Darzalex
daratumumab
Species
Monkey
Longest study
6 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Chimpanzee (pivotal); cynomolgus monkey with surrogate antibody (supportive)
“The toxicology program for daratumumab consisted of a GLP 6-week repeat-dose toxicity study in chimpanzees, and in vitro tissue cross-reactivity studies using chimpanzee and human tissues.”
Why that species
Binds human and chimpanzee CD38 only; no binding to mouse, rat, rabbit, pig, cynomolgus or rhesus CD38
“Daratumumab binds to human and chimpanzee CD38, but not to CD38 of species typically used for nonclinical toxicology testing, ie, mouse, rat, rabbit, pig, and cynomolgus and rhesus monkey.”
Surrogate molecule
Yes: HuMab-CD38 (binds cynomolgus CD38), used for a non-GLP 2-week monkey toxicity study and monkey tissue cross-reactivity
“Additional supportive studies were conducted with HuMab-CD38, a mAb that binds cynomolgus CD38, and included a pilot, non-GLP 2-week repeat-dose toxicity study in cynomolgus monkeys, and an in vitro tissue cross-reactivity study with cynomolgus monkey tissues.”
Species: general tox
Chimpanzee (GLP 6-week repeat-dose study)
“The toxicology program for daratumumab consisted of a GLP 6-week repeat-dose toxicity study in chimpanzees, and in vitro tissue cross-reactivity studies using chimpanzee and human tissues.”
Species: DART
Not conducted: not feasible in chimpanzees, the only relevant species
“No developmental and reproductive toxicity studies were performed. Developmental and reproductive toxicity testing is not feasible in chimpanzees.”
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“ICH S9 also outlines that carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer, and as such no carcinogenicity studies were needed.”
Surrogate used in
Yes: HuMab-CD38 (binds cynomolgus CD38) for a non-GLP 2-week monkey toxicity study and monkey tissue cross-reactivity
“Additional supportive studies were conducted with HuMab-CD38, a mAb that binds cynomolgus CD38, and included a pilot, non-GLP 2-week repeat-dose toxicity study in cynomolgus monkeys, and an in vitro tissue cross-reactivity study with cynomolgus monkey tissues.”
Study lengthopen answer page →
Longest pivotal study
6 weeks
“The toxicology program for daratumumab consisted of a GLP 6-week repeat-dose toxicity study in chimpanzees”
Pivotal GLP studies
GLP 6-week chimpanzee study, weekly IV infusion, 91-105-day recovery
“The nonclinical PK of daratumumab was evaluated in the 6-week repeat-dose toxicology study in chimpanzees administered weekly as an IV infusion, and followed by a 91 to 105-day recovery period.”
Route in tox
Intravenous infusion (clinical route)
“Both repeat-dose toxicity studies utilized IV dosing, which is the intended route of administration for Darzalex.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“No genotoxicity studies were conducted with daratumumab (as per ICH S6) and no carcinogenicity were conducted with daratumumab (as per ICH S6 and S9).”
Carcinogenicity
Not conducted (advanced cancer, ICH S9)
“ICH S9 also outlines that carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer, and as such no carcinogenicity studies were needed.”
Reproductive & developmental
Not conducted; no relevant species other than chimpanzee, where such studies are not feasible
“No developmental and reproductive toxicity studies were performed. Developmental and reproductive toxicity testing is not feasible in chimpanzees.”
Safety pharmacology
Incorporated into 6-week chimpanzee and 2-week monkey studies; no cardiovascular, respiratory or CNS effects
“There were no treatment-related adverse effects on cardiovascular, respiratory, or central nervous system parameters in the 6- and 2-week IV repeat-dose toxicology studies in chimpanzees and cynomolgus monkeys administered daratumumab or HuMab-CD38, respectively.”
Genotox: Ames
Not conducted (ICH S6)
“No genotoxicity studies were conducted with daratumumab (as per ICH S6) and no carcinogenicity were conducted with daratumumab (as per ICH S6 and S9).”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“No genotoxicity studies were conducted with daratumumab (as per ICH S6) and no carcinogenicity were conducted with daratumumab (as per ICH S6 and S9).”
