Epkinly
epcoritamab
Species
Monkey
Longest study
5 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“The nonclinical toxicity profile of epcoritamab was established in a series of nonclinical safety studies in cynomolgus monkeys, the only cross-reactive toxicology species.”
Why that species
Similar affinity for human and monkey CD3/CD20; no binding to dog, pig, rat, mouse CD20; CD3 not expected in other species
“The epcoritamab binding data indicates that among the species tested, the cynomolgus monkey is the only pharmacologically relevant species for toxicology studies.”
Surrogate molecule
No surrogate; clinical molecule tested in monkey
“We agree that the cynomolgus monkey is a pharmacologically relevant nonclinical species to assess the toxicity of epcoritamab, and general toxicology studies in other species are not warranted.”
Species: general tox
Cynomolgus monkey only (5-week study)
“The toxicity and toxicokinetics (TK) of epcoritamab were evaluated in a 5-week toxicity study in cynomolgus monkeys.”
Species: DART
Not conducted; monkey EFD study waived due to high immunogenicity in cynomolgus monkeys; weight-of-evidence assessment
“An EFD toxicity study of epcoritamab in cynomolgus monkeys was waived for phase 3 trials and registration of epcoritamab across ICH regions (FDA, EMEA, and PMDA) given the high potential for immunogenicity of epcoritamab in cynomolgus monkeys.”
Species: carcinogenicity
Not conducted (ICH S6(R1), S1A, S9)
“Carcinogenicity studies were not conducted for epcoritamab per ICHS6(R1), ICH S1A, and ICH S9 guidance.”
Surrogate used in
No surrogate used; clinical molecule in cynomolgus monkey, the only relevant species
“The epcoritamab binding data indicates that among the species tested, the cynomolgus monkey is the only pharmacologically relevant species for toxicology studies.”
Study lengthopen answer page →
Longest pivotal study
5 weeks
“The toxicity and toxicokinetics (TK) of epcoritamab were evaluated in a 5-week toxicity study in cynomolgus monkeys.”
Pivotal GLP studies
GLP 5-week monkey study (weekly IV, single IV, monthly SC) with 6-week recovery; 3-month study waived (ADA)
“Study: A 5-Week Toxicity Study of GEN3013 by Intravenous Infusion and Subcutaneous Injection in Cynomolgus Monkeys with Bioavailability, Local Tolerance, and a 6 Week Recovery Period / 503484 / eCTD location 4.2.3.2”
Route in tox
IV infusion (weekly or single) and SC injection (Days 1 and 29)
“Monkeys were administered epcoritamab as a once weekly (QW x 5) IV infusion (0 [control], 0.01, 0.1, or 1 mg/kg), a single IV infusion (0.1 or 1 mg/kg), or a once monthly (Days 1 and 29) subcutaneous (SC) injection (0.1, 1, or 10 mg/kg).”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1), ICH S9)
“Genotoxicity studies were not conducted for epcoritamab per ICHS6(R1) and ICH S9 guidance.”
Carcinogenicity
Not conducted (ICH S6(R1), S1A, S9)
“Carcinogenicity studies were not conducted for epcoritamab per ICHS6(R1), ICH S1A, and ICH S9 guidance.”
Reproductive & developmental
Not conducted; EFD waived due to monkey immunogenicity; WOE assessment; no reproductive organ findings in 5-week study
“An EFD toxicity study of epcoritamab in cynomolgus monkeys was waived for phase 3 trials and registration of epcoritamab across ICH regions (FDA, EMEA, and PMDA) given the high potential for immunogenicity of epcoritamab in cynomolgus monkeys.”
Safety pharmacology
Incorporated into pivotal 5-week monkey study (CNS, respiratory, CV)
“No specific safety pharmacology studies have been conducted with epcoritamab.”
Genotox: Ames
Not conducted (ICH S6(R1), ICH S9)
“Genotoxicity studies were not conducted for epcoritamab per ICHS6(R1) and ICH S9 guidance.”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1), ICH S9)
“Genotoxicity studies were not conducted for epcoritamab per ICHS6(R1) and ICH S9 guidance.”
Genotox: in vivo
Not conducted (ICH S6(R1), ICH S9)
“Genotoxicity studies were not conducted for epcoritamab per ICHS6(R1) and ICH S9 guidance.”
