Imdelltra
tarlatamab
Species
MonkeyMouse
Longest study
13 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 (pivotal); mouse surrogate muS757 for EFD and 1-month study
“The cynomolgus monkey was selected for toxicology testing given that tarlatamab similarly bound human and monkey CD3 and DLL3 but did not bind CD3 from other species.”
Why that species
Similar binding to human and monkey CD3 and DLL3; no binding to rodent, rabbit, dog, minipig T cells; DLL3 intracellular in normal tissue limits relevance
“However, the monkey may not be pharmacologically relevant considering DLL3 is expressed intracellularly in normal cells and tissues.”
Surrogate molecule
Yes: murine surrogate muS757 (binds mouse DLL3 and CD3) for 1-month mouse tox and EFD study
“Following the proposal of the FDA, a murine surrogate molecule of tarlatamab, designated muS757, was developed to evaluate potential effects of a DLL3-targeting BiTE molecule on embryofetal development in mice.”
Species: general tox
Cynomolgus monkey (10-day, 28-day and 3-month IV studies)
“The nonclinical safety assessment of tarlatamab was based on a 10-day exploratory as well as 28-day GLP and 3-month GLP repeat-dose IV toxicology studies with once weekly doses of up to 4500 µg/kg.”
Species: DART
Mouse EFD study with surrogate muS757
“Following the proposal of the FDA, a murine surrogate molecule of tarlatamab, designated muS757, was developed to evaluate potential effects of a DLL3-targeting BiTE molecule on embryofetal development in mice.”
Species: carcinogenicity
Not conducted (ICH S9)
“No carcinogenicity studies have been conducted nor are any planned in accordance with ICH S9 (ICH, 2010).”
Surrogate used in
Yes: mouse surrogate muS757 (binds mouse CD3 and DLL3) for EFD
“Two administrations of a tarlatamab surrogate, mus757, that binds mouse CD3 and DLL3, to pregnant mice on gestational days (GD) 6 and GD 13 did not result in maternal toxicity or embryo-fetal development toxicity at doses ≤4500 µg/kg.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“No adverse effects on any toxicology or safety pharmacology parameters evaluated at up to the high dose of 4500 µg/kg weekly for 3 months.”
Pivotal GLP studies
GLP cynomolgus 28-day (with 28-day recovery) and 3-month weekly IV studies up to 4500 µg/kg; non-GLP 10-day study; mouse surrogate 1-month
“The nonclinical safety assessment of tarlatamab was based on a 10-day exploratory as well as 28-day GLP and 3-month GLP repeat-dose IV toxicology studies with once weekly doses of up to 4500 µg/kg.”
Route in tox
IV infusion (clinical route)
“The IV route of administration was chosen for in vivo nonclinical studies based on the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Therefore, no genotoxicity studies have been conducted or are planned, consistent with ICH Harmonised Tripartite Guideline S6”
Carcinogenicity
Not conducted (ICH S9)
“No carcinogenicity studies have been conducted nor are any planned in accordance with ICH S9 (ICH, 2010).”
Reproductive & developmental
Mouse EFD study with surrogate muS757 (GD6, GD13): no maternal or EFD toxicity up to 4500 µg/kg; placental transfer; no fertility studies
“Two administrations of a tarlatamab surrogate, mus757, that binds mouse CD3 and DLL3, to pregnant mice on gestational days (GD) 6 and GD 13 did not result in maternal toxicity or embryo-fetal development toxicity at doses ≤4500 µg/kg.”
Safety pharmacology
Incorporated into monkey tox studies (ECG, respiratory rate, body temperature, neurologic exams)
“Electrocardiographic assessments, respiratory rate, body temperature measurements, and neurologic examinations were included on the toxicology studies in the cynomolgus monkey”
Genotox: Ames
Not conducted (ICH S6)
“Therefore, no genotoxicity studies have been conducted or are planned, consistent with ICH Harmonised Tripartite Guideline S6”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Therefore, no genotoxicity studies have been conducted or are planned, consistent with ICH Harmonised Tripartite Guideline S6”
Genotox: in vivo
Not conducted (ICH S6)
“Therefore, no genotoxicity studies have been conducted or are planned, consistent with ICH Harmonised Tripartite Guideline S6”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“No carcinogenicity studies have been conducted nor are any planned in accordance with ICH S9 (ICH, 2010).”
