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.”
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.”
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)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“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.”