Tysabri
natalizumab
Sources:EMA assessment report ↗
Species
MonkeyPigOther
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey (repeat-dose); guinea pig and monkey for reproductive toxicity
“Two cross-reactive species, the cynomolgus monkey and guinea pigs were used to”
Why that species
Antibody binds cynomolgus/rhesus, guinea pig, dog, pig and ferret lymphocytes; no binding to rat, hamster, rabbit or marmoset
“The following species are reacting with the antibody: Rhesus and cynomolgus monkey, pig, ferret, guinea pig, and dog. Lymphocytes from rat, gerbil, hamster, rabbit, or marmoset monkey are not reactive.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys and guinea pigs; rodents not used
“Standard but pharmacologically irrelevant, rodent species were not evaluated.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Chronic toxicity studies of repeated doses of natalizumab over a 26-week period, followed by a 17 week dose-free period in cynomolgus monkeys”
Pivotal GLP studies
Weekly IV infusion for six months in adult and juvenile cynomolgus monkeys; shorter alternate-day IV monkey studies; rhesus combination study with Avonex
“A six-month toxicity study with natalizumab as weekly intravenous infusion in juvenile cynomologus monkeys with a 17-week recovery period”
Route in tox
IV
“In several repeated dose toxicity studies in cynomolgus monkeys the dosing of 3, 10, or 30 mg/kg of natalizumab was performed on alternate days through day 28 by IV injection.”
Skipped studiesopen answer page →
Genotoxicity
Standard mutagenicity assays: no mutagenic potential
“There were no indications for a mutagenic potential as expected for a protein-like monoclonal antibody nor for potential contaminants or product excipients in the drug product.”
Carcinogenicity
Standard studies not conducted (protein); effects on α4-expressing human tumour cell lines studied in vitro and in SCID/nude mouse xenografts
“Standard short or long term carcinogenicity studies were not performed due to the proteinous nature of the test article. Two in vitro and three in vivo studies were performed to study the effects the natalizumab on human α 4 expressing tumour cell lines in vitro and in vivo (as transplants into SCID and nude mice).”
Reproductive & developmental
Guinea pig female fertility: pregnancy rate reduced ~50% at 30 mg/kg, not at 3 or 10 mg/kg
“Natalizumab treatment at 30 mg/kg resulted in a significant reduction (approx 50%) in pregnancy rates, an effect that was not seen at 0; 3 or 10 mg/kg.”
Safety pharmacology
IV cardiovascular study in beagle dogs: transient decreases in systemic and left ventricular pressure at 3 and 30 mg/kg
“Decreases in systemic and left ventricular pressures with associated decreases in ventricular contractile indices were seen in one dog treated with 3 mg/kg and two dogs treated with 30 mg/kg natalizumab.”
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 Tysabri 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 not stated; dose-related WBC increases persisting through recovery, elevated reticulocytes, marked spleen weight increases in monkeys (EMA assessment report, p. 10)
NOAEL / key findings
NOAEL not stated; dose-related WBC increases persisting through recovery, elevated reticulocytes, marked spleen weight increases in monkeys
“Common and reproducible effects of natalizumab in cynomolgus monkeys were: • dose related, significantly increased counts of WBC even at the end of recovery periods • elevated reticulocyte counts • severe increases in spleen weights”
Risksopen answer page →
Immune & cytokine safety
ADA-driven shock-like reactions with complement activation and immune complexes in some monkeys
“In some toxicity studies shock-like reactions with complement activation and the formation of immune complexes due to high levels of anti-natalizumab antibodies were described in some cynomolgus monkeys.”
Biodistribution & persistence
Low levels of natalizumab in breast milk of monkeys treated until parturition
“In cynomolgus monkeys treated with natalizumab until parturition, low levels of natalizumab were detected in the breast milk of some animals”
Modality-specific risk
Impaired immune function from α4-integrin blockade, with PML and opportunistic infection concern
“The findings suggest that the immune function might be affected by natalizumab treatment.”