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Precedia/Antibody-drug conjugates/Tox package

What tox package did approved ADCs have, from first-in-human to approval?

From the FDA and EMA reviews of all 14 approved ADCs. Each answer links to the regulator's own sentence.

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Short answer
1 of 14 ran first-in-human outside the US (where the reviews say so); 11 had a recovery phase in the longest repeat-dose study; 0 finished PPND after the marketing application.
First-in-human: US and ex-US1/14
First-in-human: not stated13/14
Longest repeat-dose: with recovery phase11/14
Longest repeat-dose: no recovery phase1/14
Longest repeat-dose: recovery not stated2/14
PPND: not conducted14/14
Carcinogenicity: not conducted1/14
Carcinogenicity: not required13/14

Precedent by precedent

14 approved ADCs, with the reviewers' own words.

Enhertu

fam-trastuzumab deruxtecan · HER2
First-in-human: where
Japan and US: multicenter first-in-human study (Study DS8201-A-J101)
“Study DS8201-A-J101 was a Phase 1, 2-part, multicenter, nonrandomized, open-label, multiple-dose, FIH study of fam-trastuzumab deruxtecan, with study sites in Japan and the US (see Table 19).”
✓ VerifiedFDA multi-discipline review, p. 124Source ↗
Longest repeat-dose study and recovery
3-month cynomolgus monkey IV study (every 3 weeks) with 3-month recovery
“Intermittent Dose Toxicity Study in Monkeys Treated Intravenously with DS-8201a Once per 3 Weeks for 3 Months Followed by a 3-Month Recovery Period: SBL315-526”
✓ VerifiedFDA multi-discipline review, p. 50Source ↗
PPND / ePPND: when
PPND not conducted (ICH S9), along with fertility and EFD studies
“In accordance with ICH S9, no studies were conducted to assess fertility and early embryonic development to implantation, effects on pre and postnatal development, including maternal function, or embryo-fetal developmental toxicity.”
✓ VerifiedFDA multi-discipline review, p. 67Source ↗
Carcinogenicity timing
Not required: FDA agreed carcinogenicity studies not needed
“FDA agrees that carcinogenicity studies are not needed to support this BLA submission.”
✓ VerifiedFDA multi-discipline review, p. 66Source ↗

Adcetris

brentuximab vedotin · CD30
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
Cynomolgus monkey 24-week IV infusion study (every 3 weeks × 9 doses) with 6-week recovery
“8216375 Cynomolgus monkey 5 (control) or 10 (treated) /sex/gp SGN-35: 1, 3 30 min IV infusion 24 weeks (q3wk × 9) recovery 6 weeks”
✓ VerifiedEMA assessment report, p. 30Source ↗
PPND / ePPND: when
Not conducted: no prenatal or postnatal studies submitted, acceptable for relapsed or refractory HL and sALCL
“No carcinogenicity studies, fertility and early embryonic development studies and prenatal or postnatal studies (including maternal function) or studies in which the offspring (juvenile animals) are further dosed and evaluated were submitted, which is acceptable as brentuximab vedotin is intended for the treatment of patients with relapsed or refractory HL and sALCL.”
✓ VerifiedEMA assessment report, p. 39Source ↗
Carcinogenicity timing
Not required: no carcinogenicity studies submitted, acceptable for relapsed or refractory HL and sALCL
“No carcinogenicity studies, fertility and early embryonic development studies and prenatal or postnatal studies (including maternal function) or studies in which the offspring (juvenile animals) are further dosed and evaluated were submitted, which is acceptable as brentuximab vedotin is intended for the treatment of patients with relapsed or refractory HL and sALCL.”
✓ VerifiedEMA assessment report, p. 39Source ↗

Besponsa

inotuzumab ozogamicin · CD22
First-in-human: where
Not stated in public reviews
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;”
✓ VerifiedFDA multi-discipline review, p. 34Source ↗
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.”
✓ VerifiedFDA multi-discipline review, p. 36Source ↗
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.”
✓ VerifiedFDA multi-discipline review, p. 36Source ↗

Datroway

datopotamab deruxtecan · Trop-2
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
3-month rat and cynomolgus monkey IV studies (every 3 weeks, five doses) with 2-month recovery
“To assess the general toxicity profile, 3-month intermittent intravenous dose toxicity studies (every 3 weeks (Q3W), five times in total) in rats and monkeys were conducted. The reversibility of toxic changes was also evaluated following a 2-month recovery period in the intermittent dose toxicity studies.”
✓ VerifiedEMA assessment report, p. 45Source ↗
PPND / ePPND: when
PPND not conducted (ICH S9)
“In accordance with ICH guideline S9 no prenatal and postnatal development, including maternal function studies were conducted.”
✓ VerifiedEMA assessment report, p. 57Source ↗
Carcinogenicity timing
Not required: carcinogenicity studies not warranted for this application
“Carcinogenicity studies are not warranted to support the current application.”
✓ VerifiedFDA multi-discipline review, p. 47Source ↗

