Tzield
teplizumab
Species
MonkeyMouse
Longest study
1 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
Mouse (surrogate antibody) for repeat-dose and DART; single-dose chimpanzee study with teplizumab
“As teplizumab was shown to only cross-react with CD3+ T cells from humans, gorillas, chimpanzees, and gibbons, minimal nonclinical investigations were conducted with teplizumab itself.”
Why that species
Teplizumab binds CD3+ T cells only from humans, gorillas, chimpanzees and gibbons; no rodent activity, so a mouse surrogate was used
“As teplizumab was shown to only cross-react with CD3+ T cells from humans, gorillas, chimpanzees, and gibbons, minimal nonclinical investigations were conducted with teplizumab itself.”
Surrogate molecule
Yes: anti-mouse CD3 epsilon surrogate mAb with same Fc modifications, used for mouse repeat-dose, fertility, EFD and PPND studies
“evaluation continued in mice with a surrogate antibody in a GLP 6 days repeat dose toxicology (RDT) study, male/female fertility and early embryonic (FEED) studies, embryonic development (EFD) and a pre-postnatal development (PPND) study.”
Species: general tox
CD-1 mouse with surrogate anti-mouse CD3 antibody (6-day study); chimpanzee single-dose only with teplizumab
“One GLP repeated dose toxicology study of 6 days duration with 6 weeks of recovery have been performed in CD-1 mice (study 7608-797).”
Species: DART
Mouse with surrogate antibody (male/female fertility, EFD, pre/postnatal)
“GLP-compliant reproductive studies were conducted with the surrogate antibody in mice and included separate fertility and early embryonic (FEED) studies in males and females, an embryo-fetal development (EFD) study and a prenatal and postnatal development (PPND) study.”
Species: carcinogenicity
Not conducted; no toxicologically relevant species and surrogate immunogenicity made a mouse study unfeasible
“Due to the absence of toxicologically relevant species and the use of a surrogate leading to immunogenicity, a carcinogenicity study in mice would not be feasible.”
Surrogate used in
Yes: anti-mouse CD3ε surrogate for repeat-dose, fertility, EFD and PPND studies (and NOD efficacy)
“evaluation continued in mice with a surrogate antibody in a GLP 6 days repeat dose toxicology (RDT) study, male/female fertility and early embryonic (FEED) studies, embryonic development (EFD) and a pre-postnatal development (PPND) study.”
Study lengthopen answer page →
Longest pivotal study
1 weeks
“One GLP repeated dose toxicology study of 6 days duration with 6 weeks of recovery have been performed in CD-1 mice (study 7608-797).”
Pivotal GLP studies
GLP 6-day CD-1 mouse study with surrogate antibody (SC and IV) plus recovery; no chronic studies
“One GLP repeated dose toxicology study of 6 days duration with 6 weeks of recovery have been performed in CD-1 mice (study 7608-797).”
Route in tox
Subcutaneous and intravenous
“This study utilized the surrogate antibody which was administrated both subcutaneously and intravenously to assess toxicity and toxicokinetic.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No genetic toxicology studies have been conducted with teplizumab or the surrogate.”
Carcinogenicity
Not conducted (short treatment, no rodent activity, anaphylaxis with surrogate); weight-of-evidence assessment
“The short duration of treatment, the absence of pharmacologic activity in the rodent (for teplizumab itself), and the observations of anaphylaxis and hypersensitivity following various dosing regimens in the rodent limit the utility of carcinogenic assessments”
Reproductive & developmental
Mouse surrogate: no fertility effects; EFD post-implantation loss at 20 mg/kg (NOAEL 0.3); PPND: impaired offspring immune response and F1 fertility
“In an embryofetal development study there was an increased incidence of post-implantation loss at the HD of 20 mg/kg that included the loss of the entire litter for multiple females leading to identifications of the MD (0.3 mg/kg) as the NOAEL.”
Safety pharmacology
Incorporated into single-dose chimpanzee study; no effects on temperature, ECG, heart rate, blood pressure or respiration
“No treatment-related effects on safety pharmacology endpoints, including body temperature, ECGs, heart rate, blood pressure, or respiratory rate were seen.”
Genotox: Ames
Not conducted (antibody; neither teplizumab nor surrogate tested)
“No genetic toxicology studies have been conducted with teplizumab or the surrogate.”
Genotox: in vitro mammalian
Not conducted (antibody; neither teplizumab nor surrogate tested)
“No genetic toxicology studies have been conducted with teplizumab or the surrogate.”
Genotox: in vivo
Not conducted (antibody; neither teplizumab nor surrogate tested)
“No genetic toxicology studies have been conducted with teplizumab or the surrogate.”