Genotox: in vivo
Not conducted (ICH S6)
“No genotoxicity studies were conducted with daratumumab (as per ICH S6) and no carcinogenicity were conducted with daratumumab (as per ICH S6 and S9).”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“ICH S9 also outlines that carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer, and as such no carcinogenicity studies were needed.”
Carcinogenicity timing
Not required (advanced cancer, ICH S9)
“ICH S9 also outlines that carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer, and as such no carcinogenicity studies were needed.”
hERG / QT
No stand-alone safety pharmacology; ECG unremarkable in 6-week chimpanzee study up to 25 mg/kg
“Stand-alone safety pharmacology studies were not conducted with daratumumab. ECG parameters, respiratory rates, body temperatures and pulse rates were assessed during the 6-week repeat-dose toxicology study in chimpanzees and were unremarkable at doses up to 25 mg/kg.”
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 Darzalex 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 oncology monoclonal antibodies (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Chimpanzee: infusion-related reactions, thrombocytopenia, anemia, leukopenia and elevated AST (FDA pharmacology/toxicology review, p. 7)
NOAEL / key findings
Chimpanzee: infusion-related reactions, thrombocytopenia, anemia, leukopenia and elevated AST
“The primary toxicities identified in chimpanzees were infusion related reactions, thrombocytopenia, anemia, leukopenia, in addition to elevated AST values.”
Risksopen answer page →
Immune & cytokine safety
Cytokine release (TNF-α, IL-6, IFN-γ) caused one chimpanzee death at 5 mg/kg shortly after dosing
“There was one mortality at 5 mg/kg immediately following dosing (1.5 hours) in a female chimpanzee due to cytokine release response with overinflation, edema of the lungs following dosing with detectable levels of cytokines TNF-α, IL-6 and IFN-γ in the serum prior to necropsy.”
Biodistribution & persistence
Half-life ~15.5-18.8 days in chimpanzees; 9-63 hours for surrogate HuMab-CD38 in monkeys
“Daratumumab was slowly eliminated in the blood following intravenous dosing with half-lives of approximately 15.5 to 18.8 days in chimpanzees, and 9 to 63 hours for HuMab-CD38 in the monkey.”
Modality-specific risk
Infusion-related reactions (cytokine release) and thrombocytopenia
“The two primary toxicities in the pivotal chimpanzee study were infusion-related reactions (IRRs) and thrombocytopenia.”
Anti-drug antibodies: animals
No anti-daratumumab ADA detected in the pivotal chimpanzee study
“No daratumumab anti-drug antibodies (ADAs) were detected during the study.”
Anti-drug antibodies: patients
Anti-daratumumab ADA 0.6% (9/1,563) across 9 DARZALEX FASPRO trials; 8 patients neutralizing
“With the median DARZALEX FASPRO treatment ranging from 6.5 to 56.6 months across 9 clinical trials of patients with smoldering multiple myeloma, multiple myeloma and light chain (AL) amyloidosis treated with DARZALEX as monotherapy or as combination therapies, the incidence of anti-daratumumab antibody development was 0.6% (9/1,563) and 8 patients tested positive for neutralizing antibodies.”
Label warnings
- Hypersensitivity and Other Administration Reactions
- Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis
- Infections
- Neutropenia
- Thrombocytopenia
- Embryo-Fetal Toxicity
- Interference with Serological Testing
- Interference with Determination of Complete Response
Hypersensitivity & infusion reactionsCardiovascularInfectionsCytopeniasThrombocytopeniaEmbryo-fetal toxicity
US prescribing information, 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 Darzalex 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 oncology monoclonal antibodies (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Chimpanzee: infusion-related reactions, thrombocytopenia, anemia, leukopenia and elevated AST (FDA pharmacology/toxicology review, p. 7)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-week IV chimpanzee study with 91 to 105-day recovery
“The nonclinical PK of daratumumab was evaluated in the 6-week repeat-dose toxicology study in chimpanzees administered weekly as an IV infusion, and followed by a 91 to 105-day recovery period.”
Pivotal GLP studies
GLP 6-week chimpanzee study, weekly IV infusion, 91-105-day recovery
“The nonclinical PK of daratumumab was evaluated in the 6-week repeat-dose toxicology study in chimpanzees administered weekly as an IV infusion, and followed by a 91 to 105-day recovery period.”
