exposure compared to the mid-dose animal”
Risksopen answer page →
Immune & cytokine safety
Low whole-blood cytokine release; cytokine release (IFN-g, IL-6, IL-8, TNF-a) when target and effector cells co-cultured; ADA in ~1/3 of monkeys
“In vitro cytokine release studies using whole human blood from healthy donors showed only slight increases in cytokine levels.”
Biodistribution & persistence
No distribution studies (ICH S6(R1)); limited distribution outside vascular compartment
“No distribution studies were performed.”
Modality-specific risk
Embryo-fetal toxicity (HER2/HER3 class effect; boxed warning); diarrhea/GI, skin, infusion reaction
“FDA recommends including a box warning for embryo-fetal toxicity and advising females of reproductive potential to use effective contraception”