Carcinogenicity timing
Not required (none conducted or planned per ICH S9; FDA agreed)
“No carcinogenicity studies have been conducted nor are any planned in accordance with ICH S9 (ICH, 2010). The FDA’s Assessment: The FDA agrees.”
hERG / QT
No hERG/stand-alone study; monkey ECG: slight non-adverse heart rate rise with shorter PR, RR, QT at ≥500 µg/kg
“There were tarlatamab-related slight increases in heart rate at ≥ 500 µg/kg that were associated with decreased PR, RR, and QT intervals.”
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 Imdelltra 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 multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: HNSTD 4500 µg/kg (maximum feasible dose); lymphocyte decreases, transient heart rate increase, pituitary mononuclear infiltrates (FDA multi-discipline review, p. 65)
NOAEL / key findings
HNSTD 4500 µg/kg (maximum feasible dose); lymphocyte decreases, transient heart rate increase, pituitary mononuclear infiltrates
“Tarlatamab-related changes are reversible and clinically monitorable, and the highest non-severely toxic dose was determined to be 4500 µg/kg based on the absence of any tarlatamab-related adverse findings.”
Risksopen answer page →
Immune & cytokine safety
Inflammatory markers (CRP, MCP-1, IFNg) in 10-day study; dose-related ADAs, one ADA immune-complex vascular injury case
“One animal had vascular injury-associated changes in the heart and lung that were consistent with secondary effects likely mediated by ADA-related immune complexes.”
Biodistribution & persistence
Tarlatamab detected in monkey CSF at ~0.05% of serum; surrogate fetal serum up to 30x maternal
“muS757 was detected in fetal serum at concentrations up to 30-times higher than maternal serum concentrations, indicating the potential for tarlatamab to cross the placenta.”
Modality-specific risk
T-cell activation/cytokine release and on-target DLL3 tissue effects (pituitary infiltrates; DLL3 intracellular in brain/pituitary)
“At doses ≥50 µg/kg, minimal to mild mononuclear cell infiltrates were noted in the pituitary gland of monkeys”
Anti-drug antibodies: animals
Dose-related ADA incidence in monkeys, adding exposure variability; one ADA immune-complex vascular injury
“A dose-related increase in incidence of antidrug antibodies (ADAs) occurred, which potentially contributed to variability in exposure levels at the end of the study. One animal had vascular injury-associated changes in the heart and lung that were consistent with secondary effects likely mediated by ADA-related immune complexes.”
Anti-drug antibodies: patients
8% (36/445) treatment-emergent ADA; 38% (11/29) of ADA-positive patients neutralizing
“8% (36/445) of patients who received the recommended step-up and full dose of IMDELLTRA developed treatmentemergent ADA. In DeLLphi-301 and DeLLphi-304, which included neutralizing antibody assessments, 38% (11/29) of the patients who developed treatment-emergent ADA also developed neutralizing antibodies.”
Label warnings
Boxed warning: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME
- Cytokine Release Syndrome (CRS)
- Neurologic Toxicity Including ICANS
- Cytopenias
- Infections
- Hepatotoxicity
- Hypersensitivity
- Embryo-Fetal Toxicity
Cytokine release syndromeNeurotoxicityCytopeniasInfectionsHepatotoxicityHypersensitivity & infusion reactionsEmbryo-fetal toxicity
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 Imdelltra 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 multispecifics
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: HNSTD 4500 µg/kg (maximum feasible dose); lymphocyte decreases, transient heart rate increase, pituitary mononuclear infiltrates (FDA multi-discipline review, p. 65)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month (13-week) weekly IV cynomolgus monkey study; recovery phase not stated
“Tarlatamab: 3-Month Intravenous Toxicology Study in the Cynomolgus Monkey / Study Number: 122516 /eCTD location: Module 4.2.3.2 Key Drug-related Adverse Findings No adverse effects on any toxicology or safety pharmacology parameters evaluated at up to the high dose of 4500 µg/kg weekly for 3 months.”
Pivotal GLP studies
GLP cynomolgus 28-day (with 28-day recovery) and 3-month weekly IV studies up to 4500 µg/kg; non-GLP 10-day study; mouse surrogate 1-month
“The nonclinical safety assessment of tarlatamab was based on a 10-day exploratory as well as 28-day GLP and 3-month GLP repeat-dose IV toxicology studies with once weekly doses of up to 4500 µg/kg.”
DART package
Species: DART
Mouse EFD study with surrogate muS757
“Following the proposal of the FDA, a murine surrogate molecule of tarlatamab, designated muS757, was developed to evaluate potential effects of a DLL3-targeting BiTE molecule on embryofetal development in mice.”