DART package
Species: DART
Not conducted: not feasible in chimpanzees, the only relevant species
“No developmental and reproductive toxicity studies were performed. Developmental and reproductive toxicity testing is not feasible in chimpanzees.”
Reproductive & developmental
Not conducted; no relevant species other than chimpanzee, where such studies are not feasible
“No developmental and reproductive toxicity studies were performed. Developmental and reproductive toxicity testing is not feasible in chimpanzees.”
PPND / ePPND: when
Not conducted: developmental and reproductive testing not feasible in chimpanzees, the only relevant species
“No developmental and reproductive toxicity studies were performed. Developmental and reproductive toxicity testing is not feasible in chimpanzees.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“ICH S9 also outlines that carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer, and as such no carcinogenicity studies were needed.”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“ICH S9 also outlines that carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer, and as such no carcinogenicity studies were needed.”
Carcinogenicity timing
Not required (advanced cancer, ICH S9)
“ICH S9 also outlines that carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer, and as such no carcinogenicity studies were needed.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
Chimpanzee: infusion-related reactions, thrombocytopenia, anemia, leukopenia and elevated AST
“The primary toxicities identified in chimpanzees were infusion related reactions, thrombocytopenia, anemia, leukopenia, in addition to elevated AST values.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human lymphoma xenografts in SCID mice (preventive and therapeutic), plus in vitro human/patient-derived cell assays
“Treatment with daratumumab effectively reduced growth of human lymphoma cells in SCID mice, both in the preventive and therapeutic settings.”
Why that model
Binds only human and chimpanzee CD38, not mouse, rat, rabbit, pig, cynomolgus or rhesus CD38
“Daratumumab binds to human and chimpanzee CD38, but not to CD38 of species typically used for nonclinical toxicology testing, ie, mouse, rat, rabbit, pig, and cynomolgus and rhesus monkey.”
Reviewer's view of the efficacy data
FDA: xenograft studies showed reduced tumor growth, but contribution of each mechanism to clinical efficacy remains unknown
“Importantly, the degrees to which the known mechanisms contribute to the clinical efficacy of daratumumab is still unknown. In vivo pharmacology studies showed that daratumumab reduced tumor growth and burden in human lymphoma xenograft mouse models.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
Chimpanzee the only relevant species; exploratory studies in cynomolgus monkey used surrogate antibody HuMab-CD38
Why: Daratumumab does not bind CD38 of species typically used for toxicology testing · No relevant species
“Daratumumab binds to human and chimpanzee CD38, but not to CD38 of species typically used for nonclinical toxicology testing, ie, mouse, rat, rabbit, pig, and cynomolgus and rhesus monkey. Therefore, another anti-CD38 mAb, HuMab-CD38, that binds human and cynomolgus monkey CD38 was also characterized and used in some exploratory studies.”
Study lengthVerdict not stated
No chronic toxicity study conducted
“No chronic toxicity testing has been conducted with daratumumab.”
DARTAccepted with a conditionBeyond the letter
No developmental and reproductive toxicity studies; testing not feasible in chimpanzee and surrogate monkey studies limited by anaemia and ADAs
Why: No feasible relevant species; majority of patients beyond reproductive age; included as missing information in the RMP · No relevant species · Other reason
“Developmental and reproductive toxicity testing is not feasible in chimpanzees. The use of a surrogate antibody in cynomolgus monkeys was considered, but anaemia and formation of ADAs limit the dosages and duration of any additional studies in this species.”
“In addition, as the majority of patient population is beyond reproductive age it is therefore acknowledged that such studies are not deemed necessary for marketing authorisation however in order to address the whole population studied, reproductive and developmental toxicity is included as missing information in the RMP (see discussion on clinical safety).”
Safety marginVerdict not stated
No NOAEL established in the surrogate HuMab-CD38 cynomolgus monkey study
“A NOAEL was not established in this study.”
Similar precedents
SarclisaAntibodies · isatuximab · CD38Monkey only · 3 wkBavencioAntibodies · avelumab · PD-L1Monkey only · 13 wkCyramzaAntibodies · ramucirumab · VEGFR2Monkey only · 39 wkHerceptinAntibodies · trastuzumab · HER2Monkey only · 26 wkImfinziAntibodies · durvalumab · PD-L1Monkey only · 13 wkImjudoAntibodies · tremelimumab · CTLA-4Monkey only · 26 wk