Carcinogenicity model
Not conducted (ICH S6(R1), S1A, S9)
“Carcinogenicity studies were not conducted for epcoritamab per ICHS6(R1), ICH S1A, and ICH S9 guidance.”
Carcinogenicity timing
Not required; FDA agreed carcinogenicity studies not needed for approval
“We agree that carcinogenicity studies are not needed to support the approval of BLA 761324.”
hERG / QT
No hERG assay; heart rate and RR, PR, QRS and QT intervals unaffected in monkey toxicity study
“Heart rate and RR, PR, QRS and QT intervals on Day 8 and 22 (repeated IV dosing) or Day 1 (single IV or SC dosing) were unaffected by treatment.”
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 Epkinly 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: NOAEL 0.1 mg/kg IV, 10 mg/kg SC; cytokine-related clinical signs, one death at 1 mg/kg IV; lymphoid depletion (EMA assessment report, p. 36)
NOAEL / key findings
NOAEL 0.1 mg/kg IV, 10 mg/kg SC; cytokine-related clinical signs, one death at 1 mg/kg IV; lymphoid depletion
“In the pivotal 5-week study (503484), the NOAEL in the IV repeat dosing group was 0.1 mg/kg, while the NOAEL in the SC dosing group was 10 mg/kg.”
Risksopen answer page →
Immune & cytokine safety
Dose-dependent first-dose cytokine release (lower with SC); strong neutralizing ADA at ≤0.1 mg/kg IV
“Dose-dependent increases in the plasma cytokines IL-2, IL-6, IL-8, IL-10, IL-15, IFN-γ, TNF-α, and MCP-1 were observed in all epcoritamab-treated groups after the first dose.”
Biodistribution & persistence
No ADME studies; target-mediated drug disposition; SC bioavailability 85% (males) / 49% (females)
“Epcoritamab displayed a clear pattern of target-mediated drug disposition, with faster clearance of drug at low doses compared with high doses.”
Modality-specific risk
First-dose cytokine release (CRS-like signs, mortality at ≥1 mg/kg IV); SC dosing lowered Cmax and cytokine peaks
“These findings were considered associated with elevated cytokine levels, primarily following the first dose.”
Anti-drug antibodies: animals
ADA in all monkeys at <=0.1 mg/kg and some at 1 mg/kg after repeated IV dosing
“Following repeated IV doses of epcoritamab, anti-drug antibodies (ADAs) were observed in all animals at ≤0.1 mg/kg and in some animals at 1 mg/kg.”
Anti-drug antibodies: patients
2.6% (4/156) LBCL and 4.2% (8/190) FL patients developed anti-epcoritamab antibodies; neutralizing not reported
“Anti-epcoritamab-bysp antibodies developed in 2.6% of patients (4 of 156) with LBCL and 4.2% of patients (8 of 190) with FL treated with EPKINLY in EPCORE NHL-1 (up to 10 cycles)”
Label warnings
Boxed warning: Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome
- Cytokine Release Syndrome
- Immune Effector Cell-Associated Neurotoxicity Syndrome
- Infections
- Cytopenias
- Embryo-Fetal Toxicity
Cytokine release syndromeNeurotoxicityInfectionsCytopeniasEmbryo-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 Epkinly 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: NOAEL 0.1 mg/kg IV, 10 mg/kg SC; cytokine-related clinical signs, one death at 1 mg/kg IV; lymphoid depletion (EMA assessment report, p. 36)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
5-week IV/SC cynomolgus monkey study with 6-week recovery
“Study: A 5-Week Toxicity Study of GEN3013 by Intravenous Infusion and Subcutaneous Injection in Cynomolgus Monkeys with Bioavailability, Local Tolerance, and a 6 Week Recovery Period”
Pivotal GLP studies
GLP 5-week monkey study (weekly IV, single IV, monthly SC) with 6-week recovery; 3-month study waived (ADA)
“Study: A 5-Week Toxicity Study of GEN3013 by Intravenous Infusion and Subcutaneous Injection in Cynomolgus Monkeys with Bioavailability, Local Tolerance, and a 6 Week Recovery Period / 503484 / eCTD location 4.2.3.2”
DART package
Species: DART
Not conducted; monkey EFD study waived due to high immunogenicity in cynomolgus monkeys; weight-of-evidence assessment
“An EFD toxicity study of epcoritamab in cynomolgus monkeys was waived for phase 3 trials and registration of epcoritamab across ICH regions (FDA, EMEA, and PMDA) given the high potential for immunogenicity of epcoritamab in cynomolgus monkeys.”
