Imdelltra
tarlatamab
Sources:FDA multi-discipline review ↗
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.”
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”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
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”