Empliciti
elotuzumab
Species
no relevantMonkey
Longest study
none
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
None relevant; only a single-dose rhesus monkey study for off-target toxicity
“Due to the lack of a pharmacologically-relevant animal species to conduct toxicology studies, the scope of the toxicological evaluation for elotuzumab was limited to a tissue cross-reactivity study and in vivo studies that assessed the potential for off-target toxicity and local tolerance.”
Why that species
Binds only human CS1; no recognition of mouse or any nonhuman primate CS1 tested
“HuLuc63 specifically binds only to human CS1 and does not recognize CS1 from the mouse or any NHP species tested (see Figure 5).”
Surrogate molecule
No surrogate; human SLAMF7 transgenic mouse generated but judged not a valid toxicology model
“However, the mouse characterization results indicated that the human SLAMF7 transgenic mouse was not a valid alternative animal model for toxicology testing due to a lack of human SLAMF7 expression in both resting and activated T cells in this mouse model as compared to humans.”
Species: general tox
None (no repeat-dose studies; no relevant toxicology species or valid transgenic mouse)
“Repeat-dose toxicity studies of elotuzumab were not conducted due to the lack of a relevant toxicology species or a valid transgenic mouse model.”
Species: DART
Not conducted (no pharmacologically relevant species)
“No reproductive and developmental toxicology studies were conducted due to the lack of a pharmacologically-relevant animal species.”
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“No carcinogenicity studies were conducted. Carcinogenicity studies are not necessary to support the marketing of therapeutics intended to treat patients with advanced cancer as discussed in the ICH S9 guidance document”
Surrogate used in
No surrogate used; human SLAMF7 transgenic mouse generated but judged not a valid toxicology model
“However, the mouse characterization results indicated that the human SLAMF7 transgenic mouse was not a valid alternative animal model for toxicology testing due to a lack of human SLAMF7 expression in both resting and activated T cells in this mouse model as compared to humans.”
Study lengthopen answer page →
Longest pivotal study
0 (no repeat-dose toxicity studies)
“Repeat-dose toxicity studies of elotuzumab were not conducted due to the lack of a relevant toxicology species or a valid transgenic mouse model.”
Pivotal GLP studies
No repeat-dose studies; single-dose IV rhesus monkey study (0, 30, 100 mg/kg), rabbit local tolerance, human TCR
“A single dose of intravenously infused elotuzumab (0, 30, or 100 mg/kg) was well tolerated in rhesus monkeys with no clinical signs at any dose.”
Route in tox
IV (30-minute infusion)
“In this study, elotuzumab was administered via continuous IV infusion over 30 minutes to 3 groups of rhesus monkeys (1 monkey/sex/group) at doses of 0, 30, or 100 mg/kg.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“No genetic toxicology studies were conducted. Genetic toxicology studies are generally not necessary to support marketing of biotechnology-derived pharmaceuticals such as elotuzumab as discussed in the ICH S6 guidance document.”
Carcinogenicity
Not conducted (advanced cancer, ICH S9)
“No carcinogenicity studies were conducted. Carcinogenicity studies are not necessary to support the marketing of therapeutics intended to treat patients with advanced cancer as discussed in the ICH S9 guidance document”
Reproductive & developmental
Not conducted (no pharmacologically relevant species)
“No reproductive and developmental toxicology studies were conducted due to the lack of a pharmacologically-relevant animal species.”
Safety pharmacology
Not conducted (no relevant species); no CNS or cardiovascular effects expected from SLAMF7 binding
“Binding to SLAMF7 by elotuzumab is therefore not expected to have effects on CNS parameters or cardiovascular functioning. The absence of specific safety pharmacology studies is therefore acceptable.”
Genotox: Ames
Not conducted (ICH S6)
“No genetic toxicology studies were conducted. Genetic toxicology studies are generally not necessary to support marketing of biotechnology-derived pharmaceuticals such as elotuzumab as discussed in the ICH S6 guidance document.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“No genetic toxicology studies were conducted. Genetic toxicology studies are generally not necessary to support marketing of biotechnology-derived pharmaceuticals such as elotuzumab as discussed in the ICH S6 guidance document.”
Genotox: in vivo
Not conducted (ICH S6)
“No genetic toxicology studies were conducted. Genetic toxicology studies are generally not necessary to support marketing of biotechnology-derived pharmaceuticals such as elotuzumab as discussed in the ICH S6 guidance document.”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“No carcinogenicity studies were conducted. Carcinogenicity studies are not necessary to support the marketing of therapeutics intended to treat patients with advanced cancer as discussed in the ICH S9 guidance document”
Carcinogenicity timing
Not required (advanced cancer, ICH S9)
“No carcinogenicity studies were conducted. Carcinogenicity studies are not necessary to support the marketing of therapeutics intended to treat patients with advanced cancer as discussed in the ICH S9 guidance document”
hERG / QT
Not conducted (safety pharmacology waived by prior agreement with FDA)
“With prior agreement with the FDA, the Applicant did not conduct carcinogenicity, genotoxicity, safety pharmacology, repeat dose toxicity, or reproductive and developmental toxicity studies with elotuzumab.”
