Elrexfio
elranatamab
Species
Monkey
Longest study
13 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
“Cynomolgus monkey was identified as the only relevant nonclinical toxicology species based on elranatamab binding affinities for BCMA and CD3.”
Why that species
Comparable binding to cyno and human BCMA and CD3; comparable BCMA+ cell frequency/phenotype
“Selection of cynomolgus as relevant species appears adequate, based on comparable binding affinity of elranatamab to cynomolgus and human BCMA and CD3, and a comparable frequency and phenotype of cynomolgus and human BCMA+ cells.”
Surrogate molecule
No surrogate; clinical molecule tested in monkey
“General toxicology studies were conducted in cynomolgus monkeys, a pharmacologically relevant species to assess the toxicity of elranatamab.”
Species: general tox
Cynomolgus monkey only
“General toxicology studies were conducted in cynomolgus monkeys, a pharmacologically relevant species to assess the toxicity of elranatamab.”
Species: DART
Not conducted (no stand-alone studies); reproductive organs assessed in repeat-dose monkey studies
“Stand-alone reproductive and development toxicity studies have not been conducted with elranatamab. Effects on reproductive organs were assessed as part of the repeat-dose toxicity studies.”
Species: carcinogenicity
Not conducted (ICH S9, ICH S6(R1))
“Carcinogenicity studies with elranatamab have not been conducted since they are generally not required for advanced cancer and protein-based biotherapeutics per ICH S9 and ICH S6(R1), respectively.”
Surrogate used in
No surrogate used; clinical molecule in cynomolgus monkey
“Selection of cynomolgus as relevant species appears adequate, based on comparable binding affinity of elranatamab to cynomolgus and human BCMA and CD3, and a comparable frequency and phenotype of cynomolgus and human BCMA+ cells.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“In the 3-month repeat-dose SC toxicity study, elranatamab doses of 0.3, 3, and 6 mg/kg/week (total of 14 doses) showed adverse clinical signs that correlated with decreased body weight and food consumption and contributed to mortality.”
Pivotal GLP studies
GLP cynomolgus: 1-month IV (0.01-0.3 mg/kg/wk), 1-month SC (0.3 mg/kg/wk), 3-month SC (0.3, 3, 6 mg/kg/wk); no recovery
“Recovery was not assessed in any of the general toxicology studies.”
Route in tox
IV and SC (SC is clinical route, used for longest study)
“Intravenous administration was originally assessed before subcutaneous administration was chosen as the clinical route.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies with elranatamab have not been conducted since they are generally not required for protein-based biotherapeutics per ICH S6(R1).”
Carcinogenicity
Not conducted (ICH S9 / S6(R1))
“Carcinogenicity studies with elranatamab have not been conducted since they are generally not required for advanced cancer and protein-based biotherapeutics per ICH S9 and ICH S6(R1), respectively.”
Reproductive & developmental
Not conducted (weight-of-evidence); reproductive organs assessed in 3-month monkey study, no effects
“Embryofetal developmental toxicity was evaluated using a weight of evidence (WOE) risk assessment”
Safety pharmacology
Incorporated into repeat-dose monkey studies (ECG, heart rate; respiratory/CNS by clinical observation)
“No safety pharmacology studies were conducted. Safety pharmacology was evaluated as part of the general toxicology studies performed with elranatamab.”
Genotox: Ames
Not conducted (ICH S6)
“Genotoxicity studies with elranatamab have not been conducted since they are generally not required for protein-based biotherapeutics per ICH S6(R1).”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genotoxicity studies with elranatamab have not been conducted since they are generally not required for protein-based biotherapeutics per ICH S6(R1).”
Genotox: in vivo
Not conducted (ICH S6)
“Genotoxicity studies with elranatamab have not been conducted since they are generally not required for protein-based biotherapeutics per ICH S6(R1).”
Carcinogenicity model
Not conducted (ICH S9, ICH S6(R1))
“Carcinogenicity studies with elranatamab have not been conducted since they are generally not required for advanced cancer and protein-based biotherapeutics per ICH S9 and ICH S6(R1), respectively.”
Carcinogenicity timing
Not required for advanced cancer and protein-based biotherapeutics
“Carcinogenicity studies with elranatamab have not been conducted since they are generally not required for advanced cancer and protein-based biotherapeutics per ICH S9 and ICH S6(R1), respectively.”
hERG / QT
No hERG assay; no ECG or heart rate effects in monkey toxicology studies
“We agree that the safety pharmacology assessment in the toxicology studies in cynomolgus monkeys did not show elranatamab induced effects on cardiovascular endpoints (ECG or heart rate).”
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 Elrexfio 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: No NOAEL in 3-month SC study (immunosuppression, infections, moribundity at all doses); NOAEL 0.3 mg/kg/wk in 1-month studies (FDA multi-discipline review, p. 58)
NOAEL / key findings
No NOAEL in 3-month SC study (immunosuppression, infections, moribundity at all doses); NOAEL 0.3 mg/kg/wk in 1-month studies
“Immunosuppression led to secondary infections and moribund euthanasia at all doses; no NOAEL was identified; dose-dependence was evident by incidence and timing”
Risksopen answer page →
Immune & cytokine safety
Transient cytokine increases mainly after first dose; B-cell/plasma cell depletion; ADA incidence up to 67% at low dose
“Increased cytokine levels were considered transient since they were mainly observed after the first dose but not after subsequent doses.”
Biodistribution & persistence
No tissue distribution studies; Vss ~0.1 L/kg in monkey, IgG-like limited distribution
“Protein binding and tissue distribution studies were not conducted for elranatamab in nonclinical species.”
