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
Talvey: what was done before first-in-human, and what came after?
talquetamab · GPRC5D x CD3
Before first-in-human
First-in-human: where
US and ex-US (Belgium, France, Germany, Israel, Netherlands, Poland, Korea, Spain): first-in-human dose escalation/expansion
“Study Location: This study was conducted at 47 centers that treated at least 1 participant in Belgium, France, Germany, Israel, the Netherlands, Poland, Republic of Korea, Spain, and the United States.”
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 Talvey 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 adverse effects up to 30 mg/kg weekly (highest dose); transient lymphocyte decrease, increased globulins, fibrinogen, IL-10 (FDA multi-discipline review, p. 55)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week (weekly x4) IV cynomolgus monkey study with tool molecule JNJ-64024701; no recovery period
“Monkeys were administered JNJ64024701 as a once weekly (QW x 4) IV bolus injection (0 [control], 10, or 30 mg/kg), followed by sacrifice and necropsy on Day 29; there was no recovery period.”
Pivotal GLP studies
1-month GLP IV study of tool molecule in cynomolgus monkey (0, 10, 30 mg/kg weekly x4); non-GLP 4-week talquetamab tolerability study
“JNJ-64024701 (GCDB32 GPRC5DxCD3): A 1-Month GLP Intravenous Toxicity and Toxicokinetic Study in Cynomolgus Monkeys / Study T-2017-009”
DART package
Species: DART
Not conducted: monkey EFD/enhanced PPND with talquetamab or tool molecule judged not feasible (weight-of-evidence)
“Based on a weight-of-evidence risk assessment (Mod2.6.6/Sec6.2), an embryo-fetal development or enhanced pre- and postnatal development study in cynomolgus monkeys with talquetamab or the tool molecule would not be feasible nor further inform pregnancy risk to multiple myeloma patients.”
Reproductive & developmental
Not conducted (weight-of-evidence assessment; ADA limits exposure, no relevant species); reproductive organs examined in repeat-dose study
“We agree with the Applicant’s WOE-based approach for the assessment of reproductive and developmental toxicity.”
PPND / ePPND: when
Not conducted: monkey EFD or enhanced PPND with talquetamab or tool molecule judged not feasible and uninformative (weight of evidence)
“Based on a weight-of-evidence risk assessment (Mod2.6.6/Sec6.2), an embryo-fetal development or enhanced pre- and postnatal development study in cynomolgus monkeys with talquetamab or the tool molecule would not be feasible nor further inform pregnancy risk to multiple myeloma patients.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted with talquetamab. As indicated in the ICH S9 guidance, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted with talquetamab. As indicated in the ICH S9 guidance, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not required (FDA agrees not warranted)
“We agree that carcinogenicity studies are not warranted to support the approval of BLA 761342.”
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
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
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