Tepezza
teprotumumab
Species
Monkey
Longest study
39 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
“Toxicity studies were conducted in a single species, i.e. cynomolgus monkeys, based on comparable binding affinity and functional activity of teprotumumab to human and cynomolgus IGF-1R and lack of reactivity with rodent IGF-1R.”
Why that species
Comparable binding affinity and functional activity at human and cynomolgus IGF-1R; no reactivity with rodent IGF-1R
“Toxicity studies were conducted in a single species, i.e. cynomolgus monkeys, based on comparable binding affinity and functional activity of teprotumumab to human and cynomolgus IGF-1R and lack of reactivity with rodent IGF-1R.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“Toxicity studies were conducted in a single species, i.e. cynomolgus monkeys, based on comparable binding affinity and functional activity of teprotumumab to human and cynomolgus IGF-1R and lack of reactivity with rodent IGF-1R.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Adult monkeys have been dosed for up to 39 weeks. Juvenile monkeys were tested in two separate studies (both 13 weeks).”
Pivotal GLP studies
GLP cynomolgus monkey IV studies: 7-week (twice weekly), 13-week and 39-week (once weekly, up to 75 mg/kg), plus 13-week juvenile
“Teprotumumab was administered at doses up to 75 mg/kg, with a frequency of 2x/wk in the initial 7-wk study, and 1x/wk in the longer 13-wk and 39-wk studies.”
Route in tox
Intravenous (bolus or slow bolus, once weekly)
“GLP toxicology studies in cynomolgus monkeys administered teprotumumab once weekly by intravenous (IV) bolus or slow IV bolus injection.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted, in accordance with ICH S6(R1).”
Carcinogenicity
Not conducted (ICH S6(R1)); weight-of-evidence: no neoplastic lesions in 39-week monkey study, anti-proliferative mechanism, low risk
“Based on the mechanism of action and supporting literature, the risk of carcinogenicity can be expected to be low.”
Reproductive & developmental
Monkey EFD (non-GLP): reduced fetal growth and teratogenicity (cranial/skull malformations) in all fetuses; no fertility or PPND studies
“Teprotumumab reduced fetal growth (measured by ultrasound in-life; body weight and measurements at C-section) and was clearly teratogenic in all 5/5 fetuses.”
Safety pharmacology
Incorporated into repeat-dose monkey studies (13- and 39-week); no treatment-related cardiovascular effects
“The 13-week monkey toxicology study (report # AGD00022) and the 39-week monkey toxicology study (report # AGD00061) included cardiovascular safety pharmacology endpoints; no treatment-related effects were apparent in either study.”
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 Tepezza 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: No NOAEL (LOAEL 3 mg/kg/week): halted weight gain, decreased ALP, thymic atrophy; juveniles also reduced bone growth and density (FDA pharmacology/toxicology review, p. 21)
NOAEL / key findings
No NOAEL (LOAEL 3 mg/kg/week): halted weight gain, decreased ALP, thymic atrophy; juveniles also reduced bone growth and density
“For adults, the low-dose (3 mg/kg/week IV) is the lowest adverse effect level (LOAEL), and a no observed adverse effect level (NOAEL) was not identified.”
Risksopen answer page →
Immune & cytokine safety
Reversible thymic atrophy/lymphoid depletion without peripheral T-cell depletion or infections; juvenile TDAR (KLH) unimpaired; ADA accelerated clearance
“In these studies, thymic lymphoid depletion did not result in depletion of T cells and was not associated with an increase in infections.”
Biodistribution & persistence
TCR: widespread staining (epithelial, endothelial, smooth muscle, nerve cells) in all human tissues except bone marrow
“Teprotumumab staining was detected in all human tissues examined, except for bone marrow.”
Modality-specific risk
Embryo-fetal toxicity from IGF signalling inhibition (fetal growth restriction, teratogenicity); impaired growth and bone in juveniles
“The developmental adverse effects observed are consistent with the pharmacology of teprotumumab as an inhibitor of IGF signalling pathways which are known to be involved in regulation of fetal growth and development.”