Enhertu
fam-trastuzumab deruxtecan · HER2Japan and US: multicenter first-in-human study (Study DS8201-A-J101)
Mylotarg: what was done before first-in-human, and what came after?
gemtuzumab ozogamicin · CD33
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 Mylotarg 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: 6-week NOAEL 2.4 mg/m2/wk monkey, 0.6 rat; 12-week monkey no NOAEL; liver, kidney, marrow, lymphoid, reproductive organs (FDA pharmacology/toxicology review, p. 18)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
12-week GLP cynomolgus monkey study (12 weekly IV bolus doses)
“A GLP-compliant general toxicity study in monkeys was also completed in which 12 doses of gemtuzumab ozogamicin were given once weekly by intravenous bolus injection to groups of 3 male and 3 female cynomolgus monkeys at doses of 0 (sterile water), 2.2, 6.6, or 11 mg/m2 /week.”
Pivotal GLP studies
6-week (weekly IV) rat and monkey with 4-week recovery; 6-cycle monkey cell-line bridging study; 12-week weekly IV monkey
“Rats were administered 6 weekly doses at 0 (PBS control), 7.2 (hP67.6 antibody control), or CL 555,201 (GO) at doses of 0.6, 2.4, or 7.2 mg/m2 /week and observed for an additional 4 weeks.”
DART package
Species: DART
Rat only (fertility and EFD); FDA agreed one species sufficient after positive pilot study
“Based on the unequivocally positive results obtained from a pilot study, the Agency previously agreed with the Applicant that one species would be sufficient to support an NDA application for CMA-676 in a leukemia indication.”
Reproductive & developmental
Rat male/female fertility and rat EFD (one species agreed); embryolethal, teratogenic, male fertility impaired; no PPND
“Based on the unequivocally positive results obtained from a pilot study, the Agency previously agreed with the Applicant that one species would be sufficient to support an NDA application for CMA-676 in a leukemia indication.”
PPND / ePPND: when
Peri- and postnatal studies not conducted
“Since peri- and postnatal studies were not conducted, no information is available on the effect of CMA-676 on parturition, lactation, functional development, locomotion or learning ability.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Formal carcinogenicity studies have not been conducted with gemtuzumab ozogamicin.”
Carcinogenicity model
Not conducted (formal studies); preneoplastic liver oval cell hyperplasia seen in rat toxicity studies
“Formal carcinogenicity studies have not been conducted with gemtuzumab ozogamicin. In toxicity studies, rats developed preneoplastic lesions (minimal to slight oval cell hyperplasia) in the liver”
Carcinogenicity timing
Not conducted
“No carcinogenicity studies have been conducted with gemtuzumab ozogamicin”
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
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