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
Rybrevant: what was done before first-in-human, and what came after?
amivantamab · EGFR x MET
Before first-in-human
First-in-human: where
US and ex-US (Australia, Canada, China, France, Japan, Korea, Spain, Taiwan, UK): first-in-human dose escalation/expansion in advanced NSCLC
“Ongoing Australia, Canada, China, France, Japan, Republic of Korea, Spain, Taiwan, UK, US 53 Phase 1 First-in-human, openlabel, 2- part, dose escalation and dose expansion, multicenter study Men and women ≥18 years of age with histologically or cytologically confirmed advanced NSCLC”
Repeat-dose tox before first-in-human
6-week GLP cynomolgus monkey IV study (0, 20, 60, 120 mg/kg/week) reviewed with the original IND
“Dr. Stephanie Aungst reviewed the 6-week GLP-compliant repeat dose toxicology study in cynomolgus monkeys dosed with JNJ-61186372 at 0, 20, 60, and 120 mg/kg/week at the time of original IND submission;”
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Rybrevant 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 120 mg/kg/wk (highest dose; >=5.3x human AUC); minimal liver, kidney, stomach findings (FDA multi-discipline review, p. 57)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey IV study, weekly 60 or 120 mg/kg
“Janssen conducted a GLP-compliant 13-week toxicology study in cynomolgus monkeys. Monkeys received intravenous amivantamab once weekly at doses of 0, 60, or 120 mg/kg.”
Pivotal GLP studies
Cynomolgus IV weekly: 4-week non-GLP tolerability, 6-week GLP (6-week recovery), 13-week GLP; 2-week SC local tolerance
“The repeat-dose toxicity of amivantamab in cynomolgus monkeys was evaluated in a 4-week tolerability non-GLP study, and 6-week toxicity with 6-week recovery and 13-week toxicity GLP studies.”
DART package
Species: DART
Not conducted; weight-of-evidence assessment instead
“Rather than conducting a dedicated embryofetal development study, Janssen provided a weight-of-evidence-based assessment of the potential for amivantamab to cause reproductive and embryofetal toxicity.”
Reproductive & developmental
Not conducted; weight-of-evidence (EGFR/MET knockouts, lazertinib rat EFD, zalutumumab monkey EFD); embryofetal warning
“Rather than conducting a dedicated embryofetal development study, Janssen provided a weight-of-evidence-based assessment of the potential for amivantamab to cause reproductive and embryofetal toxicity.”
PPND / ePPND: when
Not conducted: fertility and pre-/postnatal development studies not necessary for the BLA in this indication
“fertility and early embryonic development and prenatal and postnatal development studies are not necessary for the submission of a BLA for the proposed indication.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not necessary for advanced cancer)
“In addition, Janssen did not conduct dedicated studies to assess fertility or carcinogenicity as these studies are not necessary to support the development of a drug intended to treat patients with advanced cancer.”
Carcinogenicity model
Not conducted (not necessary for advanced cancer)
“In addition, Janssen did not conduct dedicated studies to assess fertility or carcinogenicity as these studies are not necessary to support the development of a drug intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not required (advanced cancer)
“In addition, Janssen did not conduct dedicated studies to assess fertility or carcinogenicity as these studies are not necessary to support the development of a drug intended to treat patients with advanced cancer.”
Same question, other multispecifics
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
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