Reproductive & developmental
Mouse EFD study with surrogate muS757 (GD6, GD13): no maternal or EFD toxicity up to 4500 µg/kg; placental transfer; no fertility studies
“Two administrations of a tarlatamab surrogate, mus757, that binds mouse CD3 and DLL3, to pregnant mice on gestational days (GD) 6 and GD 13 did not result in maternal toxicity or embryo-fetal development toxicity at doses ≤4500 µg/kg.”
PPND / ePPND: when
No PPND study; reproduction testing limited to mouse EFD with murine surrogate
“Animal reproduction studies have not been conducted with tarlatamab-dlle. In an embryo-fetal developmental toxicity study, a murine surrogate molecule was administered intravenously to pregnant mice during the period of organogenesis.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9)
“No carcinogenicity studies have been conducted nor are any planned in accordance with ICH S9 (ICH, 2010).”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“No carcinogenicity studies have been conducted nor are any planned in accordance with ICH S9 (ICH, 2010).”
Carcinogenicity timing
Not required (none conducted or planned per ICH S9; FDA agreed)
“No carcinogenicity studies have been conducted nor are any planned in accordance with ICH S9 (ICH, 2010). The FDA’s Assessment: The FDA agrees.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
HNSTD 4500 µg/kg (maximum feasible dose); lymphocyte decreases, transient heart rate increase, pituitary mononuclear infiltrates
“Tarlatamab-related changes are reversible and clinically monitorable, and the highest non-severely toxic dose was determined to be 4500 µg/kg based on the absence of any tarlatamab-related adverse findings.”
Efficacy evidenceopen answer page →
Efficacy evidence
Xenograft models in NSG mice injected with activated, expanded human T cells
“As tarlatamab does not cross-react to mouse CD3, the xenograft models used in the nonclinical pharmacology studies were conducted in immunocompromised mice (non-obese diabetic/severe combined immunodeficiency, interleukin 2 receptor gamma [NSG]) that were injected with activated, expanded human T cells before treatment with tarlatamab.”
Why that model
Tarlatamab does not bind mouse CD3, so human T cells were engrafted into immunodeficient mice
“Because tarlatamab does not bind mouse CD3, the in vivo anti-tumor activity of tarlatamab was evaluated using immunodeficient mice administered human PBMCs or T cells by IV infusion prior to treatment with tarlatamab.”
Reviewer's view of the efficacy data
FDA: no outstanding pharmacology/toxicology issues preventing approval
“Recommendation: There are no outstanding issues from a pharmacology/toxicology perspective that would prevent the approval of IMDELLTRA.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesQuestioned
Monkey used as the only toxicology species although DLL3 is intracellular in normal tissues, so toxicity may be underrepresented
Why: Monkey chosen because tarlatamab binds human and monkey CD3 and DLL3 similarly in vitro
“Though the monkey was chosen for toxicity testing based on the ability of tarlatamab to bind human and monkey CD3 and DLL3 similarly in in vitro assays, toxicity associated with tarlatamab may be underrepresented in the monkey given that immunohistochemistry data described above indicates that DLL3 is expressed intracellularly in normal tissues and cells.”
DARTAcceptedBeyond the letter
Embryo-fetal development assessed only in mice with a murine surrogate (muS757), not with tarlatamab
Why: Surrogate muS757 binds mouse CD3 and DLL3; developed at FDA's proposal · Pharmacology or kinetics
“Following the proposal of the FDA, a murine surrogate molecule of tarlatamab, designated muS757, was developed to evaluate potential effects of a DLL3-targeting BiTE molecule on embryofetal development in mice.”
“The FDA generally agrees with the Applicant’s conclusion and acknowledges that muS757 (a tarlatamab surrogate that binds mouse CD3 and DLL3) crossed the placental barrier.”
DARTAccepted
No dedicated fertility studies
Why: Not needed to support marketing of a drug for patients with advanced cancer · Within the guideline · Serious disease
“In addition, the Applicant did not conduct dedicated studies to assess fertility. In general, these studies are not needed to support a marketing application for a drug intended to treat patients with advanced cancer.”
Similar precedents
BlincytoMultispecifics · blinatumomab · CD19 x CD3Monkey + rodent · 13 wkColumviMultispecifics · glofitamab · CD20 x CD3Monkey only · 4 wkElrexfioMultispecifics · elranatamab · BCMA x CD3Monkey only · 13 wkEpkinlyMultispecifics · epcoritamab · CD20 x CD3Monkey only · 5 wkKimmtrakMultispecifics · tebentafusp · CD3 x gp100 (TCR fusion)No relevant species · noneKorjunyMultispecifics · catumaxomab · EpCAM x CD3No relevant species · none