Emrelis
telisotuzumab vedotin
Sources:FDA multi-discipline review ↗
Species
MonkeyRat
Longest study
13 wk
Genotox
Partial / alternative Partial / alternative
Carcinogenicity
Not conducted Not conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey (relevant); rat non-binding (exploratory, MMAE-related effects)
“In addition, these studies support the use of cynomolgus monkey as the pharmacologically relevant species for toxicity assessments of telisotuzumab vedotin.”
Why that species
Binds human and monkey c-Met with similar EC50 (1.3 vs 1.5 nM); no binding to mouse, rat, rabbit c-Met
“In vitro, telisotuzumab bound to cells overexpressing human or monkey c-Met with EC50 values of 1.3 and 1.5 nM, respectively, but did not bind to cells expressing mouse, rat, or rabbit c-Met.”
Surrogate molecule
No surrogate; clinical ADC in monkey; MMAE payload data via Seagen right of reference
“The Applicant used information on the pharmacology, pharmacokinetics (PK), and toxicology profile of MMAE provided via right of reference from Seagen.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“The Applicant evaluated the safety of telisotuzumab vedotin in GLP-compliant 4- and 13-week studies in cynomolgus monkeys with the intended IV route of administration.”
Pivotal GLP studies
GLP IV cyno 4-week (Q3W x2) and 13-week (Q2W x7), 8-week recovery; non-GLP 2-week rat; MMAE rat/monkey studies
“In the 13-week GLP-compliant repeat-dose toxicology study in monkeys (Report No. R&D/18/0622, Study No. 2100-287), telisotuzumab vedotin was intravenously administered at doses of 0.5, 1.5, and 3 mg/kg every 2 weeks for a total of seven doses, followed by an 8-week recovery period.”
Route in tox
IV (clinical route)
“Route of administration: Intravenous”
Skipped studiesopen answer page →
Genotoxicity
Not conducted with ADC; MMAE aneugenic (positive rat micronucleus), Ames and mouse lymphoma negative
“Genetic toxicology studies were not conducted with telisotuzumab vedotin but were conducted with the MMAE payload.”
Carcinogenicity
Not conducted (not warranted for advanced cancer)
“FDA agrees that carcinogenicity studies are not warranted to support this application.”
Reproductive & developmental
Not conducted with ADC (ICH S9); MMAE rat EFD teratogenic; ovary/uterus and testis findings in repeat-dose
“Reproductive toxicology studies with telisotuzumab vedotin are not warranted to support this application because MMAE is genotoxic and affects actively dividing cells.”
Safety pharmacology
Incorporated into GLP monkey repeat-dose studies (ECG, clinical signs); MMAE hERG IC50 >100 µM
“Stand-alone safety pharmacology studies were not conducted with telisotuzumab vedotin.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
13-week cyno: no adverse findings to 3 mg/kg; 4-week: neutropenia/marrow at ≥6 mg/kg, ovary/uterus ≥3 mg/kg, eye, thymus
“Myelosuppression occurred at the middle and high doses, which correlated histologically with decreased bone marrow cellularity.”
Risksopen answer page →
Immune & cytokine safety
No substantial cytokine release from human PBMC; no ADA in 13-week monkey study; low C1q, no complement activation
“In an analysis of cytokine induction in PBMC cultures, telisotuzumab vedotin did not trigger any substantial release of pro-inflammatory cytokines IL-1b, IL-2, IL-6, TNF-α or IFN-γ from human PBMC after 48-hour treatment.”
Biodistribution & persistence
MMAE widely distributed in rat (bile, GI tract, bladder), mainly fecal elimination; ADC target-mediated disposition in monkey
“Radiolabeled MMAE was widely distributed following single IV administration to rats, with highest concentrations in the bile, gastrointestinal (GI) tract, and urinary bladder.”
Modality-specific risk
MMAE payload: myelosuppression, peripheral neuropathy, ocular, GI and reproductive toxicity; aneugenic payload
“Clinically, peripheral neuropathy occurred in 43% of patients. Peripheral neuropathy is a known toxicity of microtubule inhibitors such as MMAE.”