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.”
Species: general tox
Cynomolgus monkey
“Chronic toxicity studies of repeated doses of natalizumab over a 26-week period, followed by a 17 week dose-free period in cynomolgus monkeys”
Species: DART
Guinea pig (fertility, EFD) and cynomolgus monkey (EFD, pre/postnatal)
“Studies addressing fertility and early embryonic development were performed in guinea pigs.”
Species: carcinogenicity
Not conducted (protein); human α4-expressing tumour xenografts in SCID and nude mice instead
“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).”
Surrogate used in
No surrogate used; cross-reactive guinea pig and monkey used instead of rodents
“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.”
Genotox: Ames
Specific assays not named; two standard mutagenicity assays showed no mutagenic potential
“Natalizumab was tested in two genotoxicity studies utilising two standard assays for the testing of the mutagenic potential of the mAb.”
Genotox: in vitro mammalian
Specific assays not named; no indication of 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.”
Genotox: in vivo
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.
Carcinogenicity model
Not conducted (protein); tumour xenograft studies in SCID and nude mice
“Standard short or long term carcinogenicity studies were not performed due to the proteinous nature of the test article.”
Carcinogenicity timing
Not required: standard studies not performed because natalizumab is a protein
“Standard short or long term carcinogenicity studies were not performed due to the proteinous nature of the test article.”
hERG / QT
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 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
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 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.”
Anti-drug antibodies: animals
ADA in almost all monkeys within 2-4 weeks; apparently neutralising titres up to 1600 µg/ml
“Antigenicity was detected in almost all animals within 2-4 weeks depending on the administered dose of natalizumab that is interfering with the anti-natalizumab antibodies detection assays. High titres of apparently neutralising anti-natalizumab antibodies up to 1600µg/ml are induced in cynomolgus monkeys.”
Anti-drug antibodies: patients
HAHA incidence 10% in phase III; persistent ADA in ~6% of MS patients over 2 years
“After repeat infusions the HAHA incidence was reduced to 12%, and in the phase III studies to 10%. In 2-year controlled clinical trials in MS patients, persistent anti-natalizumab antibodies (one positive test reproducible on retesting at least 6 weeks later) developed in approximately 6% of patients.”
Label warnings
Boxed warning: Progressive multifocal leukoencephalopathy
- Progressive Multifocal Leukoencephalopathy
- TYSABRI TOUCH® Prescribing Program
- Herpes Infections
- Hepatotoxicity
- Hypersensitivity/Antibody Formation
- Immunosuppression/Infections
- Laboratory Test Abnormalities
- Hematological Abnormalities
- Immunizations
InfectionsNeurotoxicityHepatotoxicityHypersensitivity & infusion reactionsCytopenias
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 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
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 not stated; dose-related WBC increases persisting through recovery, elevated reticulocytes, marked spleen weight increases in monkeys (EMA assessment report, p. 10)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey (IV) with 17-week dose-free recovery
“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”
DART package
Species: DART
Guinea pig (fertility, EFD) and cynomolgus monkey (EFD, pre/postnatal)
“Studies addressing fertility and early embryonic development were performed in guinea pigs.”
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.”
PPND / ePPND: when
Pre/postnatal development study in cynomolgus monkey (with infant immune function) completed before the marketing application
“One study (309-033-11) evaluated the potential for developmental effects in infants born to females treated with natalizumab and addressed the influence of natalizumab on the immune function.”
Carcinogenicity
Species: carcinogenicity
Not conducted (protein); human α4-expressing tumour xenografts in SCID and nude mice instead
“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).”
Carcinogenicity model
Not conducted (protein); tumour xenograft studies in SCID and nude mice
“Standard short or long term carcinogenicity studies were not performed due to the proteinous nature of the test article.”
Carcinogenicity timing
Not required: standard studies not performed because natalizumab is a protein
“Standard short or long term carcinogenicity studies were not performed due to the proteinous nature of the test article.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Guinea pig EAE (MS model): natalizumab 3 mg/kg s.c. had beneficial effects on active EAE
“The studies in the guinea pig EAE model on the efficacy of natalizumab were performed at 3 mg/kg dose (MAD) administered s.c. on day 7 and 14 days after EAE induction. Natalizumab induced beneficial effects on active EAE, as a model of MS.”
Why that model
Natalizumab binds guinea pig lymphocytes with affinity similar to human (Kd 0.3 nM); rodents such as rat are non-reactive
“The affinity of AN100226m and AN100226 (the humanized form of the antibody) for guinea pig lymphocytes was very similar to that for human lymphocytes (Kd = 0.3 nM).”
Reviewer's view of the efficacy data
EMA: natalizumab had beneficial effects in guinea pig EAE as a model of MS
“Natalizumab induced beneficial effects on active EAE, as a model of MS.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityVerdict not stated
No standard carcinogenicity studies; in vitro and SCID/nude mouse xenograft studies with human alpha-4 expressing tumour cells instead
Why: Proteinous nature of the test article
“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).”
DARTAcceptedBeyond the letter
Fertility and early embryonic development studied in guinea pigs; standard rodent species not used
Why: Rodents pharmacologically irrelevant; guinea pig suitability as a reproductive model shown with a negative control · No relevant species
“Standard but pharmacologically irrelevant, rodent species were not evaluated. Fertility and early embryonic development Studies addressing fertility and early embryonic development were performed in guinea pigs.”
“The suitability of the guinea pig as a reproductive model was shown including a negative control (mifepristone), which disrupted the pregnancies from approx. 75% (natalizumab group) to 5% (mifepristone group).”
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