Modality-specific risk
CRS from T-cell activation and immunosuppression/infection from BCMA+ B/plasma cell depletion
“The mode of action of elranatamab is associated with T cell activation and induction of cytokine release. Cytokine release syndrome is an identified risk for elranatamab and adequately addressed in the SmPC and the RMP.”
Anti-drug antibodies: animals
Monkey ADA incidence highest at low IV dose (67%), not detected (0%) at high dose
“Exposure increased in an approximately dose proportional manner and antibody drug antibody (ADA) incidence was greatest at the low dose (67%) and not detected (0%) at the high dose.”
Anti-drug antibodies: patients
9.5% (16/168) ADA-positive; 56% (9/16) of these neutralizing
“of the 168 participant who received recommended step-up and full dosage of ELREXFIO for up to 36 months and are evaluable for presence of ADA against elranatamab-bcmm, 9.5% (16/168) of patients tested positive for anti-elranatamab-bcmm-antibodies. Among the 16 patients who tested positive for ADAs, 56% (9/16) tested positive for 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 Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)
- Elrexfio rems
- Infections
- Neutropenia
- Hepatotoxicity
- Embryo-Fetal Toxicity
Cytokine release syndromeNeurotoxicityInfectionsCytopeniasHepatotoxicityEmbryo-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 Elrexfio 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: No NOAEL in 3-month SC study (immunosuppression, infections, moribundity at all doses); NOAEL 0.3 mg/kg/wk in 1-month studies (FDA multi-discipline review, p. 58)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month (13-week) SC cynomolgus monkey study (14 weekly doses), no recovery phase
“Cynomolgus monkeys (3/sex/group, 5-8 years of age, sexually mature, Mauritius origin) were administered elranatamab at 0, 0.3, 3 and 6 mg/kg SC, Q1W for 14 doses. Scheduled necropsy was performed on Day 93; one day after the last dose. A recovery period was not included.”
Pivotal GLP studies
GLP cynomolgus: 1-month IV (0.01-0.3 mg/kg/wk), 1-month SC (0.3 mg/kg/wk), 3-month SC (0.3, 3, 6 mg/kg/wk); no recovery
“Recovery was not assessed in any of the general toxicology studies.”
DART package
Species: DART
Not conducted (no stand-alone studies); reproductive organs assessed in repeat-dose monkey studies
“Stand-alone reproductive and development toxicity studies have not been conducted with elranatamab. Effects on reproductive organs were assessed as part of the repeat-dose toxicity studies.”
Reproductive & developmental
Not conducted (weight-of-evidence); reproductive organs assessed in 3-month monkey study, no effects
“Embryofetal developmental toxicity was evaluated using a weight of evidence (WOE) risk assessment”
PPND / ePPND: when
No PPND or other DART studies; reproductive organs assessed in monkey studies plus weight-of-evidence assessment
“No reproductive and/or developmental toxicity studies have been conducted with elranatamab. Effects on reproductive organs were assessed in pivotal studies using sexually mature male and female cynomolgus monkeys. Additionally, an integrated weight of evidence assessment was conducted to evaluate the potential for elranatamab to elicit developmental effects.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9, ICH S6(R1))
“Carcinogenicity studies with elranatamab have not been conducted since they are generally not required for advanced cancer and protein-based biotherapeutics per ICH S9 and ICH S6(R1), respectively.”
Carcinogenicity model
Not conducted (ICH S9, ICH S6(R1))
“Carcinogenicity studies with elranatamab have not been conducted since they are generally not required for advanced cancer and protein-based biotherapeutics per ICH S9 and ICH S6(R1), respectively.”
Carcinogenicity timing
Not required for advanced cancer and protein-based biotherapeutics
“Carcinogenicity studies with elranatamab have not been conducted since they are generally not required for advanced cancer and protein-based biotherapeutics per ICH S9 and ICH S6(R1), respectively.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL/LOEL 0.3 mg/kg exposure well below human exposure (0.1x or 0.2x)
“At the NOAEL/LOEL of 0.3 mg/kg, exposure in cynomolgus was well below the human exposure (0.1x or 0.2x).”
NOAEL / key findings
No NOAEL in 3-month SC study (immunosuppression, infections, moribundity at all doses); NOAEL 0.3 mg/kg/wk in 1-month studies
“Immunosuppression led to secondary infections and moribund euthanasia at all doses; no NOAEL was identified; dose-dependence was evident by incidence and timing”
Efficacy evidenceopen answer page →
Efficacy evidence
Multiple myeloma xenograft models (MM.1S, OPM2, MOLP8) with varying BCMA expression
“The anti-tumor activity of elranatamab was evaluated in MM xenograft models (with MM.1S, OPM2, and MOLP8 cell lines) that had varying levels of BCMA expression.”
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
EMA: in vivo xenograft studies provide sufficient proof-of-concept for use in multiple myeloma
“These in vivo studies provide sufficient proof-of-concept for the use of elranatamab in treatment of Multiple Myeloma.”
Flexibilityopen answer page →
Flexibility accepted
DARTVerdict not stated
No reproductive or developmental toxicity studies; reproductive organs assessed in the 3-month study in sexually mature monkeys
Why: No effects on reproductive organs in sexually mature monkeys
“Reproductive and developmental toxicity studies have not been conducted with elranatamab. No effects on reproductive organs were observed in the 3-months toxicity study in sexually mature monkeys.”
RecoveryVerdict not stated
No recovery phase in any general toxicology study
Why: Effects are expected to recover
“Recovery was not formally assessed in any study, but effects are expected to recover.”
Safety marginVerdict not stated
No exposure margin at the monkey NOAEL/LOEL of 0.3 mg/kg: 0.1x to 0.2x human exposure
“At the NOAEL/LOEL of 0.3 mg/kg, exposure in cynomolgus was well below the human exposure (0.1x or 0.2x).”
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