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
Hemlibra: what was done before first-in-human, and what came after?
emicizumab · FIXa x FX
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 Hemlibra 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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: NOAEL 30 mg/kg/wk SC (26-week), ~11x clinical AUC; findings limited to injection-site reactions and aPTT shortening (EMA assessment report, p. 35)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week SC cynomolgus monkey study (weekly) with 13-week recovery
“A 26-week intermittent dose (once weekly, 27 doses) subcutaneous administration toxicity study of CH5534262 in mature cynomolgus monkeysfollowed by a 13-week recovery period / Study report no. 1060134”
Pivotal GLP studies
Cynomolgus: 4-week IV (up to 100 mg/kg/wk), 4- and 13-week SC, 26-week SC weekly (1, 6, 30 mg/kg)
“Repeat-dose toxicity was also evaluated in cynomolgus monkeys dosed once weekly in a 4-week IV dose toxicity study (1060140) and 4- and 13-week SC dose toxicity studies (1060133 and 1060134).”
DART package
Species: DART
Not conducted (hemophilia A is X-linked recessive)
“Animal reproductive and developmental toxicology studies were not conducted with emicizumab as hemophilia A is inherited in an X-linked recessive manner.”
Reproductive & developmental
Not conducted (99% of patients male); no reproductive organ effects in 26-week monkey study
“Animal reproductive and developmental toxicology studies were not conducted with emicizumab as hemophilia A is inherited in an X-linked recessive manner.”
PPND / ePPND: when
No PPND or other DART studies: hemophilia A is X-linked recessive (patients mostly male)
“Animal reproductive and developmental toxicology studies were not conducted with emicizumab as hemophilia A is inherited in an X-linked recessive manner.”
Carcinogenicity
Species: carcinogenicity
Not conducted (no pharmacologically relevant rodent species)
“Carcinogenicity studies were not conducted due to lack of a pharmacologically relevant rodent species.”
Carcinogenicity model
Not conducted (not active in mice or rats; restoring hemostasis not expected to increase tumorigenesis)
“Carcinogenicity studies have not been conducted with emicizumab because the product is not active in mice or rats; restoring hemostasis is not expected to increase the potential for tumorigenesis.”
Carcinogenicity timing
Not required; carcinogenicity assessment accepted and ECAC agreed no studies needed
“The ECAC agreed with the Division that there was no need for additional nonclinical carcinogenicity studies for emicizumab on August 7, 2015.”
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
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