Xolair
omalizumab
Species
MonkeyMouse
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey (pivotal); 4-week mouse study also conducted
“Two pivotal repeated-dose toxicity studies were performed in Cynomolgus monkeys”
Why that species
Binds cynomolgus and human IgE with similar affinity; does not bind non-primate IgE
“The Cynomolgus monkey was chosen as model to predict human pharmacology and toxicology since omalizumab binds Cynomolgus and human IgE with similar affinity but does not bind non-primate IgE.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys (no non-anaphylactogenic anti-mouse IgE surrogate available)
“Rodent asthma models were not considered because of the species specificity of omalizumab and because there were no appropriate non-anaphylactogenic surrogate antibodies available for evaluation in rodent models.”
Species: general tox
Cynomolgus monkey (4-week and 6-month studies)
“Two pivotal repeated-dose toxicity studies were performed in Cynomolgus monkeys: a 4-week iv/sc study with a 4-week recovery period, dosing three times weekly in the range 0.1-5.0 mg/kg, and a 6- month iv/sc study”
Species: DART
Cynomolgus monkey (fertility, embryo-fetal, late gestation); omalizumab does not bind rodent/rabbit IgE
“Male and female fertility, embryotoxicity/teratology, and late gestational/placental transfer were studied in Cynomolgus monkeys, since omalizumab would not bind to rodent/rabbit IgE”
Species: carcinogenicity
Not conducted (omalizumab does not bind rodent IgE)
“No carcinogenicity study with omalizumab was performed since omalizumab does not bind rodent IgE.”
Surrogate used in
No surrogate used: no non-anaphylactogenic anti-murine IgE surrogate antibody available
“since omalizumab would not bind to rodent/rabbit IgE, and a non-anaphylactogenic anti-murine IgE Mab surrogate antibody was not available.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Juvenile (8- to 10-month old) Cynomolgus monkeys received sc doses of 50 or 250 mg/kg omalizumab weekly for 26 weeks.”
Pivotal GLP studies
Monkey 4-week and 6-month IV/SC studies, three times weekly, 0.1-5.0 mg/kg; juvenile monkey 26-week SC weekly study
“a 4-week iv/sc study with a 4-week recovery period, dosing three times weekly in the range 0.1-5.0 mg/kg, and a 6- month iv/sc study with an 8-week recovery period, dosing three times weekly in the range 0.1-5.0 mg/kg.”
Route in tox
IV and SC
“Two pivotal repeated-dose toxicity studies were performed in Cynomolgus monkeys: a 4-week iv/sc study with a 4-week recovery period”
Skipped studiesopen answer page →
Genotoxicity
Ames test negative; full genotoxicity battery not conducted (no relevant species)
“A standard Ames test was negative. A full genotoxicity test battery and carcinogenicity evaluation have not been conducted for omalizumab, due to the absence of a relevant species appropriate for such studies.”
Carcinogenicity
Not conducted (no binding to rodent IgE); no plausible mechanism for IgE inhibition causing carcinogenesis
“No carcinogenicity study with omalizumab was performed since omalizumab does not bind rodent IgE.”
Reproductive & developmental
Monkey male/female fertility, EFD and late-gestation studies up to 75 mg/kg: no reproductive toxicity, embryotoxicity or teratogenicity
“at doses of 0, 3, 15 and 75 mg/kg once daily on Days 20-22, and then once weekly through Day 50 did not elicit maternal toxicity, embryotoxicity or teratogenicity.”
Safety pharmacology
Incorporated into 4-week and 6-month monkey studies (blood pressure, ECG, heart and respiration rate); no drug-related effects
“Safety parameters were monitored at regular intervals in the 4-week and 6-month monkey toxicology studies. These parameters included vital functions such as blood pressure, electrocardiograph measurements, heart rate and respiration rate.”
Genotox: Ames
Genotox: in vitro mammalian
Not conducted (no relevant species)
“A full genotoxicity test battery and carcinogenicity evaluation have not been conducted for omalizumab, due to the absence of a relevant species appropriate for such studies.”
Genotox: in vivo
Not conducted (no relevant species)
“A full genotoxicity test battery and carcinogenicity evaluation have not been conducted for omalizumab, due to the absence of a relevant species appropriate for such studies.”