Reproductive & developmental
Not conducted; EFD waived due to monkey immunogenicity; WOE assessment; no reproductive organ findings in 5-week study
“An EFD toxicity study of epcoritamab in cynomolgus monkeys was waived for phase 3 trials and registration of epcoritamab across ICH regions (FDA, EMEA, and PMDA) given the high potential for immunogenicity of epcoritamab in cynomolgus monkeys.”
PPND / ePPND: when
No PPND study, per ICH S9 (advanced cancer); EFD also waived
“Per ICH S9, studies of fertility and early embryonic development, and pre- and postnatal toxicity were not conducted.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6(R1), S1A, S9)
“Carcinogenicity studies were not conducted for epcoritamab per ICHS6(R1), ICH S1A, and ICH S9 guidance.”
Carcinogenicity model
Not conducted (ICH S6(R1), S1A, S9)
“Carcinogenicity studies were not conducted for epcoritamab per ICHS6(R1), ICH S1A, and ICH S9 guidance.”
Carcinogenicity timing
Not required; FDA agreed carcinogenicity studies not needed for approval
“We agree that carcinogenicity studies are not needed to support the approval of BLA 761324.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey SC NOAEL 10 mg/kg: 5x clinical steady-state AUC; IV 1 mg/kg exposure equal to clinical AUC
“the NOAEL in the SC dosing group was 10 mg/kg. At the highest IV dose of 1 mg/kg, the exposure in males and females was the same as the clinical AUC0-t at steady state. At the highest SC dose of 10 mg/kg, the exposure margins in males and females were 5x the clinical AUC0-t at steady state.”
NOAEL / key findings
NOAEL 0.1 mg/kg IV, 10 mg/kg SC; cytokine-related clinical signs, one death at 1 mg/kg IV; lymphoid depletion
“In the pivotal 5-week study (503484), the NOAEL in the IV repeat dosing group was 0.1 mg/kg, while the NOAEL in the SC dosing group was 10 mg/kg.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human lymphoma cell line-derived xenograft (CDX) mouse models and one patient-derived xenograft (PDX) model
“The in vivo antitumor activity of epcoritamab was evaluated in various human lymphoma cell line-derived xenograft (CDX) mouse models and in one patient-derived xenograft (PDX) mouse model.”
Why that model
Epcoritamab does not bind dog, pig, rat or mouse CD20
“Epcoritamab bound a cell line transfected with rabbit CD20 (KD=6.93 nM), but did not bind cells expressing dog, pig, rat, or mouse CD20 under the conditions tested.”
Reviewer's view of the efficacy data
FDA: antitumor activity in prophylactic, established and late-treatment settings, but relative activity could not be established due to varied study designs
“Antitumor activity was observed in each of the prophylactic, established, and late treatment settings, but the relative antitumor activities could not be established due to the varied study designs and treatments.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAcceptedBeyond the letter
No 3-month monkey study; exposure could not be maintained with repeated dosing
Why: Exposure could not be maintained with repeated dosing; longer studies would not provide meaningful information · Pharmacology or kinetics
“A 3-month repeat-dose toxicity study of epcoritamab in cynomolgus monkeys was waived for phase 3 trials and registration of epcoritamab across the ICH regions (FDA, EMEA, and PMDA) based on the inability to maintain sufficient exposures to epcoritamab with repeated dosing.”
“We also agree that longer-duration repeat-dose toxicity studies in cynomolgus monkeys would not provide meaningful information and are not warranted.”
DARTAcceptedBeyond the letter
Embryo-fetal development study waived; weight-of-evidence risk assessment instead
Why: High immunogenicity in monkeys; weight of evidence from mechanism of action and other B-cell targeting agents · Weight of evidence · Class precedent · Pharmacology or kinetics
“An EFD toxicity study of epcoritamab in cynomolgus monkeys was waived for phase 3 trials and registration of epcoritamab across ICH regions (FDA, EMEA, and PMDA) given the high potential for immunogenicity of epcoritamab in cynomolgus monkeys. A risk assessment-based on a weight of evidence approach was conducted considering the mechanism of action of epcoritamab and relevant information from other B-cell targeting agents (Module 2.6.6).”
“Based on the above information, an EFD study can be waived.”
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