Carcinogenicity model
Not conducted with teplizumab or the surrogate
“Carcinogenicity studies were not performed with teplizumab or the surrogate.”
Carcinogenicity timing
Not required: weight-of-evidence assessment per ICH S1B(R1) and S6(R1)
“The absence of carcinogenicity studies is justified by the weight of evidence approach in line with the ICH S1B (R1) and ICH S6 (R1) guidelines.”
hERG / QT
No hERG (antibody); no ECG, heart rate or blood pressure effects in single-dose chimpanzee study
“No treatment-related effects on safety pharmacology endpoints, including body temperature, ECGs, heart rate, blood pressure, or respiratory rate were seen.”
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 Tzield 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 <0.3 mg/kg in intermittent-dose mouse surrogate study due to severe hypersensitivity; T-cell depletion and thymic medulla hypocellularity (FDA pharmacology/toxicology review, p. 8)
NOAEL / key findings
NOAEL <0.3 mg/kg in intermittent-dose mouse surrogate study due to severe hypersensitivity; T-cell depletion and thymic medulla hypocellularity
“The NOAEL was <0.3 mg/kg based on severe hypersensitivity reactions.”
Risksopen answer page →
Immune & cytokine safety
Transient cytokine increases (TNF, IL-6, IL-10, IFN-gamma) in chimpanzees; slight IL-6/IL-12 rise with surrogate in mice; anaphylaxis on intermittent surrogate dosing
“At both doses evaluated, slight increases (<3.5-fold) in IL-6 and IL-12 levels were evident, consistent with the release of cytokines seen following treatment of chimps with teplizumab.”
Biodistribution & persistence
Human TCR: staining restricted to T-cell regions of spleen, lymph nodes, MALT and thymus; no B-region staining
“Staining of lymphoid cells in B regions or non-T regions of lymphoid tissues was not observed.”
Modality-specific risk
T-cell depletion/immunosuppression (infection, EBV-like lymphoproliferation), cytokine release syndrome, hypersensitivity/anaphylaxis
“Increases in cytokines were also noted, indicating that cytokine release syndrome (CRS) may occur.”
Anti-drug antibodies: animals
Surrogate exposure lost in mouse DART studies, partly attributed to ADA; ADA not measured in pivotal studies
“Exposure was not maintained throughout the reproduction toxicity studies with Q3D SC dosing with the surrogate at low and/or mid doses. This has been partly attributed to ADA occurrence however the presence of ADA was not investigated in any pivotal study.”
Anti-drug antibodies: patients
ADA in 50-94% after first course across 4 studies; almost 100% after a second course
“Based on this evaluation, teplizumab is immunogenic with the overall ADA incidence varying between 50-94% as observed during the first course across the various treatment regimens and across the 4 studies. ADA incidence increased to almost 100%, when a second course of treatment was administered.”
Label warnings
Boxed warning: Viral Reactivation
- Viral Reactivation
- Cytokine Release Syndrome
- Serious Infections
- Lymphopenia
- Hypersensitivity Reactions
- Vaccinations
InfectionsCytokine release syndromeCytopeniasHypersensitivity & infusion reactions
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 Tzield 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 <0.3 mg/kg in intermittent-dose mouse surrogate study due to severe hypersensitivity; T-cell depletion and thymic medulla hypocellularity (FDA pharmacology/toxicology review, p. 8)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
1-month mouse surrogate study (SC every 3 days) with 3-month recovery, interrupted at recovery week 9
“Study 8233170 which was interrupted at week 9 of the 3-month recovery, included Q3D SC dosing of the surrogate in CRl:CDI(ICR) mice at 0.3; 3 and 20 mg/kg for 1 month.”
Pivotal GLP studies
GLP 6-day CD-1 mouse study with surrogate antibody (SC and IV) plus recovery; no chronic studies
“One GLP repeated dose toxicology study of 6 days duration with 6 weeks of recovery have been performed in CD-1 mice (study 7608-797).”
DART package
Species: DART
Mouse with surrogate antibody (male/female fertility, EFD, pre/postnatal)
“GLP-compliant reproductive studies were conducted with the surrogate antibody in mice and included separate fertility and early embryonic (FEED) studies in males and females, an embryo-fetal development (EFD) study and a prenatal and postnatal development (PPND) study.”
Reproductive & developmental
Mouse surrogate: no fertility effects; EFD post-implantation loss at 20 mg/kg (NOAEL 0.3); PPND: impaired offspring immune response and F1 fertility
“In an embryofetal development study there was an increased incidence of post-implantation loss at the HD of 20 mg/kg that included the loss of the entire litter for multiple females leading to identifications of the MD (0.3 mg/kg) as the NOAEL.”
