Adcetris
brentuximab vedotin
Species
MonkeyRat
Longest study
26 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey (monkey the antigen-binding species)
“Single- and repeat-dose toxicology studies were conducted in rats and monkeys. The pivotal repeat-dose toxicity studies were GLP compliant.”
Why that species
Binds human and cynomolgus CD30 with equal affinity (Kd 0.2 nM), not rat or mouse; rat used for target-independent payload toxicity
“Both brentuximab vedotin and unconjugated brentuximab bound with a Kd of 0.2 nM to human and cynomolgus CD30-positive primary lymphocytes, but not to rat or mouse CD30-positive cells or cells not expressing CD30.”
Surrogate molecule
No surrogate; clinical ADC tested in rat and monkey, with free MMAE and unconjugated cAC10 comparator arms
“The administration of unconjugated brentuximab at all doses was well tolerated, with no apparent target organ toxicity or clinically significant adverse effects.”
Species: general tox
Rat and cynomolgus monkey
“Single- and repeat-dose toxicology studies were conducted in rats and monkeys.”
Species: DART
Rat (embryo-fetal development, IV, organogenesis)
“In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13).”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.”
Surrogate used in
No surrogate used; clinical ADC binds human and cynomolgus CD30 equally
“Both brentuximab vedotin and unconjugated brentuximab bound with a Kd of 0.2 nM to human and cynomolgus CD30-positive primary lymphocytes, but not to rat or mouse CD30-positive cells or cells not expressing CD30.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The haematologic changes observed in the 26-week repeat-dose toxicity study were similar to those of the 11-week study.”
Pivotal GLP studies
Rat 4-week IV (weekly x4) with recovery; cynomolgus 9-week (q3w x4) and 24/26-week (q3w x9) IV infusion studies
“With repeat-dose administration of brentuximab vedotin, unconjugated brentuximab, and MMAE in rats and monkeys the principal test article-related effects of brentuximab vedotin and MMAE in both species included changes in the bone marrow and lymphoid tissues;”
Route in tox
IV (bolus in rat, 30-60 min infusion in monkey)
“Since SGN-35 has been developed for intravenous (IV) administration all non-clinical studies were conducted using the IV route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Conducted on MMAE: Ames and mouse lymphoma negative; rat micronucleus positive (aneugenic)
“MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism.”
Carcinogenicity
Not conducted (relapsed/refractory HL and sALCL indication)
“Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.”
Reproductive & developmental
Rat EFD: embryo-fetal lethality at >=3 mg/kg, placental transfer; no fertility studies; testicular toxicity in rat repeat-dose
“In rats, brentuximab vedotin was clearly embryo-foetal toxic, causing loss of almost all embryos at 3 mg/kg and above.”
Safety pharmacology
Dedicated GLP telemetry study in cynomolgus (CV, respiratory, CNS) plus in vitro hERG with MMAE
“In a dedicated safety pharmacology study in cynomolgus monkeys a single IV infusion of brentuximab vedotin up to 3 mg/kg had no effect on the cardiovascular, respiratory or central nervous systems.”
Genotox: Ames
MMAE: negative in Ames test
“MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.”
Genotox: in vitro mammalian
MMAE: negative in L5178Y mouse lymphoma forward mutation assay
“MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.”
Genotox: in vivo
MMAE: positive in rat bone marrow micronucleus assay (aneugenic)
“MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism.”
Carcinogenicity model
Not conducted (relapsed or refractory HL and sALCL indication)
“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.”
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.”
hERG / QT
MMAE blocked hERG tail current only at 100 µM, not at 10 µM
“With regard to safety pharmacology, MMAE produced a fractional block of peak hERG tail current that was significantly different from the negative control at high MMAE concentration (100 µM) but not at the low concentration (10 µM).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Adcetris 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: Monkey NOAEL 1 mg/kg, HNSTD 3 mg/kg, 6 mg/kg lethal; rat HNSTD 5 mg/kg; bone marrow/neutropenia, lymphoid, rat liver and testis (EMA assessment report, p. 37)
NOAEL / key findings
Monkey NOAEL 1 mg/kg, HNSTD 3 mg/kg, 6 mg/kg lethal; rat HNSTD 5 mg/kg; bone marrow/neutropenia, lymphoid, rat liver and testis
“At 3 mg/kg (HNSTD), a similar, but less severe cyclic decrease in neutrophil counts was observed, while at 1 mg/kg (NOAEL) no biologically relevant effects on neutrophil counts was observed.”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibodies (PAHA) in monkeys reduced ADC exposure but increased MMAE exposure without added toxicity
“The positive immunogenic responses in monkeys appeared to reduce the concentrations of brentuximab vedotin and TAb after multiple doses, and conversely increased the concentrations of MMAE after multiple doses in of the animals with high anti-brentuximab antibody (PAHA) levels.”
Biodistribution & persistence
Low Vss for ADC; free MMAE widely distributed (pituitary, adrenal, thyroid, lung, kidney, liver), biliary/fecal excretion; placental transfer
“MMAE was mainly distributed to pituitary gland, adrenal gland, thyroid, lung, kidney, liver and subsequently bile and intestine.”
Modality-specific risk
MMAE payload toxicity: myelotoxicity/neutropenia, testicular toxicity; peripheral neuropathy not reproduced in animals
“Neutropenia and associated mortality was the clinically most significant toxicity observed in non-clinical studies in monkeys.”
Anti-drug antibodies: animals
Monkey anti-drug antibodies (PAHA) reduced ADC and total antibody levels and increased MMAE in high-titre animals
“The positive immunogenic responses in monkeys appeared to reduce the concentrations of brentuximab vedotin and TAb after multiple doses, and conversely increased the concentrations of MMAE after multiple doses in of the animals with high anti-brentuximab antibody (PAHA) levels.”
