Tezspire
tezepelumab
Species
Monkey
Longest study
26 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
“Cynomolgus monkey was selected as the pharmacologically relevant animal model for non-clinical safety assessment”
Why that species
Binds human and cynomolgus TSLP with picomolar affinity (KD 15.8 and 32.2 pM)
“based on tezepelumab binding to human and cynomolgus monkey TSLP with picomolar affinity (KD vales of 15.8 pM and 32.2 pM, respectively)”
Surrogate molecule
No surrogate in toxicology studies; mouse surrogate M702 was developed for in vivo studies as tezepelumab does not bind mouse TSLP
“Because of the lack of binding of tezepelumab to mouse TSLP, M702, a mouse surrogate antibody was developed for in vivo studies.”
Species: general tox
Cynomolgus monkey only
“As tezepelumab only binds human and cynomolgus monkey TSLP, cynomolgus monkey represents the only suitable species to investigate the toxicology of tezepelumab.”
Species: DART
Cynomolgus monkey (ePPND, IV from early gestation through delivery)
“In the maternal, embryo-fetal, and neonatal toxicity (ePPND) study, pregnant female cynomolgus monkeys were dosed Q7D at 50 or 300 mg/kg IV from early gestation through delivery.”
Species: carcinogenicity
Not conducted: no binding to rodent TSLP
“The conduct of carcinogenicity studies in rodents was not feasible as tezepelumab does not bind to rodents’ TSLP.”
Surrogate used in
Yes: mouse surrogate anti-TSLP mAb M702 for in vivo pharmacology models only
“Of this total, ten studies were non-clinical pharmacology studies (including in vivo models using a murine surrogate anti-TSLP mAb, M702) and one study was a safety pharmacology study, which is described together with the non-clinical pharmacology reports.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“A 6-month SC and IV study in cynomolgus monkeys (once weekly dosing) represented the pivotal toxicology study to support the marketing approval of tezepelumab.”
Pivotal GLP studies
4 GLP cynomolgus monkey repeat-dose studies of up to 6 months
“The tezepelumab non-clinical safety package included 4 GLP cynomolgus monkey repeat-dose toxicology studies of up to 6 months in duration”
Route in tox
Subcutaneous and intravenous
“Tezepelumab was administered to cynomolgus monkeys at doses up to 300 mg/kg SC Q7D for 1, 3, and 6 months; up to 300 mg/kg IV Q7D for 1 month; and at 50 mg/kg IV Q7D for 6 months.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“In line with the guideline on the pre-clinical safety evaluation of biotechnology-derived pharmaceuticals (ICH S6 R1), no genotoxicity studies were carried out.”
Carcinogenicity
Not conducted; rodent studies not feasible (no binding to rodent TSLP); carcinogenicity risk assessment conducted
“The conduct of carcinogenicity studies in rodents was not feasible as tezepelumab does not bind to rodents’ TSLP. Therefore, a carcinogenicity risk assessment was conducted.”
Reproductive & developmental
Monkey ePPND (IV 50 or 300 mg/kg Q7D, early gestation through delivery): no maternal, fetal or infant effects
“In the maternal, embryo-fetal, and neonatal toxicity (ePPND) study, pregnant female cynomolgus monkeys were dosed Q7D at 50 or 300 mg/kg IV from early gestation through delivery. There were no tezepelumab-related effects (maternal, fetal, or infant).”
Safety pharmacology
Single-dose IV monkey study up to 300 mg/kg: no effect on hemodynamics, body temperature, respiration, ECG or neurobehavior
“In an in vivo safety pharmacology study conducted in the cynomolgus monkey, single dose IV injection of tezepelumab up to 300 mg/kg did not affect hemodynamic parameters, body temperature, respiration rate, ECG, or neurological behavior.”
Genotox: Ames
Not conducted (ICH S6(R1))
“In line with the guideline on the pre-clinical safety evaluation of biotechnology-derived pharmaceuticals (ICH S6 R1), no genotoxicity studies were carried out.”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“In line with the guideline on the pre-clinical safety evaluation of biotechnology-derived pharmaceuticals (ICH S6 R1), no genotoxicity studies were carried out.”
Genotox: in vivo
Not conducted (ICH S6(R1))
“In line with the guideline on the pre-clinical safety evaluation of biotechnology-derived pharmaceuticals (ICH S6 R1), no genotoxicity studies were carried out.”
Carcinogenicity model
Not conducted: rodent studies not feasible (no binding to rodent TSLP)
“The conduct of carcinogenicity studies in rodents was not feasible as tezepelumab does not bind to rodents’ TSLP.”
