Enhertu
fam-trastuzumab deruxtecan · HER2Japan and US: multicenter first-in-human study (Study DS8201-A-J101)
Tivdak: what was done before first-in-human, and what came after?
tisotumab vedotin · Tissue factor
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 Tivdak 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: Monkey NOAEL 1 mg/kg (females; <1 mg/kg males), HNSTD 3 mg/kg; skin, bone marrow, eye, testes; skin deaths at 5 mg/kg (EMA assessment report, p. 50)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey (IV every three weeks, five doses) with 6-week recovery
“In a 13-week GLP repeat-dose study with a 6-week recovery period tisotumab vedotin was administered i.v. at doses of 1, 3 or 5 mg/kg every three weeks on five occasions to cynomolgus monkeys.”
Pivotal GLP studies
13-week GLP monkey ADC (q3w IV, 6-week recovery); MMAE 4-week rat, 11-week monkey; 13-week monkey naked antibody
“In a 13-week GLP repeat-dose study with a 6-week recovery period tisotumab vedotin was administered i.v. at doses of 1, 3 or 5 mg/kg every three weeks on five occasions to cynomolgus monkeys.”
DART package
Species: DART
Rat (MMAE embryo-fetal development only); ADC reproductive organ effects assessed in monkey repeat-dose study
“The Applicant assessed the effects tisotumab vedotin on reproductive organs as part of the repeat-dose toxicology study in monkeys and provided results from an EFD study in rats evaluating the MMAE payload.”
Reproductive & developmental
Not conducted with ADC (ICH S9); MMAE rat EFD teratogenic/embryolethal; male repro toxicity in monkey
“MMAE was teratogenic and embryo lethal when administered to pregnant rats via two intravenous doses of 0.2 mg/kg during the period of organogenesis on gestational days 6 and 13.”
PPND / ePPND: when
No pre- and postnatal development study; not needed for advanced cancer (ICH S9)
“Fertility and early embryonic development and pre- and post-natal studies were not needed to support the proposed advanced cancer population in accordance with ICH S9.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with tisotumab vedotin in accordance with ICH S9 guidance.”
Carcinogenicity model
Not conducted (ICH S9)
“Carcinogenicity studies were not conducted with tisotumab vedotin in accordance with ICH S9 guidance.”
Carcinogenicity timing
Not required for advanced cancer (ICH S9); FDA agreed
“The FDA agrees with the Applicant’s position; carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer in accordance with ICH S9.”
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
Emrelis
telisotuzumab vedotin · c-MetNot 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
Trodelvy
sacituzumab govitecan · Trop-2Not stated in public reviews
Zynlonta
loncastuximab tesirine · CD19Not stated in public reviews