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
Ziihera: what was done before first-in-human, and what came after?
zanidatamab · HER2 x HER2 (biparatopic)
Before first-in-human
First-in-human: where
North America and South Korea: first-in-human study ZWI-ZW25-101 in HER2-expressing cancers
“Supportive ZWI-ZW25-101 (Phase 1) NCT02892123 N Am (12) S Korea (5) Locally advanced (unresectable) and/or metastatic HER2-expressing cancers”
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 Ziihera 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 150 mg/kg QW x13 weeks (highest dose); only non-adverse soft/watery feces, mild BUN increase (FDA multi-discipline review, p. 44)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week weekly IV GLP cynomolgus monkey study (8-week interim termination) with 8-week recovery
“ZW25: A 13-Week Intravenous Infusion Toxicity Study With an 8-Week Interim Termination in Cynomolgus Monkeys With 8-Week Recovery Periods (GLP).”
Pivotal GLP studies
GLP cynomolgus 13-week weekly IV infusion study (8-week interim, 8-week recovery), 5/50/150 mg/kg
“Doses of 0 (vehicle control), 5, 50, and 150 mg/kg QW Route of administration: 1 hour IV infusion Formulation/Vehicle: sucrose, pH Species/Strain: Cynomolgus monkey”
DART package
Species: DART
Not conducted; HER2 antibody class embryo-fetal toxicity (weight of evidence)
“Consequently, the conduct of de novo developmental and reproductive toxicity (DART) studies is not warranted for zanidatamab.”
Reproductive & developmental
Not conducted; weight-of-evidence, HER2 antibody class embryo-fetal toxicant (oligohydramnios)
“Consequently, the conduct of de novo developmental and reproductive toxicity (DART) studies is not warranted for zanidatamab.”
PPND / ePPND: when
Not conducted: de novo developmental and reproductive toxicity studies not warranted (zanidatamab considered an embryofetal toxicant)
“Jazz proposes that zanidatamab should be considered an embryofetal toxicant. Consequently, the conduct of de novo developmental and reproductive toxicity (DART) studies is not warranted for zanidatamab.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“No carcinogenicity studies have been conducted with zanidatamab.”
Carcinogenicity model
Not conducted (ICH S9; advanced cancer, no mechanistic concern)
“Thus, given the intended patient population and lack of mechanistic concern, carcinogenicity studies are not planned with zanidatamab (ICH S9)”
Carcinogenicity timing
Not required; FDA: carcinogenicity studies not warranted
“Carcinogenicity studies were not warranted.”
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
Bizengri
zenocutuzumab · HER2 x HER3Not stated in public reviews
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