Carcinogenicity timing
Not required: weight of evidence; additional studies would not add clinically relevant data
“Therefore, given the limitations of the available rodent models and the weight of evidence indicating a lack of product-specific concern for the carcinogenicity potential for tezepelumab, it was determined that additional nonclinical studies would not offer new significant clinically relevant data to inform the risk”
hERG / QT
No hERG assay; single IV 300 mg/kg in telemetered monkeys: no effect on ECG or hemodynamics
“In an in vivo safety pharmacology study conducted in the cynomolgus monkey, single dose IV injection of tezepelumab up to 300 mg/kg did not affect hemodynamic parameters, body temperature, respiration rate, ECG, or neurological behavior.”
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 Tezspire 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 was the highest dose tested in each study; minimal to mild serum cholesterol decrease at 300 mg/kg (EMA assessment report, p. 30)
NOAEL / key findings
NOAEL was the highest dose tested in each study; minimal to mild serum cholesterol decrease at 300 mg/kg
“The NOAEL was the highest dose tested for each route of administration in each repeat-dose study. Serum cholesterol was minimally to mildly decreased at the 300 mg/kg dose level in most repeat-dose studies.”
Risksopen answer page →
Immune & cytokine safety
Mild to moderate decrease in anti-KLH IgG titers (TDAR) at 300 mg/kg
“Mean anti-KLH IgG titers were mildly to moderately decreased at 300 mg/kg.”
Biodistribution & persistence
Vss about 50 mL/kg in monkeys, similar to plasma volume; limited extravascular distribution
“The volume of distribution (Vss) estimated in the PK study (108662) in cynomolgus monkey was approximately 50 mL/kg which is similar to the plasma volume and demonstrated limited extravascular distribution.”
Modality-specific risk
Unknown malignancy risk from chronic TSLP inhibition
“the malignancy risk in humans by chronic inhibition of TSLP via tezepelumab treatment is currently unknown.”
Anti-drug antibodies: animals
ADA formed in monkeys but did not affect exposure; no effect on toxicology evaluation
“The formation of ADA did not affect exposure to tezepelumab during the dosing phase, and because all surviving animals maintained levels of bioactive drug, there was no effect on the toxicologic evaluation of tezepelumab.”
Anti-drug antibodies: patients
Asthma: ADA in 5% (29/601); treatment-emergent 2% (11); neutralizing in 1 patient (<1%)
“In patients with asthma (NAVIGATOR and an additional trial), anti-drug antibodies (ADA) were detected at any time in 29 (5%) out of 601 patients who received TEZSPIRE at the recommended dosing regimen during the 48 to 52‑week study period. Of these 29 patients, 11 patients (2% of patients treated with TEZSPIRE) developed treatment-emergent antibodies and 1 patient (<1% of patients treated with TEZSPIRE) developed neutralizing antibodies.”
Label warnings
- Hypersensitivity Reactions
- Acute Asthma Symptoms or Deteriorating Disease
- Risk Associated with Abrupt Reduction of Corticosteroid Dosage
- Parasitic (Helminth) Infection
- Live Attenuated Vaccines
Hypersensitivity & infusion reactionsInfections
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not stated; first-in-human single ascending dose study in adult healthy subjects
“This was a first-time-in-human study, conducted in adult healthy subjects.”
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 Tezspire 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 was the highest dose tested in each study; minimal to mild serum cholesterol decrease at 300 mg/kg (EMA assessment report, p. 30)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month (26-week) SC and IV cynomolgus monkey study (108824) with 5-month treatment-free phase
“A 6-Month (one weekly) subcutaneous and intravenous injection toxicity study of tezepelumab in Cynomolgus monkeys with a 5-Month treatment-free phase (Study: 108824)”
Pivotal GLP studies
4 GLP cynomolgus monkey repeat-dose studies of up to 6 months
“The tezepelumab non-clinical safety package included 4 GLP cynomolgus monkey repeat-dose toxicology studies of up to 6 months in duration”
DART package
Species: DART
Cynomolgus monkey (ePPND, IV from early gestation through delivery)
“In the maternal, embryo-fetal, and neonatal toxicity (ePPND) study, pregnant female cynomolgus monkeys were dosed Q7D at 50 or 300 mg/kg IV from early gestation through delivery.”