Carcinogenicity model
Not conducted (omalizumab does not bind rodent IgE)
“No carcinogenicity study with omalizumab was performed since omalizumab does not bind rodent IgE.”
Carcinogenicity timing
Not required: omalizumab does not bind rodent IgE
“No carcinogenicity study with omalizumab was performed since omalizumab does not bind rodent IgE.”
hERG / QT
No drug-related ECG, blood pressure or heart rate effects in 4-week and 6-month monkey studies
“Safety parameters were monitored at regular intervals in the 4-week and 6-month monkey toxicology studies. These parameters included vital functions such as blood pressure, electrocardiograph measurements, heart rate and respiration rate. No drug-related effects were observed for any of these endpoints.”
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 Xolair 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: Well tolerated except dose-related, age-dependent platelet decreases (greater in juveniles); injection-site haemorrhage (EMA assessment report, p. 33)
NOAEL / key findings
Well tolerated except dose-related, age-dependent platelet decreases (greater in juveniles); injection-site haemorrhage
“Chronic administration of omalizumab was well tolerated in non-human primates, with the exception of a dose-related and age-dependent decrease in blood platelets, with a greater sensitivity in juvenile animals.”
Risksopen answer page →
Immune & cytokine safety
Omalizumab:IgE complexes without immune complex disease; anti-drug antibodies in monkeys (all positive after inhalation), non-neutralizing
“Despite the presence of omalizumab:IgE complexes in the monkey studies, there were no indications of immune complex-mediated disease.”
Biodistribution & persistence
Crosses placenta (fetal serum ~33% of maternal) and into milk; tissue binding limited to IgE-synthesizing lymphoid cells
“Measurable levels of omalizumab were observed in amniotic fluid (~3.3% of maternal serum levels), milk (~0.154%), and fetal (~33%) and neonatal (~33%) serum.”
Modality-specific risk
Thrombocytopenia (mechanism unknown, juvenile monkeys most sensitive); theoretical parasitic infection risk from IgE blockade
“In spite of the mechanistic in vivo/vitro studies performed by the Applicant, the mechanism of the omalizumab-platelet interaction and the epitope responsible for the interaction remain unknown.”
Anti-drug antibodies: animals
Anti-omalizumab antibodies in monkeys: non-neutralising, no effect on PK (except one juvenile) or toxicity
“Anti-omalizumab-antibodies did not affect the pharmacokinetics of omalizumab (with the exception of one juvenile monkey) nor did they have neutralising activity, nor did they elicit any toxicity, based on data from monkey toxicology studies.”
Anti-drug antibodies: patients
<0.1% (1/1723) in asthma patients 12 years and older
“Antibodies to XOLAIR were detected in approximately 1/1723 (<0.1%) of patients treated with XOLAIR in the clinical studies evaluated for asthma in patients 12 years of age and older.”
Label warnings
Boxed warning: Anaphylaxis
- Anaphylaxis
- Malignancy
- Acute Asthma Symptoms and Deteriorating Disease
- Corticosteroid Reduction
- Eosinophilic Conditions
- Fever, Arthralgia, and Rash
- Parasitic (Helminth) Infection
- Laboratory Tests
- Potential Medication Error Related to Emergency Treatment of Anaphylaxis
Hypersensitivity & infusion reactionsSecondary malignancySkin reactionsInfections
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 Xolair 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: Well tolerated except dose-related, age-dependent platelet decreases (greater in juveniles); injection-site haemorrhage (EMA assessment report, p. 33)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week juvenile cynomolgus monkey (SC, weekly) with 26-week recovery
“Juvenile (8- to 10-month old) Cynomolgus monkeys received sc doses of 50 or 250 mg/kg omalizumab weekly for 26 weeks. Reversibility of any toxic effects was assessed during a 26-week recovery period.”
Pivotal GLP studies
Monkey 4-week and 6-month IV/SC studies, three times weekly, 0.1-5.0 mg/kg; juvenile monkey 26-week SC weekly study
“a 4-week iv/sc study with a 4-week recovery period, dosing three times weekly in the range 0.1-5.0 mg/kg, and a 6- month iv/sc study with an 8-week recovery period, dosing three times weekly in the range 0.1-5.0 mg/kg.”
