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.”
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.”
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 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 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.”