PPND / ePPND: when
PPND in mouse with surrogate antibody completed before the marketing application
“In a pre- and postnatal toxicity study, pharmacologic effects on T and B cells were the only observations in maternal animals.”
Carcinogenicity
Species: carcinogenicity
Not conducted; no toxicologically relevant species and surrogate immunogenicity made a mouse study unfeasible
“Due to the absence of toxicologically relevant species and the use of a surrogate leading to immunogenicity, a carcinogenicity study in mice would not be feasible.”
Carcinogenicity model
Not conducted with teplizumab or the surrogate
“Carcinogenicity studies were not performed with teplizumab or the surrogate.”
Carcinogenicity timing
Not required: weight-of-evidence assessment per ICH S1B(R1) and S6(R1)
“The absence of carcinogenicity studies is justified by the weight of evidence approach in line with the ICH S1B (R1) and ICH S6 (R1) guidelines.”
Safety marginopen answer page →
Safety margin at NOAEL
Chimpanzee single-dose NOAEL ~4x total human dose per treatment cycle (BSA)
“mg/kg, approximately 4x the total human dose administered in a cycle of treatment based on body surface area (BSA).”
NOAEL / key findings
NOAEL <0.3 mg/kg in intermittent-dose mouse surrogate study due to severe hypersensitivity; T-cell depletion and thymic medulla hypocellularity
“The NOAEL was <0.3 mg/kg based on severe hypersensitivity reactions.”
Efficacy evidenceopen answer page →
Efficacy evidence
NOD mouse (spontaneous T1D) with anti-mouse CD3 surrogate: diabetes onset delayed ~5 weeks, incidence reduced ~30%
“In pharmacology studies in non-obese diabetic (NOD) mice, a model of spontaneous autoimmune development of diabetes, a single 5-day treatment cycle with the surrogate delayed the onset and reduced the incidence of diabetes by approximately 5 weeks and 30%, respectively.”
Why that model
CD3 poorly conserved; teplizumab binds only human, gorilla, chimpanzee and gibbon CD3
“CD3 is poorly conserved across species. Teplizumab cross-reacts only with human, gorilla, chimpanzee, and gibbon CD3+ T cells.”
Reviewer's view of the efficacy data
EMA: package limited; teplizumab active only in chimpanzee, so most knowledge comes from the mouse surrogate
“The non-clinical package is limited by that fact that teplizumab being only pharmacologically active in the chimpanzee (in addition to humans) and therefore most knowledge comes from studies with a mouse surrogate CD3 monoclonal antibody.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted
Teplizumab tested only in a single-dose chimpanzee study; repeat-dose and DART studies used a mouse surrogate anti-CD3 antibody
Why: No cross-reactivity except human, gorilla, chimpanzee and gibbon; no other relevant species · No relevant species · Within the guideline
“Lack of cross-reactivity with other species than human, gorilla, chimpanzee and gibbon was confirmed in silico, and it is therefore agreed that, in addition to chimpanzee, no relevant species for further non-clinical testing of teplizumab are available.”
Study lengthAcceptedBeyond the letter
No chronic toxicity study with the surrogate; the study that would have covered it was interrupted
Why: No target organ of toxicity in either species; comparable PD of teplizumab and surrogate · Weight of evidence · Pharmacology or kinetics
“No chronic studies with the surrogate were conducted in accordance with the ICH S6 (R1) guideline. The interrupted study 8233170 would have covered this requirement.”
“Considering the absence of target organ for toxicity in both species and the comparable PD effect of teplizumab and the mouse surrogate on the immune cell populations, the absence of longer duration studies can be accepted.”
CarcinogenicityAccepted
No carcinogenicity studies for a non-oncology immunomodulator; weight-of-evidence assessment instead
Why: Weight of evidence from literature, animal and clinical data; short-term treatment schedule · Weight of evidence · Within the guideline · Human data
“Carcinogenicity The absence of carcinogenicity studies is justified by the weight of evidence approach in line with the ICH S1B (R1) and ICH S6 (R1) guidelines.”
“Based on the weight-of-evidence from literature and teplizumab data from animal toxicology studies and clinical trials, and considering the short-term clinical treatment schedule, the theoretical risk of carcinogenicity is considered extremely low under the conditions of the labelled dosing.”
Juvenile toxAcceptedBeyond the letter
No juvenile animal toxicity study
Why: No relevant species; a rodent juvenile study with the surrogate would not add value · No relevant species
“The applicant justifies the absence of an animal juvenile study based on that there is no relevant animals’ species for teplizumab for this type of study and that a rodent juvenile toxicity study with the surrogate antibody would not add any value, which is agreed.”
Similar precedents
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