Adcetris
brentuximab vedotin · CD30Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen
Datroway: what flexibility did regulators accept, and why?
datopotamab deruxtecan · Trop-2
Flexibility accepted
DARTAccepted
No fertility, embryo-fetal or pre- and postnatal development studies; fertility assessed from repeat-dose studies
Why: Payload DXd is genotoxic and toxic to actively dividing cells · Within the guideline · Pharmacology or kinetics
“The Applicant did not conduct fertility or embryo-fetal development toxicology studies with datopotamab deruxtecan as DXd is genotoxic and affects actively dividing cells, and therefore, these studies are not warranted to support the proposed indication.”
“The FDA agrees with the Applicant’s conclusions. Because DXd is genotoxic and is toxic to actively dividing cells, reproductive toxicology studies are not warranted to support this application.”
Safety marginAccepted
Monkey NOAEL for lung, cornea, skin, liver and thymus toxicity gave a margin of exposure of 0.25; no margin for intestinal toxicity
Why: Sought indication is within the scope of ICH S9 · Within the guideline · Serious disease
“In monkeys, slight intestinal toxicity was observed at ≥10 mg/kg, and no exposure margin was determined (margin of exposure <0.25). The NOAEL for pulmonary, corneal, dermal, hepatic and lymphoid (thymic) toxicity was concluded to be 10 mg/kg corresponding to a margin of exposure of 0.25.”
“Considering the sought indication low margins of exposure are acceptable and within the scope of the ICH guideline S9.”
Safety pharmacologyAcceptedBeyond the letter
Safety pharmacology study in male monkeys only
Why: No significant gender differences in exposure or target organs of toxicity · Pharmacology or kinetics
“Only male monkeys were used in the safety pharmacology study; however, this was sufficiently justified and supported by a lack of significant gender differences in exposure or target organs of toxicity.”
Same question, other ADCs
Besponsa
inotuzumab ozogamicin · CD22No pharmacologically relevant toxicology species: antibody does not bind rat or monkey CD22, so only target-independent payload toxicity assessed
Decnupaz
pivekimab sunirine · CD123No pharmacologically relevant toxicology species: no CD123 cross-reactivity in mouse, rat or cynomolgus monkey; monkey studies assess off-target and payload toxicity only
Elahere
mirvetuximab soravtansine · FRαNo reproductive or developmental toxicity studies at all, including embryo-fetal development
Emrelis
telisotuzumab vedotin · c-MetNo fertility, embryo-fetal or pre/postnatal development studies with the ADC; MMAE payload EFD data relied on
Enhertu
fam-trastuzumab deruxtecan · HER2No embryo-fetal development or other reproductive toxicity studies with the ADC
Kadcyla
ado-trastuzumab emtansine · HER2No embryo-fetal development studies with the ADC
Mylotarg
gemtuzumab ozogamicin · CD33No pharmacologically relevant species: antibody does not bind monkey CD33 or rat and monkey tissues; toxicity studies address off-target effects only
Padcev
enfortumab vedotin · Nectin-4Chronic (13-week) toxicity in rat only; monkey limited to 4 weeks
Polivy
polatuzumab vedotin · CD79bPolatuzumab does not bind monkey CD79b; target-mediated toxicity assessed with a surrogate ADC binding monkey CD79b
Tivdak
tisotumab vedotin · Tissue factorNo embryo-fetal development study with the ADC; rat EFD study of the MMAE payload (from brentuximab vedotin) relied on
Trodelvy
sacituzumab govitecan · Trop-2No embryo-fetal development or fertility studies; genotoxic SN-38 payload assumed teratogenic
Zynlonta
loncastuximab tesirine · CD19No pharmacologically relevant species; CD19-mediated toxicity could not be evaluated in any nonclinical species