Bizengri
zenocutuzumab
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.”
Species: general tox
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.”
Species: DART
Not conducted; literature-based weight-of-evidence assessment (HER2/HER3 role in embryo-fetal development)
“The Applicant did not conduct reproductive or embryo-fetal developmental toxicology studies with zenocutuzumab. Rather, the Applicant provided a literature-based weight-of-evidence (WOE) assessment of the potential reproductive toxicity of zenocutuzumab based on its mechanism of action”
Species: carcinogenicity
Not conducted (not appropriate for antibody-based therapies)
“Carcinogenicity and genetic toxicology studies with zenocutuzumab were not conducted as they are generally not appropriate for antibody-based therapies.”
Surrogate used in
No surrogate used; clinical molecule 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.”
Genotox: Ames
Not conducted (ICH S6)
“Standard genotoxicity studies are not considered appropriate for this class of biological product, in line with the ICH S6 (R1) guideline.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Standard genotoxicity studies are not considered appropriate for this class of biological product, in line with the ICH S6 (R1) guideline.”
Genotox: in vivo
Not conducted (ICH S6)
“Standard genotoxicity studies are not considered appropriate for this class of biological product, in line with the ICH S6 (R1) guideline.”
Carcinogenicity model
Not conducted (ICH S6(R1) and 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.”
Carcinogenicity timing
Not required; FDA agreed carcinogenicity studies not warranted
“FDA agrees that carcinogenicity studies are not warranted to support this BLA submission.”
hERG / QT
No hERG assay; no ECG, blood pressure or respiratory effects in monkey repeat-dose studies up to 101 mg/kg/week
“No effect was observed on ECG, blood pressure, respiration rate, body temperature or CNS safety pharmacology parameters evaluated as part of the general toxicology studies performed in cynomolgus monkeys with MCLA-128 up to 101 mg/kg/week”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Bizengri don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
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 (FDA multi-discipline review, p. 58)
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”
Anti-drug antibodies: animals
ADA in monkeys likely reduced exposure in individual animals, causing loss of dose proportionality
“This lack of dose proportionality was likely the result of reduced exposure in individual animals due to ADA formation.”
Anti-drug antibodies: patients
8% (15/188) treatment-emergent ADA; 60% (9/15) of these neutralizing
“In patients who received zenocutuzumab-zbco at the approved recommended dosage for up to 30 months, 8% (15/188) of patients developed treatment-emergent anti-zenocutuzumab antibodies. Of the patients who developed treatment-emergent anti-zenocutuzumab antibodies, 60% (9/15) patients also developed neutralizing antibodies.”
Label warnings
Boxed warning: Embryo-fetal toxicity
- Infusion-Related Reactions/Hypersensitivity/Anaphylactic Reactions
- Interstitial Lung Disease/Pneumonitis
- Left Ventricular Dysfunction
- Embryo-Fetal Toxicity
Embryo-fetal toxicityHypersensitivity & infusion reactionsImmune-mediated reactionsPulmonary toxicityCardiovascular
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Bizengri don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
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 (FDA multi-discipline review, p. 58)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week IV cynomolgus monkey study (weekly doses) with 6-week recovery
“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.”
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.”
DART package
Species: DART
Not conducted; literature-based weight-of-evidence assessment (HER2/HER3 role in embryo-fetal development)
“The Applicant did not conduct reproductive or embryo-fetal developmental toxicology studies with zenocutuzumab. Rather, the Applicant provided a literature-based weight-of-evidence (WOE) assessment of the potential reproductive toxicity of zenocutuzumab based on its mechanism of action”
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.”
PPND / ePPND: when
No PPND or other reproductive/developmental studies; literature-based weight-of-evidence assessment instead
“Reproductive and developmental toxicology studies have not been performed. The Sponsor is of the opinion that sufficient data are available in the public domain to assess a hazard to reproduction for MCLA-128”
Carcinogenicity
Species: carcinogenicity
Not conducted (not appropriate for antibody-based therapies)
“Carcinogenicity and genetic toxicology studies with zenocutuzumab were not conducted as they are generally not appropriate for antibody-based therapies.”
Carcinogenicity model
Not conducted (ICH S6(R1) and 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.”
Carcinogenicity timing
Not required; FDA agreed carcinogenicity studies not warranted
“FDA agrees that carcinogenicity studies are not warranted to support this BLA submission.”
Safety marginopen answer page →
Safety margin at NOAEL
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenografts: HER2+ breast cancer (JIMT-1) and NRG1 fusion-positive lung and pancreatic patient-derived xenografts
“In vivo, zenocutuzumab showed antitumor activity in a HER2-positive breast cancer cell line xenograft model, which was associated with inhibition of HER2:HER3 dimerization and PI3K/Akt signaling.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
FDA: in vitro and xenograft/PDX studies support the proposed mechanism of action; nonclinical data adequate for approval
“derived xenograft (PDX) models. These studies support the proposed mechanism of action of zenocutuzumab.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No reproductive or developmental toxicity studies; literature-based weight-of-evidence assessment of HER2/HER3 inhibition instead
Why: Mechanism-based literature weight of evidence, an alternative approach described in FDA oncology reproductive toxicity guidance · Within the guideline · Weight of evidence · Pharmacology or kinetics
“Rather, the Applicant provided a literature-based weight-of-evidence (WOE) assessment of the potential reproductive toxicity of zenocutuzumab based on its mechanism of action, consistent with the alternative approach described in the FDA Guidance for Industry, Oncology Pharmaceuticals: Reproductive Toxicity Testing and Labeling Recommendations.”
“FDA agreed that the weight-of-evidence approach for reproductive risk assessment appeared acceptable and sufficient to support the filing of a BLA.”
Similar precedents
ZiiheraMultispecifics · zanidatamab · HER2 x HER2 (biparatopic)Monkey only · 13 wkHerceptinAntibodies · trastuzumab · HER2Monkey only · 26 wkMargenzaAntibodies · margetuximab · HER2Monkey only · 13 wkPerjetaAntibodies · pertuzumab · HER2Monkey only · 26 wkEnhertuADCs · fam-trastuzumab deruxtecan · HER2Monkey + rodent · 13 wkHernexeosSmall molecules · zongertinib · HER2 (mutant)Rodent + dog or minipig · 13 wk