Emrelis
telisotuzumab vedotin
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.”
Species: general tox
Cynomolgus monkey (GLP 4- and 13-week IV studies)
“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.”
Species: DART
Not conducted with the ADC (MMAE genotoxic, advanced cancer; ICH S9)
“The Applicant did not conduct reproductive or embryofetal development (EFD) toxicology studies with telisotuzumab vedotin as MMAE is genotoxic and affects rapidly dividing cells and the intended indication is for the treatment of patients with advanced cancer, in accordance with the ICH S9 guidance.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies in animals have not been performed with telisotuzumab vedotin-tllv or the small molecule MMAE.”
Surrogate used in
No surrogate used; cynomolgus monkey is the pharmacologically relevant species
“In addition, these studies support the use of cynomolgus monkey as the pharmacologically relevant species for toxicity assessments of telisotuzumab vedotin.”
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.”
Genotox: Ames
MMAE payload: negative in Ames assay
“MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178Y TK +/- mouse lymphoma forward mutation assay.”
Genotox: in vitro mammalian
MMAE payload: negative in L5178Y TK+/- mouse lymphoma forward mutation assay
“MMAE was not mutagenic in the bacterial reverse mutation (Ames) assay or the L5178Y TK +/- mouse lymphoma forward mutation assay.”
Genotox: in vivo
MMAE payload: positive in rat bone marrow micronucleus (aneugenic)
“MMAE was positive for genotoxicity in the in vivo rat bone marrow micronucleus study through an aneugenic mechanism.”
Carcinogenicity model
Not conducted (ADC or MMAE)
“Carcinogenicity studies in animals have not been performed with telisotuzumab vedotin-tllv or the small molecule MMAE.”
Carcinogenicity timing
Not required: FDA agreed carcinogenicity studies not warranted
“FDA agrees that carcinogenicity studies are not warranted to support this application.”
hERG / QT
MMAE: <50% hERG inhibition up to 100 µM; no QT prolongation in monkey repeat-dose study
“The MMAE payload exhibited limited (<50%) inhibition of human ether-a-go-go (hERG) channel currents up to 100 µM. Additionally, in vivo assessments in the repeat-dose toxicology study in monkeys with telisotuzumab vedotin did not show QT prolongation or any other cardiac electrophysiologic effect.”
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 Emrelis 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 ADCs
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: 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 (FDA multi-discipline review, p. 34)
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.”
Anti-drug antibodies: animals
No evidence of ADA in 13-week monkey study
“There were no apparent sex differences in exposure or accumulation over the 13-week period and no evidence of anti-drug antibody (ADA) development.”
Anti-drug antibodies: patients
22% (60/269) treatment-emergent ADA; 38% of ADA+ neutralizing
“Following administration of EMRELIS in LUMINOSITY, 22% (60/269) of patients tested positive for treatment-emergent antibodies against telisotuzumab vedotin-tllv at one or more post-baseline time points. Of those who tested positive for anti-drug antibody, neutralizing antibodies were detected in 38% (23/60) of patients.”
Label warnings
- Peripheral Neuropathy
- Interstitial Lung Disease /Pneumonitis
- Ocular Surface Disorders
- Infusion-Related Reactions
- 5 Embryo-Fetal Toxicity
NeurotoxicityImmune-mediated reactionsPulmonary toxicityOcular toxicityHypersensitivity & infusion reactionsEmbryo-fetal toxicity
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 Emrelis 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 ADCs
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: 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 (FDA multi-discipline review, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey IV study (every 2 weeks, seven doses) with 8-week recovery
“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.”
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.”
DART package
Species: DART
Not conducted with the ADC (MMAE genotoxic, advanced cancer; ICH S9)
“The Applicant did not conduct reproductive or embryofetal development (EFD) toxicology studies with telisotuzumab vedotin as MMAE is genotoxic and affects rapidly dividing cells and the intended indication is for the treatment of patients with advanced cancer, in accordance with the ICH S9 guidance.”
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.”
PPND / ePPND: when
PPND not conducted (with fertility and EFD studies); ICH S9, advanced cancer
“Fertility and early embryonic development, embryo-fetal development, and prenatal/postnatal development studies were not conducted for telisotuzumab vedotin. In accordance with ICH S9, studies to assess effects on fertility and early embryonic development are not warranted to support marketing of pharmaceuticals intended for the treatment of patients with advanced cancer.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies in animals have not been performed with telisotuzumab vedotin-tllv or the small molecule MMAE.”
Carcinogenicity model
Not conducted (ADC or MMAE)
“Carcinogenicity studies in animals have not been performed with telisotuzumab vedotin-tllv or the small molecule MMAE.”
Carcinogenicity timing
Not required: FDA agreed carcinogenicity studies not warranted
“FDA agrees that carcinogenicity studies are not warranted to support this application.”
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
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
c-Met-positive NSCLC cell line-derived and patient-derived xenograft mouse models
“In vivo, telisotuzumab vedotin exhibited antitumor activity in c-Met-positive NSCLC cell line-derived xenograft mouse models and an NSCLC patient-derived xenograft model.”
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 agreed with the Applicant's pharmacology conclusions; objected only to promotional terms like 'potent'
“The Applicant uses terminology such as “potent” to describe results; such terms should be avoided as they are vague, subjective, and promotional. FDA agrees with the Applicant’s conclusions, with additional pertinent details below.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No fertility, embryo-fetal or pre/postnatal development studies with the ADC; MMAE payload EFD data relied on
Why: MMAE is genotoxic and affects actively dividing cells; advanced cancer indication per ICH S9 · Within the guideline · Pharmacology or kinetics · Serious disease
“The Applicant did not conduct reproductive or embryofetal development (EFD) toxicology studies with telisotuzumab vedotin as MMAE is genotoxic and affects rapidly dividing cells and the intended indication is for the treatment of patients with advanced cancer, in accordance with the ICH S9 guidance.”
“The FDA's Assessment: Reproductive toxicology studies with telisotuzumab vedotin are not warranted to support this application because MMAE is genotoxic and affects actively dividing cells.”
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