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.”
Species: general tox
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.”
Species: DART
Cynomolgus monkey (non-GLP embryo-fetal dose range-finding study only)
“The nonclinical program consisted primarily of primary and safety pharmacology studies, intravenous toxicity studies in monkeys (up to 39 weeks), and a non-GLP embryo-fetal dose range-finding study in monkeys.”
Species: carcinogenicity
Not conducted (ICH S6(R1))
“No carcinogenicity studies were conducted. In line with ICH S6(R1), this is acceptable.”
Surrogate used in
No surrogate used
“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.”
Genotox: Ames
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted, in accordance with ICH S6(R1).”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted, in accordance with ICH S6(R1).”
Genotox: in vivo
Not conducted (ICH S6(R1))
“Genotoxicity studies have not been conducted, in accordance with ICH S6(R1).”
Carcinogenicity model
Not conducted: no pharmacologically active rodent model, so rodent bioassays not feasible
“No pharmacologically-active rodent model was identified for teprotumumab; therefore, rodent carcinogenicity bioassays are not feasible.”
Carcinogenicity timing
Not required (FDA concurs)
“P/T concurs that no carcinogenicity studies are needed to support the safety of teprotumumab.”
hERG / QT
No hERG assay; no treatment-related cardiovascular findings in monkey repeat-dose studies (up to 150 mg/kg/week)
“Throughout the repeat-dose toxicity studies, no treatment-related findings were observed on cardiovascular and respiratory endpoints at teprotumumab doses of up to 150 mg/kg/week for 7 weeks and up to 75 mg/kg/week for 39 weeks.”
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
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: 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.”
Anti-drug antibodies: animals
ADA in some monkey samples, causing accelerated clearance
“The presence of ADAs was confirmed in some samples, which resulted in an accelerated clearance of teprotumumab.”
Anti-drug antibodies: patients
0% (0 of 41) of TEPEZZA-treated patients ADA-positive over 24 weeks (HZNP-TEP-301)
“In a randomized placebo-controlled study, HZNP-TEP-301, where active TED patients were administered placebo or TEPEZZA over a 24-week period, 2.4% (1 of 42) of placebo and 0% (0 of 41) of TEPEZZA treated patients tested positive for anti-teprotumumab antibodies at post-baseline visits.”
Label warnings
- Infusion Reactions
- Inflammatory Bowel Disease
- Hyperglycemia
- Hearing Impairment Including Hearing Loss
- Encephalopathy
Hypersensitivity & infusion reactionsGastrointestinalMetabolic & endocrineNeurotoxicity
US prescribing information, 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 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
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week IV cynomolgus monkey study with 24-week recovery
“A 39-Week Toxicity Study of RO4858696 Administered Once Weekly by Intravenous Injection to Cynomolgus Monkeys, with a 24-Week Recovery Period”
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.”
DART package
Species: DART
Cynomolgus monkey (non-GLP embryo-fetal dose range-finding study only)
“The nonclinical program consisted primarily of primary and safety pharmacology studies, intravenous toxicity studies in monkeys (up to 39 weeks), and a non-GLP embryo-fetal dose range-finding study in monkeys.”
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.”
PPND / ePPND: when
Not conducted; PPND study not warranted (mechanism-based teratogen), waiver requested and FDA concurred
“The Applicant did not submit a prenatal and postnatal development (PPND) study for teprotumumab, and P/T concurs that a PPND study is not warranted to support the TED indication at the labeled dose level.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6(R1))
“No carcinogenicity studies were conducted. In line with ICH S6(R1), this is acceptable.”
Carcinogenicity model
Not conducted: no pharmacologically active rodent model, so rodent bioassays not feasible
“No pharmacologically-active rodent model was identified for teprotumumab; therefore, rodent carcinogenicity bioassays are not feasible.”
Carcinogenicity timing
Not required (FDA concurs)
“P/T concurs that no carcinogenicity studies are needed to support the safety of teprotumumab.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey repeat-dose exposure ~8x human AUC (schedule-normalised)
“The cynomolgus AUC values were normalised to account for the difference in dosing schedule and provide a sufficient margin (approx. 8x) to the human exposure.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human tumour xenografts in nude mice: single 6 mg/kg IP dose down-regulated tumour IGF-1R (target engagement, not a TED model)
“In nude mice bearing human tumours expressing IGF-1R, single dose of teprotumumab (6 mg/kg IP) lead to down-regulation of IGF-1R on the tumour cells as demonstrated ex vivo.”
Why that model
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.
Reviewer's view of the efficacy data
FDA: TED mechanism of action plausible but not demonstrated to labeling standard; no PD study of autoantibody blockade
“Considering the overall weight of evidence (detailed in section 4.1.2 of this review, below), this reviewer concludes that the Applicant’s hypothesis may be accurate, but has not been demonstrated at the level usually expected for Investigator Brochure claims or labeling.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No definitive GLP embryofetal study; only a preliminary non-GLP monkey EFD study, GLP study waived
Why: Results of the preliminary non-GLP study · Weight of evidence
“This non-GLP study was intended as a preliminary EFD assay prior to the definitive GLP EFD study.”
“Based on the results, the Applicant requested that the GLP EFD study be waived, and DTOP concurred for the TED indication.”
DARTAcceptedBeyond the letter
No pre- and postnatal development study
Why: Mechanism-based teratogen with possible fetal loss; PPND study in monkeys not practical or feasible · Pharmacology or kinetics
“A PPND study was not performed. This is justified, because teprotumumab is a mechanism-based teratogen and potential increased foetal loss could not be ruled out, therefore studies evaluating PPND in cynomolgus monkeys would not be practical or feasible.”
“The Applicant did not submit a prenatal and postnatal development (PPND) study for teprotumumab, and P/T concurs that a PPND study is not warranted to support the TED indication at the labeled dose level.”
DARTAccepted
No stand-alone fertility study; fertility assessed by reproductive organ histopathology in monkey repeat-dose studies
Why: Mating studies not practical in non-human primates · Within the guideline
“A formal fertility study with teprotumumab has not been performed, since mating studies are not practical for NHPs.”
“No stand-alone studies to assess fertility and early embryonic development (FEED) were conducted with teprotumumab, and P/T concurs that a stand-alone FEED study is not warranted to support the TED indication at the labeled dose level.”
Safety marginVerdict not stated
No NOAEL in juvenile monkeys; lowest dose (3 mg/kg/week IV) was the LOAEL
“For juveniles, the low-dose (3 mg/kg/week IV) is the lowest adverse effect level (LOAEL), and no NOAEL was identified.”
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