Xolair
omalizumab
Sources:EMA assessment report ↗
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.”
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.”
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 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: 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.”