Decnupaz

pivekimab sunirine · CD123
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey IV study (every 3 weeks, five doses) with 8-week recovery
“a 13-week repeat-dose GLP study with pivekimab sunirine in cynomolgus monkeys (0, 0.01, 0.03, or 0.1 mg/kg administered once every three weeks for five doses) with an 8-week recovery period.”
✓ VerifiedFDA multi-discipline review, p. 42Source ↗
PPND / ePPND: when
Not conducted: no reproductive and developmental studies, per ICH S9 and FDA feedback
“No reproductive and developmental studies have been conducted with PVEK, in accordance with ICH S9 and FDA feedback (Reference ID: 4704103).”
✓ VerifiedFDA multi-discipline review, p. 62Source ↗
Carcinogenicity timing
Not required (ICH S9); none conducted
“In accordance with ICH S9, carcinogenicity studies have not been conducted with PVEK.”
✓ VerifiedFDA multi-discipline review, p. 62Source ↗

Elahere

mirvetuximab soravtansine · FRα
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
10-week cynomolgus monkey IV study (every 3 weeks, 4 doses) with 5-week recovery
“IMGN853 at doses of 0, 2, 4, and 8 mg/kg/dose was administered intravenously (slow push) to cynomolgus monkeys once every 3 weeks for up to 10 weeks (a total of 4 doses) with a 5- week recovery period (n=6/sex/group).”
✓ VerifiedFDA multi-discipline review, p. 54Source ↗
PPND / ePPND: when
Not conducted: no reproductive or developmental studies (DM4 genotoxic, toxic to dividing cells)
“No reproductive or developmental animal toxicity studies were conducted with mirvetuximab soravtansine. The cytotoxic component of ELAHERE, DM4, disrupts microtubule function, is genotoxic, and can be toxic to actively dividing cells, suggesting it has the potential to cause embryotoxicity and teratogenicity.”
✓ VerifiedFDA multi-discipline review, p. 59Source ↗
Carcinogenicity timing
Not required for the advanced cancer indication (ICH S9)
“Carcinogenicity studies were not needed to support the advanced cancer indication, consistent with ICH S9 guidance.”
✓ VerifiedFDA multi-discipline review, p. 59Source ↗

Emrelis

telisotuzumab vedotin · c-Met
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey IV study (every 2 weeks, seven doses) with 8-week recovery
“In the 13-week GLP-compliant repeat-dose toxicology study in monkeys (Report No. R&D/18/0622, Study No. 2100-287), telisotuzumab vedotin was intravenously administered at doses of 0.5, 1.5, and 3 mg/kg every 2 weeks for a total of seven doses, followed by an 8-week recovery period.”
✓ VerifiedFDA multi-discipline review, p. 50Source ↗
PPND / ePPND: when
PPND not conducted (with fertility and EFD studies); ICH S9, advanced cancer
“Fertility and early embryonic development, embryo-fetal development, and prenatal/postnatal development studies were not conducted for telisotuzumab vedotin. In accordance with ICH S9, studies to assess effects on fertility and early embryonic development are not warranted to support marketing of pharmaceuticals intended for the treatment of patients with advanced cancer.”
✓ VerifiedFDA multi-discipline review, p. 52Source ↗
Carcinogenicity timing
Not required: FDA agreed carcinogenicity studies not warranted
“FDA agrees that carcinogenicity studies are not warranted to support this application.”
✓ VerifiedFDA multi-discipline review, p. 52Source ↗

Kadcyla

ado-trastuzumab emtansine · HER2
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
Chronic cynomolgus monkey IV study (8 doses every 3 weeks) with 6-week recovery
“The animals received doses of TDM1 of 0 1, 3, or 10 mg/kg once every three weeks for 8 doses. Half the monkeys were allowed to recover for six weeks after the last dose.”
✓ VerifiedFDA pharmacology/toxicology review, p. 153Source ↗
PPND / ePPND: when
Not conducted: no new reproductive toxicity studies after FDA consultation (DM1 genotoxic)
“After consultation with the FDA, the Applicant did not conduct new reproductive toxicity studies with trastuzumab emtansine. The small molecule component, DM1, is a microtubule inhibitor which is genotoxic.”
✓ VerifiedFDA pharmacology/toxicology review, p. 154Source ↗
Carcinogenicity timing
Not required and not submitted
“Not required and not submitted.”
✓ VerifiedFDA pharmacology/toxicology review, p. 132Source ↗

