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
Lynozyfic: what was done before first-in-human, and what came after?
linvoseltamab · BCMA x CD3
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 Lynozyfic 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: 5-week: HNSTD 10 mg/kg/wk; 9/14-week: NOAEL not determined (early sacrifice at all doses; multi-organ inflammation, peritonitis/pleuritis, body weight loss) (EMA assessment report, p. 36)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9- or 14-week IV cynomolgus monkey study with 13-week recovery
“For the remaining animals the study was then divided into a 9-week (20 mg/kg group) or 14-week (1 and 5 mg/kg groups) repeat-dose study, each followed by a 13-week recovery phase.”
Pivotal GLP studies
GLP cynomolgus 5-week IV (0.1/1/10 mg/kg, 12-wk recovery) and 9- or 14-week IV (1/5/20 mg/kg, 13-wk recovery) studies
“Study R5458-TX-17179: A 5-Week Intravenous Infusion Toxicity and Toxicokinetic Study in Cynomolgus Monkeys With a 12-Week Dose-Free Recovery Phase”
DART package
Species: DART
Not conducted (weight-of-evidence risk assessment)
“No animal reproductive or developmental toxicity studies have been conducted with linvoseltamab.”
Reproductive & developmental
Not conducted; weight-of-evidence (T-cell activation, cytokine release, B-cell depletion, placental IgG transfer)
“The Applicant provided a weight of evidence (WOE)-based risk assessment to assess the potential for reproductive and developmental toxicities.”
PPND / ePPND: when
Not conducted: no animal reproductive or developmental toxicity studies; immune activation may compromise pregnancy maintenance
“No animal reproductive or developmental toxicity studies have been conducted with linvoseltamab. Linvoseltamab causes T cell activation and cytokine release; immune activation may compromise pregnancy maintenance.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9, advanced malignancies)
“As linvoseltamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with linvoseltamab, consistent with ICH S9 guideline Nonclinical Evaluation of Anticancer Pharmaceuticals.”
Carcinogenicity model
Not conducted (ICH S9, advanced malignancies)
“As linvoseltamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with linvoseltamab, consistent with ICH S9 guideline Nonclinical Evaluation of Anticancer Pharmaceuticals.”
Carcinogenicity timing
Not required (ICH S9)
“As linvoseltamab is intended for use in patients with advanced malignancies, carcinogenicity studies were not conducted with linvoseltamab, consistent with ICH S9 guideline Nonclinical Evaluation of Anticancer Pharmaceuticals.”
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
Kimmtrak
tebentafusp · CD3 x gp100 (TCR fusion)Not stated in public reviews
Korjuny
catumaxomab · EpCAM 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