Anti-drug antibodies: patients
58 ATA-positive patients in phase II studies; 62% of them had neutralizing antibodies
“Of 58 patients with ATA-positive samples, 18 (31%) patients were negative for the presence of neutralizing antibodies, 36 (62%) had at least one sample that was positive for the presence of neutralizing antibodies, and 4 (7%) were of unknown status due to insufficient sample.”
Label warnings
Boxed warning: Progressive multifocal leukoencephalopathy (pml)
- Peripheral Neuropathy
- Anaphylaxis and Infusion Reactions
- Hematologic Toxicities
- Serious Infections and Opportunistic Infections
- Tumor Lysis Syndrome
- Increased Toxicity in the Presence of Severe Renal Impairment
- Increased Toxicity in the Presence of Moderate or Severe Hepatic Impairment
- Hepatotoxicity
- Progressive Multifocal Leukoencephalopathy
- Pulmonary Toxicity
- Serious Dermatologic Reactions
- Gastrointestinal Complications
- Hyperglycemia
- Embryo-Fetal Toxicity
InfectionsNeurotoxicityHypersensitivity & infusion reactionsCytopeniasSecondary malignancyNephrotoxicityHepatotoxicityPulmonary toxicitySkin reactionsGastrointestinalMetabolic & endocrineEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
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 Adcetris 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: Monkey NOAEL 1 mg/kg, HNSTD 3 mg/kg, 6 mg/kg lethal; rat HNSTD 5 mg/kg; bone marrow/neutropenia, lymphoid, rat liver and testis (EMA assessment report, p. 37)
Longest repeat-dose systemic studies
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”
Pivotal GLP studies
Rat 4-week IV (weekly x4) with recovery; cynomolgus 9-week (q3w x4) and 24/26-week (q3w x9) IV infusion studies
“With repeat-dose administration of brentuximab vedotin, unconjugated brentuximab, and MMAE in rats and monkeys the principal test article-related effects of brentuximab vedotin and MMAE in both species included changes in the bone marrow and lymphoid tissues;”
DART package
Species: DART
Rat (embryo-fetal development, IV, organogenesis)
“In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13).”
Reproductive & developmental
Rat EFD: embryo-fetal lethality at >=3 mg/kg, placental transfer; no fertility studies; testicular toxicity in rat repeat-dose
“In rats, brentuximab vedotin was clearly embryo-foetal toxic, causing loss of almost all embryos at 3 mg/kg and above.”
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.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.”
Carcinogenicity model
Not conducted (relapsed or refractory HL and sALCL indication)
“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.”
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.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL serum exposure ~2 to 3x human exposure at the clinical dose
“The serum exposure to SGN-35 in monkeys at the NOAEL was approximately 2 to 3 times that in humans.”
NOAEL / key findings
Monkey NOAEL 1 mg/kg, HNSTD 3 mg/kg, 6 mg/kg lethal; rat HNSTD 5 mg/kg; bone marrow/neutropenia, lymphoid, rat liver and testis
“At 3 mg/kg (HNSTD), a similar, but less severe cyclic decrease in neutrophil counts was observed, while at 1 mg/kg (NOAEL) no biologically relevant effects on neutrophil counts was observed.”
Efficacy evidenceopen answer page →
Efficacy evidence
Three xenograft models from human HL and ALCL cell lines
“In vivo anti-tumour activity of brentuximab vedotin was demonstrated in three xenograft transplant models derived from human HL and ALCL cell lines.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: proposed anti-tumour mechanism sufficiently demonstrated
“Taken together, the anti-tumour effector mechanism mediated by brentuximab vedotin as proposed by the applicant was sufficiently demonstrated.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAcceptedBeyond the letter
Exposure ratios derived from single-dose studies and a different dosing scheme rather than repeat-dose data matching the clinical regimen
Why: Similar single- and multiple-dose kinetics and the life-threatening indication · Pharmacology or kinetics · Serious disease
“Basis for calculation of exposure ratios were non-clinical studies with a different dosing scheme than the clinical one (for Cmax data from rat study) or single dose studies instead of repeat-dose studies (for AUC data from rat and monkey studies).”
“In light of the similarity of single and multiple dose kinetics and the life-threatening indication, calculation of exposure ratios can, however be accepted.”
Safety marginCriticised but acceptedBeyond the letter
Patient MMAE plasma levels about two orders of magnitude above those in monkeys; animal hepatotoxicity data do not cover human exposure
Why: Hepatobiliary enzyme elevations were reversible and easily monitored in patients · Human data
“However, it should be considered that MMAE plasma levels in patients are two orders of magnitude higher than those observed in monkeys. Therefore, hepatotoxicity might still be of concern.”
“Yet, the hepatobiliary enzyme elevations were reversible and can be easily monitored in patients.”
OtherAcceptedBeyond the letter
No studies of interaction with Fc-gamma receptors submitted
Why: Brentuximab vedotin lacks immunological effector functions · Pharmacology or kinetics
“No studies addressing the potential interaction of brentuximab vedotin with FC-gamma receptors were submitted. However, this is acceptable given the lack of immunological effector functions induced by brentuximab vedotin.”
OtherVerdict not stated
No dedicated local tolerance studies; injection sites examined within repeat-dose studies in rats and monkeys
Why: No injection-site effects in rat and monkey repeat-dose studies
“Dedicated studies evaluating local tolerance of brentuximab vedotin were not submitted. Microscopic examination of the injections sites as part of the repeat-dose toxicology studies in both rats and monkeys identified no test article-related effects at the injection sites.”
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