Lunsumio
mosunetuzumab · CD20 x CD3US, Republic of Korea, Canada: dose-escalation part (Group A) of study GO29781 in patients with R/R B-cell NHL
Bizengri: what was done before first-in-human, and what came after?
zenocutuzumab · HER2 x HER3
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.”
Same question, other multispecifics
Rybrevant
amivantamab · EGFR x METUS and ex-US (Australia, Canada, China, France, Japan, Korea, Spain, Taiwan, UK): first-in-human dose escalation/expansion in advanced NSCLC
Talvey
talquetamab · GPRC5D x CD3US and ex-US (Belgium, France, Germany, Israel, Netherlands, Poland, Korea, Spain): first-in-human dose escalation/expansion
Tecvayli
teclistamab · BCMA x CD3US and ex-US (Belgium, Canada, France, Germany, Italy, Netherlands, Spain, Sweden, UK): first-in-human study
Ziihera
zanidatamab · HER2 x HER2 (biparatopic)North America and South Korea: first-in-human study ZWI-ZW25-101 in HER2-expressing cancers
Blincyto
blinatumomab · CD19 x CD3Not stated in public reviews
Columvi
glofitamab · CD20 x CD3Not stated in public reviews
Elrexfio
elranatamab · BCMA x CD3Not stated in public reviews
Epkinly
epcoritamab · CD20 x CD3Not stated in public reviews
Hemlibra
emicizumab · FIXa x FXNot stated in public reviews
Imdelltra
tarlatamab · DLL3 x CD3Not stated in public reviews
Kimmtrak
tebentafusp · CD3 x gp100 (TCR fusion)Not stated in public reviews
Korjuny
catumaxomab · EpCAM x CD3Not stated in public reviews
Lynozyfic
linvoseltamab · BCMA x CD3Not stated in public reviews
Ordspono
odronextamab · CD20 x CD3Not stated in public reviews
Removab
catumaxomab · EpCAM x CD3Not stated in public reviews
Vabysmo
faricimab · VEGF-A x Ang-2Not stated in public reviews