Reproductive & developmental
Monkey ePPND (IV 50 or 300 mg/kg Q7D, early gestation through delivery): no maternal, fetal or infant effects
“In the maternal, embryo-fetal, and neonatal toxicity (ePPND) study, pregnant female cynomolgus monkeys were dosed Q7D at 50 or 300 mg/kg IV from early gestation through delivery. There were no tezepelumab-related effects (maternal, fetal, or infant).”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed before the marketing application
“The tezepelumab non-clinical safety package included 4 GLP cynomolgus monkey repeat-dose toxicology studies of up to 6 months in duration, a maternal, embryo-fetal, and neonatal toxicity (ePPND) study in pregnant cynomolgus monkeys”
Carcinogenicity
Species: carcinogenicity
Not conducted: no binding to rodent TSLP
“The conduct of carcinogenicity studies in rodents was not feasible as tezepelumab does not bind to rodents’ TSLP.”
Carcinogenicity model
Not conducted: rodent studies not feasible (no binding to rodent TSLP)
“The conduct of carcinogenicity studies in rodents was not feasible as tezepelumab does not bind to rodents’ TSLP.”
Carcinogenicity timing
Not required: weight of evidence; additional studies would not add clinically relevant data
“Therefore, given the limitations of the available rodent models and the weight of evidence indicating a lack of product-specific concern for the carcinogenicity potential for tezepelumab, it was determined that additional nonclinical studies would not offer new significant clinically relevant data to inform the risk”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 6-month SC NOAEL 300 mg/kg: ~134x MRHD (210 mg Q4W) on AUC, 128x on Cmax
“These nonclinical safety data provide adequate margins of exposure between the observed 6-month repeat-dose study SC NOAEL (300 mg/kg) and the maximum recommended human dose (MRHD) of 210 mg SC every 4 weeks (approximately 134 times the MRHD on an AUC at steady state basis, and 128 times the MRHD on a Cmax at steady state basis).”
NOAEL / key findings
NOAEL was the highest dose tested in each study; minimal to mild serum cholesterol decrease at 300 mg/kg
“The NOAEL was the highest dose tested for each route of administration in each repeat-dose study. Serum cholesterol was minimally to mildly decreased at the 300 mg/kg dose level in most repeat-dose studies.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse surrogate M702 in OVA-induced asthma model: decreased airway hyperresponsiveness and BALF leukocytes
“M702 (anti-mouse TSLP surrogate antibody) decreased airway hyperresponsiveness and total leukocytes (neutrophils and eosinophils) in the bronchoalveolar lavage fluid (BALF) of animals treated with M702 in a mouse model of OVA-induced asthma.”
Why that model
Tezepelumab does not bind mouse TSLP, so a mouse surrogate antibody was developed
“Because of the lack of binding of tezepelumab to mouse TSLP, M702, a mouse surrogate antibody was developed for in vivo studies.”
Reviewer's view of the efficacy data
EMA: M702 data indicate TSLP blockade ameliorates allergic inflammation in OVA asthma model
“In an OVA challenge study, the data indicate that blockade of TSLP using M702 ameliorates signs of allergic inflammation in the OVA model of asthma.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies; weight-of-evidence risk assessment from chronic monkey data and TSLP literature
Why: No binding to rodent TSLP; weight of evidence shows no product-specific carcinogenicity concern · No relevant species · Weight of evidence
“The conduct of carcinogenicity studies in rodents was not feasible as tezepelumab does not bind to rodents’ TSLP. Therefore, a carcinogenicity risk assessment was conducted.”
“Therefore, given the limitations of the available rodent models and the weight of evidence indicating a lack of product-specific concern for the carcinogenicity potential for tezepelumab, it was determined that additional non-clinical studies would not offer new significant clinically relevant data to inform the risk.”
DARTAccepted
No fertility/early embryonic development study; fertility assessed only via reproductive organs in the 6-month monkey study
Why: Mating studies not practical in cynomolgus monkeys; no adverse effects in 6-month study · No relevant species · Within the guideline
“No development toxicity studies with tezepelumab were conducted to evaluate early embryonic development to implantation as it is not practical to do mating studies in cynomolgus monkeys.”
“Male and female fertility was indirectly assessed as components of the 6- month repeat-dose study and there were no tezepelumab-related adverse effects.”
DARTAcceptedBeyond the letter
No surrogate (M702) studies on TSLP role in early pregnancy and placentation
Why: Published mouse results strain-dependent · Other reason
“However, the applicant clarified that studies were not carried out using M702 due to strain-dependence of the results described in the published literature. The lack of studies is acceptable.”
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