DART package
Species: DART
Cynomolgus monkey (fertility, embryo-fetal, late gestation); omalizumab does not bind rodent/rabbit IgE
“Male and female fertility, embryotoxicity/teratology, and late gestational/placental transfer were studied in Cynomolgus monkeys, since omalizumab would not bind to rodent/rabbit IgE”
Reproductive & developmental
Monkey male/female fertility, EFD and late-gestation studies up to 75 mg/kg: no reproductive toxicity, embryotoxicity or teratogenicity
“at doses of 0, 3, 15 and 75 mg/kg once daily on Days 20-22, and then once weekly through Day 50 did not elicit maternal toxicity, embryotoxicity or teratogenicity.”
PPND / ePPND: when
Late-gestation, delivery and nursing study in cynomolgus monkey (dosing through Day 28 postpartum) completed before the marketing application
“Omalizumab was given once daily on Days 120, 121 and 122 of gestation as a loading dose, and once weekly through Day 150 of gestation for the Cesarean section group, or through Day 28 postpartum for the natural delivery group.”
Carcinogenicity
Species: carcinogenicity
Not conducted (omalizumab does not bind rodent IgE)
“No carcinogenicity study with omalizumab was performed since omalizumab does not bind rodent IgE.”
Carcinogenicity model
Not conducted (omalizumab does not bind rodent IgE)
“No carcinogenicity study with omalizumab was performed since omalizumab does not bind rodent IgE.”
Carcinogenicity timing
Not required: omalizumab does not bind rodent IgE
“No carcinogenicity study with omalizumab was performed since omalizumab does not bind rodent IgE.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey EFD study: no maternal or fetal toxicity at ~5x MRHD (mg/kg, up to 75 mg/kg/week)
“There was no evidence of maternal toxicity, embryotoxicity, or teratogenicity when omalizumab was administered throughout the period of organogenesis at doses that produced exposures approximately 5 times the MRHD (on a mg/kg basis with maternal subcutaneous doses up to 75 mg/kg/week).”
NOAEL / key findings
Well tolerated except dose-related, age-dependent platelet decreases (greater in juveniles); injection-site haemorrhage
“Chronic administration of omalizumab was well tolerated in non-human primates, with the exception of a dose-related and age-dependent decrease in blood platelets, with a greater sensitivity in juvenile animals.”
Efficacy evidenceopen answer page →
Efficacy evidence
Skin test reactivity in ragweed-sensitised cynomolgus monkeys; otherwise in vitro studies
“Except for skin test reactivity studies in Cynomolgus monkeys sensitised to ragweed, no animal model of disease was used.”
Why that model
Primate-only IgE binding; no primate asthma models; no non-anaphylactogenic rodent surrogate
“At the time the studies were performed there were no well-characterised primate asthma models available. Rodent asthma models were not considered because of the species specificity of omalizumab”
Reviewer's view of the efficacy data
EMA: given clinical experience, developing new animal models not justified
“Considering the clinical experience with Xolair, it is not justified to try to develop any new animal models at this stage.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity study for chronic asthma use; carcinogenic potential to be judged from clinical safety data
Why: Omalizumab does not bind rodent IgE; clinical safety data to inform carcinogenic potential · No relevant species · Human data
“No carcinogenicity study with omalizumab was performed since omalizumab does not bind rodent IgE.”
“Formal carcinogenicity studies have not been conducted with omalizumab. Assessment on carcinogenic potential should be made on the basis of available clinical safety data.”
Efficacy modelAcceptedBeyond the letter
No animal disease model; only skin test reactivity in ragweed-sensitised monkeys
Why: Clinical experience with the product makes developing new animal models unjustified · Human data
“Except for skin test reactivity studies in Cynomolgus monkeys sensitised to ragweed, no animal model of disease was used.”
“Considering the clinical experience with Xolair, it is not justified to try to develop any new animal models at this stage.”
DARTVerdict not stated
Late-gestation monkey study without further dosing or evaluation of offspring, e.g. immunotoxicity
“There was no evidence of late gestational maternal or offspring toxicity. However, further dosing and evaluation of the offspring were not performed, for example with regard to immunotoxicity.”
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