Enhertu
fam-trastuzumab deruxtecan · HER2Japan and US: multicenter first-in-human study (Study DS8201-A-J101)
Polivy: what was done before first-in-human, and what came after?
polatuzumab vedotin · CD79b
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 Polivy 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: Rat STD10 10 mg/kg; monkey surrogate HNSTD 3 mg/kg; bone marrow, lymphoid, liver, male reproductive organs (testes irreversible) (EMA assessment report, p. 55)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Cynomolgus monkey, polatuzumab vedotin or surrogate ADC IV Q3W for 4 doses, with 9-week recovery
“In Cynomolgus monkeys, IV doses of 1, 3, and 5 mg/kg polatuzumab vedotin or 3 and 5 mg/kg of the surrogate ADC were administered Q3W for a total of 4 doses, followed by a 9-week recovery period.”
Pivotal GLP studies
Rat 4 weekly IV doses (6-week recovery); monkey Q3W x4 IV ADC and surrogate (9-week recovery); MMAE rat and monkey
“In Cynomolgus monkeys, IV doses of 1, 3, and 5 mg/kg polatuzumab vedotin or 3 and 5 mg/kg of the surrogate ADC were administered Q3W for a total of 4 doses, followed by a 9-week recovery period.”
DART package
Species: DART
Rat (MMAE embryo-fetal development only); no fertility study
“In an embryo-fetal developmental study, pregnant rats were given 2 intravenous doses of 0.2 mg/kg MMAE during the period of organogenesis on gestation Days 6 and 13.”
Reproductive & developmental
No fertility study (ICH S9); MMAE rat EFD embryolethal and teratogenic; testicular toxicity in rat repeat-dose
“A designated fertility study was not conducted with polatuzumab vedotin or MMAE and is not needed for the proposed indication.”
PPND / ePPND: when
No dedicated pre- and postnatal development study conducted
“No dedicated pre- and postnatal development studies have been conducted (see discussion on Non-Clinical aspects).”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted for the indication)
“Carcinogenicity studies in animals have not been performed with polatuzumab vedotin or MMAE and are not warranted for the proposed indication.”
Carcinogenicity model
Not conducted with polatuzumab vedotin or MMAE (not warranted for the indication)
“Carcinogenicity studies in animals have not been performed with polatuzumab vedotin or MMAE and are not warranted for the proposed indication.”
Carcinogenicity timing
Not conducted with polatuzumab vedotin or MMAE; not warranted for the indication
“Carcinogenicity studies in animals have not been performed with polatuzumab vedotin or MMAE and are not warranted for the proposed indication.”
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
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