Mylotarg

gemtuzumab ozogamicin · CD33
First-in-human: where
Not stated in public reviews
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.”
✓ VerifiedEMA assessment report, p. 35Source ↗
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.”
✓ VerifiedFDA pharmacology/toxicology review, p. 7Source ↗
Carcinogenicity timing
Not conducted
“No carcinogenicity studies have been conducted with gemtuzumab ozogamicin”
✓ VerifiedEMA assessment report, p. 38Source ↗

Padcev

enfortumab vedotin · Nectin-4
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
13-week GLP rat IV study (once weekly); no recovery phase
“Methods: In this study, rats were intravenously administered enfortumab vedotin (0.5, 2, or 5 mg/kg) once weekly for 13 weeks. Recovery was not evaluated.”
✓ VerifiedFDA multi-discipline review, p. 65Source ↗
PPND / ePPND: when
PPND not conducted: late stage and advanced cancer indication
“Since enfortumab vedotin is intended for the treatment of patients with late stage and advanced cancer, studies of fertility and early embryonic development and pre- and postnatal toxicity were not conducted.”
✓ VerifiedEMA assessment report, p. 58Source ↗
Carcinogenicity timing
Not required for advanced cancer; none conducted
“Carcinogenicity studies were not conducted or needed to support marketing of PADCEV in patients with advanced cancer.”
✓ VerifiedFDA multi-discipline review, p. 85Source ↗

Polivy

polatuzumab vedotin · CD79b
First-in-human: where
Not stated in public reviews
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.”
✓ VerifiedEMA assessment report, p. 36Source ↗
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).”
✓ VerifiedEMA assessment report, p. 51Source ↗
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.”
✓ VerifiedFDA pharmacology/toxicology review, p. 12Source ↗

Tivdak

tisotumab vedotin · Tissue factor
First-in-human: where
Not stated in public reviews
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.”
✓ VerifiedEMA assessment report, p. 43Source ↗
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.”
✓ VerifiedFDA multi-discipline review, p. 57Source ↗
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.”
✓ VerifiedFDA multi-discipline review, p. 57Source ↗

Trodelvy

sacituzumab govitecan · Trop-2
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
13-week cynomolgus monkey, IV once weekly for 2 weeks of each 3-week cycle, 4 cycles; recovery phase included
“In a 13-week toxicity study, monkeys were given sacituzumab govitecan at doses of 12.5, 25, and 50 mg/kg once weekly via a 1-hour infusion for 2 weeks of a 3-week cycle for 4 treatment cycles.”
✓ VerifiedFDA multi-discipline review, p. 176Source ↗
PPND / ePPND: when
No reproductive and developmental toxicity studies conducted or required (genotoxic SN-38 payload)
“There were no reproductive and developmental toxicology studies conducted with sacituzumab govitecan or required to support this BLA. Sacituzumab govitecan contains a genotoxic component, SN-38, and is toxic to rapidly dividing cells.”
✓ VerifiedFDA multi-discipline review, p. 193Source ↗
Carcinogenicity timing
Not required for advanced cancer (ICH S9)
“No assessment of carcinogenicity has been conducted in accordance with ICH S9 according to which carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
✓ VerifiedEMA assessment report, p. 31Source ↗

Zynlonta

loncastuximab tesirine · CD19
First-in-human: where
Not stated in public reviews
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey (ADC) with 12-week recovery
“The Applicant conducted GLP 4‐week and 13‐week repeat‐dose general toxicology studies in which cynomolgus monkeys were dosed with the ADC, followed by a 12‐week recovery period.”
✓ VerifiedFDA multi-discipline review, p. 50Source ↗
PPND / ePPND: when
No reproductive and developmental toxicity studies; genotoxic cytotoxic ADC expected to be embryo-fetal toxic and teratogenic
“Reproductive and developmental toxicology studies were not conducted since cytotoxic (i.e. genotoxic) drugs that affect actively dividing cells, such as loncastuximab tesirine, are expected to be embryo/feto toxic and teratogenic.”
✓ VerifiedFDA multi-discipline review, p. 39Source ↗
Carcinogenicity timing
Not required: genotoxic payload, advanced cancer (ICH S9, S6(R1), S1A)
“In accordance with ICH S9, ICH S6(R1) and ICH S1A, no carcinogenicity studies were conducted with loncastuximab tesirine or SG3199 given the genotoxic mode of action of SG3199 (see Section 5.5.2) and the intended clinical use in patients with advanced cancer.”
✓ VerifiedFDA multi-discipline review, p. 63Source ↗