Enhertu
fam-trastuzumab deruxtecan · HER2Japan and US: multicenter first-in-human study (Study DS8201-A-J101)
Besponsa: what was done before first-in-human, and what came after?
inotuzumab ozogamicin · CD22
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 Besponsa 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: No NOAEL in rat or monkey chronic studies; liver (sinusoidal injury), hematolymphoid, reproductive organs; monkey glomerulonephritis death at 5 ug/kg (FDA multi-discipline review, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month (26-week) once-weekly IV studies in rat and cynomolgus monkey
“The Applicant conducted repeat-dose toxicity studies of up to 6 months duration in rats and cynomolgus monkeys to investigate the chronic toxicity of inotuzumab ozogamicin;”
Pivotal GLP studies
GLP 4-week and 26-week once-weekly IV studies in rats and cynomolgus monkeys, with 4-week recovery
“In the 6-month cynomolgus monkey study, inotuzumab ozogamicin was administered IV at doses of 0.5, 1.5, or 5 μg/kg once weekly.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“Embryo-fetal development studies were conducted in rabbits and rats.”
Reproductive & developmental
Rat fertility and rat/rabbit EFD conducted: rat embryo-fetal toxicity (resorptions, low fetal weight); no PPND (ICH S9)
“Embryo-fetal development studies were conducted in rabbits and rats.”
PPND / ePPND: when
PPND not conducted: not required for products to treat advanced cancer
“pre- and postnatal development studies as these studies are not required to support a marketing application for products intended to treat patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
Carcinogenicity timing
Not required for the current indication; none conducted
“No carcinogenicity studies were conducted or required to support a marketing application for the current indication.”
Same question, other ADCs
Adcetris
brentuximab vedotin · CD30Not 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
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