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
Kimmtrak: what was done before first-in-human, and what came after?
tebentafusp · CD3 x gp100 (TCR fusion)
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 Kimmtrak 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: No NOAEL (no animal tox); in vitro reactivity vs melanocytes at 10-100 pM, loss of specificity from 1 nM (FDA multi-discipline review, p. 41)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (human HLA-restricted; all toxicology in vitro)
“Tebentafusp can only recognize human HLA; therefore, all nonclinical toxicology studies were conducted in vitro.”
Pivotal GLP studies
No in vivo tox; GLP human tissue cross-reactivity (35 tissues) plus in vitro normal-cell, alloreactivity, whole-blood cytokine, platelet assays
“Tebentafusp was also investigated in toxicology studies to assess its cross‐reactivity with normal tissues in a GLP‐compliant tissue cross‐reactivity study.”
DART package
Species: DART
Not conducted (specificity for human targets)
“Due to the specificity for human targets, embryo-fetal development (EFD) studies cannot be conducted in nonclinical species.”
Reproductive & developmental
Not conducted (no relevant species); weight-of-evidence; FDA concluded possible fetal harm to skin, inner ear, eye
“Due to the specificity for human targets, embryo-fetal development (EFD) studies cannot be conducted in nonclinical species. Therefore, a weight of evidence assessment was conducted to evaluate the risk of tebentafusp administration on pregnancy and embryo-fetal development.”
PPND / ePPND: when
No PPND or other in vivo DART studies (no relevant species); weight-of-evidence assessment
“Due to the specificity for human targets, embryo-fetal development (EFD) studies cannot be conducted in nonclinical species. Therefore, a weight of evidence assessment was conducted to evaluate the risk of tebentafusp administration on pregnancy and embryo-fetal development.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity or genotoxicity studies have been conducted with tebentafusp-tebn.”
Carcinogenicity model
Not conducted (not warranted for the advanced-cancer indication)
“The FDA’s Assessment: Carcinogenicity studies were not warranted for the proposed indication.”
Carcinogenicity timing
Not required for the proposed indication
“The FDA’s Assessment: Carcinogenicity studies were not warranted for the proposed indication.”
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
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
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