Zinbryta
daclizumab
Species
Monkey
Longest study
39 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“General toxicity studies were conducted in cynomolgus monkey, the only pharmacologically relevant species.”
Why that species
Comparable affinity for human and monkey CD25 (KD 0.49 vs 0.42 nM); no activity in rat or mouse lymphocytes
“DAC-HYP had no pharmacological effect on primary lymphocytes isolated from rats or mice. Plasmon surface resonance revealed comparable affinity of DAC-HYP for human (KD = 0.49 nM) and monkey (KD = 0.42 nM) CD25.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“There was no pharmacological activity in primary lymphocytes isolated from rodents. All in vivo toxicology studies were, therefore, conducted in cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Toxicity studies of daclizumab were conducted in monkeys with up to 39 weeks duration.”
Pivotal GLP studies
Cynomolgus 13-week, 39-week and 9-month SC studies, dosed every 2 weeks, with 3-month recovery
“The pivotal studies were 13- and 39-week studies and a 9-month study. All were conducted with DAC HYP, administered Q2W by subcutaneous injection, and included 3-month recovery periods.”
Route in tox
Subcutaneous (clinical route), every 2 weeks
“Repeat-dose toxicology studies were conducted with daclizumab administered SC (clinical and commercial route of administration) q2W.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; antibody not expected to interact directly with DNA
“Genetic toxicology studies were not conducted because, as a monoclonal antibody, DAC HYP is not expected to interact directly with DNA.”
Carcinogenicity
Not conducted; not feasible because pharmacologically active only in monkey
“Because DAC HYP is pharmacologically active only in monkey, carcinogenicity studies are not feasible; therefore, the carcinogenic potential of DAC HYP was not assessed.”
Reproductive & developmental
Monkey PPND (50 mg/kg weekly, GD 50-160): no effects; embryo-fetal study: increased fetal loss at 200 mg/kg weekly
“Once-weekly SC dosing with 50 mg/kg DAC-HYP during gestation days (GD) 50-160 did not affect pre- or postnatal development. However, once-weekly SC administration of 200 mg/kg DAC-HYP administered during the first 5 weeks of pregnancy increased the incidence of fetal loss.”
Safety pharmacology
Assessed in cynomolgus monkeys after SC dosing; good safety profile
“Safety pharmacology of daclizumab was performed in cynomolgus monkeys (Macaca fascicularis), by subcutaneous administration. Overall studies showed a good safety profile.”
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 Zinbryta 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 monoclonal antibodies outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAEL 10 mg/kg biweekly for CNS microglial aggregates in 39-week and 9-month studies (FDA pharmacology/toxicology review, p. 22)
NOAEL / key findings
NOAEL 10 mg/kg biweekly for CNS microglial aggregates in 39-week and 9-month studies
“In the 39-week and 9-month studies, the NOAEL for microglial aggregates was 10 mg/kg administered biweekly”
Risksopen answer page →
Immune & cytokine safety
ADA detected in monkeys, reducing exposure in some animals without compromising study adequacy
“While ADAs were detected, and associated with decreases in plasma exposure in some animals, the adequacy of the studies was not adversely affected.”
Biodistribution & persistence
Placental transfer (cord:maternal blood ratio 0.1-0.8) and low milk excretion in monkeys
“Studies in pregnant and lactating monkeys demonstrated placental transfer (umbilical cord blood:maternal blood ratios of 0.1-0.8) and excretion in milk”
Modality-specific risk
Skin and CNS (microglial aggregate) toxicities, proposed to result from raised IL-2 stimulating intermediate-affinity IL-2 receptors
“The sponsor has proposed that the dermal and CNS toxicities in monkeys are due to increases in plasma IL-2 levels that result in stimulation of intermediate-affinity IL-2 receptors.”