Enhertu
fam-trastuzumab deruxtecan · HER2Japan and US: multicenter first-in-human study (Study DS8201-A-J101)
Emrelis: what was done before first-in-human, and what came after?
telisotuzumab vedotin · c-Met
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 Emrelis 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 ADCs
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: 13-week cyno: no adverse findings to 3 mg/kg; 4-week: neutropenia/marrow at ≥6 mg/kg, ovary/uterus ≥3 mg/kg, eye, thymus (FDA multi-discipline review, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey IV study (every 2 weeks, seven doses) with 8-week recovery
“In the 13-week GLP-compliant repeat-dose toxicology study in monkeys (Report No. R&D/18/0622, Study No. 2100-287), telisotuzumab vedotin was intravenously administered at doses of 0.5, 1.5, and 3 mg/kg every 2 weeks for a total of seven doses, followed by an 8-week recovery period.”
Pivotal GLP studies
GLP IV cyno 4-week (Q3W x2) and 13-week (Q2W x7), 8-week recovery; non-GLP 2-week rat; MMAE rat/monkey studies
“In the 13-week GLP-compliant repeat-dose toxicology study in monkeys (Report No. R&D/18/0622, Study No. 2100-287), telisotuzumab vedotin was intravenously administered at doses of 0.5, 1.5, and 3 mg/kg every 2 weeks for a total of seven doses, followed by an 8-week recovery period.”
DART package
Species: DART
Not conducted with the ADC (MMAE genotoxic, advanced cancer; ICH S9)
“The Applicant did not conduct reproductive or embryofetal development (EFD) toxicology studies with telisotuzumab vedotin as MMAE is genotoxic and affects rapidly dividing cells and the intended indication is for the treatment of patients with advanced cancer, in accordance with the ICH S9 guidance.”
Reproductive & developmental
Not conducted with ADC (ICH S9); MMAE rat EFD teratogenic; ovary/uterus and testis findings in repeat-dose
“Reproductive toxicology studies with telisotuzumab vedotin are not warranted to support this application because MMAE is genotoxic and affects actively dividing cells.”
PPND / ePPND: when
PPND not conducted (with fertility and EFD studies); ICH S9, advanced cancer
“Fertility and early embryonic development, embryo-fetal development, and prenatal/postnatal development studies were not conducted for telisotuzumab vedotin. In accordance with ICH S9, studies to assess effects on fertility and early embryonic development are not warranted to support marketing of pharmaceuticals intended for the treatment of patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies in animals have not been performed with telisotuzumab vedotin-tllv or the small molecule MMAE.”
Carcinogenicity model
Not conducted (ADC or MMAE)
“Carcinogenicity studies in animals have not been performed with telisotuzumab vedotin-tllv or the small molecule MMAE.”
Carcinogenicity timing
Not required: FDA agreed carcinogenicity studies not warranted
“FDA agrees that carcinogenicity studies are not warranted to support this application.”
Same question, other ADCs
Adcetris
brentuximab vedotin · CD30Not stated in public reviews
Besponsa
inotuzumab ozogamicin · CD22Not stated in public reviews
Datroway
datopotamab deruxtecan · Trop-2Not stated in public reviews
Decnupaz
pivekimab sunirine · CD123Not stated in public reviews
Elahere
mirvetuximab soravtansine · FRαNot stated in public reviews
Kadcyla
ado-trastuzumab emtansine · HER2Not stated in public reviews
Mylotarg
gemtuzumab ozogamicin · CD33Not stated in public reviews
Padcev
enfortumab vedotin · Nectin-4Not stated in public reviews
Polivy
polatuzumab vedotin · CD79bNot stated in public reviews
Tivdak
tisotumab vedotin · Tissue factorNot stated in public reviews
Trodelvy
sacituzumab govitecan · Trop-2Not stated in public reviews
Zynlonta
loncastuximab tesirine · CD19Not stated in public reviews