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.”
Species: general tox
Cynomolgus monkey only
“General toxicity studies were conducted in cynomolgus monkey, the only pharmacologically relevant species.”
Species: DART
Cynomolgus monkey (reproductive, embryo-foetal and pre/postnatal studies)
“Pharmacokinetic (PK)/toxicokinetic (TK) profiles of daclizumab were comprehensively evaluated in single dose intravenous IV and single and repeat-dose SC studies (acute, sub-chronic, chronic, reproductive, embryo-foetal, and pre- and post-natal toxicology studies) in cynomolgus monkeys.”
Species: carcinogenicity
Not conducted (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.”
Surrogate used in
No surrogate used; all in vivo toxicology in cynomolgus monkeys (no activity in rodent lymphocytes)
“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.”
Genotox: Ames
Not conducted (monoclonal antibody)
“Genetic toxicology studies were not conducted because, as a monoclonal antibody, DAC HYP is not expected to interact directly with DNA.”
Genotox: in vitro mammalian
Not conducted (monoclonal antibody)
“Genetic toxicology studies were not conducted because, as a monoclonal antibody, DAC HYP is not expected to interact directly with DNA.”
Genotox: in vivo
Not conducted (monoclonal antibody)
“Genetic toxicology studies were not conducted because, as a monoclonal antibody, DAC HYP is not expected to interact directly with DNA.”
Carcinogenicity model
Not conducted; not feasible as 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.”
Carcinogenicity timing
Not required: carcinogenicity studies not feasible
“Because DAC HYP is pharmacologically active only in monkey, carcinogenicity studies are not feasible; therefore, the carcinogenic potential of DAC HYP was not assessed.”
hERG / QT
No ECG abnormalities in the 39-week monkey study
“Examinations were performed twice during the prestudy phase, on Study Day 129 and Week 39, and on the recovery group animals. There were no ECG abnormalities.”
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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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.”
Anti-drug antibodies: animals
ADA detected in monkeys, decreasing exposure in some animals; study adequacy not affected
“While ADAs were detected, and associated with decreases in plasma exposure in some animals, the adequacy of the studies was not adversely affected.”
Anti-drug antibodies: patients
Treatment-emergent ADA 4% (Study 201) and 19% (Study 301); neutralizing 3% and 8%
“Treatment-emergent ADAs were observed in 4% and 19% of evaluable subjects during the study in Study 201 and Study 301, respectively. Treatment-emergent neutralizing antibodies (NAbs) were observed in 3% and 8% of evaluable subjects in Study 201 and Study 301, respectively.”
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 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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week and 9-month cynomolgus monkey studies (SC, every 2 weeks), each 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.”
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.”
DART package
Species: DART
Cynomolgus monkey (reproductive, embryo-foetal and pre/postnatal studies)
“Pharmacokinetic (PK)/toxicokinetic (TK) profiles of daclizumab were comprehensively evaluated in single dose intravenous IV and single and repeat-dose SC studies (acute, sub-chronic, chronic, reproductive, embryo-foetal, and pre- and post-natal toxicology studies) in cynomolgus monkeys.”
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.”
PPND / ePPND: when
PPND in cynomolgus monkey (SC weekly, GD 50-160; offspring to PND 180) completed before the marketing application
“In the pre- and postnatal development study, DAC HYP was administered to pregnant females at SC doses of 0 and 50 mg/kg QW on GDs 50-160. Offspring were sacrificed on PND 180-181.”
Carcinogenicity
Species: carcinogenicity
Not conducted (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.”
Carcinogenicity model
Not conducted; not feasible as 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.”
Carcinogenicity timing
Not required: carcinogenicity studies not feasible
“Because DAC HYP is pharmacologically active only in monkey, carcinogenicity studies are not feasible; therefore, the carcinogenic potential of DAC HYP was not assessed.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 10 mg/kg for CNS microglial aggregates: ~7x human exposure at recommended dose
“it appears that the low dose used in these studies (10 mg/kg) was the NOAEL for microglial aggregates. This dose produced exposures in monkeys approximately 7 times the exposure in humans at the recommended dose.”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
In vitro inhibition of IL-2-induced proliferation and cytokine secretion in human and monkey primary lymphocytes
“In vitro studies demonstrated that DAC-HYP prevents IL-2 induced proliferation and cytokine secretion in human and monkey primary lymphocytes.”
Why that model
No pharmacological activity in rat or mouse lymphocytes
“DAC-HYP had no pharmacological effect on primary lymphocytes isolated from rats or mice.”
Reviewer's view of the efficacy data
EMA: the submitted pharmacology dataset was in vitro only
“The dataset presented addressed only in vitro pharmacology of daclizumab (Zinbryta).”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityVerdict not stated
Carcinogenic potential not assessed at all (no studies, no weight-of-evidence assessment) for a chronic MS immunomodulator
Why: Pharmacologically active only in monkey, so carcinogenicity studies not feasible · No relevant species
“Because DAC HYP is pharmacologically active only in monkey, carcinogenicity studies are not feasible; therefore, the carcinogenic potential of DAC HYP was not assessed.”
Juvenile toxAcceptedBeyond the letter
Juvenile animal toxicology study waived
Why: Serious toxicities in adults preclude paediatric use · Human data
“The general requirement for a juvenile animal toxicology study is waived because the clinical team has concluded that the serious toxicities observed in adults administered DAC HYP preclude its use in the pediatric population.”
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