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 Empliciti 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 oncology monoclonal antibodies (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Single IV doses of 30 or 100 mg/kg well tolerated in rhesus monkeys (EMA assessment report, p. 20)
NOAEL / key findings
Single IV doses of 30 or 100 mg/kg well tolerated in rhesus monkeys
“Single IV administration of elotuzumab at dose levels of 30 or 100 mg/kg (≤ AUC[INF] range of 335 to 447 mg•h/mL) were well tolerated.”
Risksopen answer page →
Immune & cytokine safety
In vitro human whole-blood assay: elevated levels of 10 cytokines with elotuzumab
“An in vitro cytokine release experiment identified elevated levels of 10 cytokines in response to elotuzumab treatment.”
Biodistribution & persistence
Human TCR: staining of plasma cells/immunoblasts in multiple tissues only; no staining of any nonhuman tissue
“In the human tissues examined, elotuzumab stained the membrane and/or cytoplasm of plasma cells and/or immunoblasts in the bone marrow, breast, cervix, esophagus, Fallopian tube, gastrointestinal tract, liver, lymph node, pancreas, salivary gland, small intestine, spleen, stomach, thymus, thyroid, tonsil, ureter, and uterus.”
Modality-specific risk
Human-specific target: no in vivo animal safety data, so safety characterization relies on clinical data
“Elotuzumab only recognizes human SLAMF7 protein. Because elotuzumab does not recognize non-human forms of SLAMF7 protein, in vivo safety data from animal studies are irrelevant.”
Anti-drug antibodies: animals
Not analyzed in the mouse or monkey studies
“ADAs were not analyzed in either the mouse study or the monkey study, as it was not deemed pertinent to the interpretation of the results.”
Anti-drug antibodies: patients
18.5% (72/390) across four trials; 36% (19/53) in ELOQUENT-3
“Of 390 patients across four clinical studies including ELOQUENT-2 and in 53 patients in the ELOQUENT-3 trial, who were treated with EMPLICITI and evaluable for the presence of anti-product antibodies, 72 patients (18.5%) in the four clinical trials and 19 patients (36%) in the ELOQUENT-3 trial tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay.”
Label warnings
- Infusion Reactions
- Infections
- Second Primary Malignancies
- Hepatotoxicity
- Interference with Determination of Complete Response
Hypersensitivity & infusion reactionsInfectionsSecondary malignancyHepatotoxicity
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 Empliciti 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 oncology monoclonal antibodies (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Single IV doses of 30 or 100 mg/kg well tolerated in rhesus monkeys (EMA assessment report, p. 20)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
No repeat-dose study (no relevant toxicology species or valid transgenic mouse model)
“Repeat-dose toxicity studies of elotuzumab were not conducted due to the lack of a relevant toxicology species or a valid transgenic mouse model.”
Pivotal GLP studies
No repeat-dose studies; single-dose IV rhesus monkey study (0, 30, 100 mg/kg), rabbit local tolerance, human TCR
“A single dose of intravenously infused elotuzumab (0, 30, or 100 mg/kg) was well tolerated in rhesus monkeys with no clinical signs at any dose.”
DART package
Species: DART
Not conducted (no pharmacologically relevant species)
“No reproductive and developmental toxicology studies were conducted due to the lack of a pharmacologically-relevant animal species.”
Reproductive & developmental
Not conducted (no pharmacologically relevant species)
“No reproductive and developmental toxicology studies were conducted due to the lack of a pharmacologically-relevant animal species.”
PPND / ePPND: when
Not conducted: no pharmacologically relevant species; not warranted for advanced cancer (ICH S9)
“Due to the lack of pharmacologically relevant species, and because animal studies of fertility, early embryonic development and pre- and post-natal effect are not generally warranted to support marketing of pharmaceuticals intended for the treatment of patients with advanced cancer (as per ICH S9), these types of studies were not conducted with elotuzumab.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“No carcinogenicity studies were conducted. Carcinogenicity studies are not necessary to support the marketing of therapeutics intended to treat patients with advanced cancer as discussed in the ICH S9 guidance document”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“No carcinogenicity studies were conducted. Carcinogenicity studies are not necessary to support the marketing of therapeutics intended to treat patients with advanced cancer as discussed in the ICH S9 guidance document”
Carcinogenicity timing
Not required (advanced cancer, ICH S9)
“No carcinogenicity studies were conducted. Carcinogenicity studies are not necessary to support the marketing of therapeutics intended to treat patients with advanced cancer as discussed in the ICH S9 guidance document”
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
Single IV doses of 30 or 100 mg/kg well tolerated in rhesus monkeys
“Single IV administration of elotuzumab at dose levels of 30 or 100 mg/kg (≤ AUC[INF] range of 335 to 447 mg•h/mL) were well tolerated.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human myeloma xenografts (L363, OPM2) in immunodeficient mice treated with elotuzumab (HuLuc63)
“The anti-tumor activities of MuLuc63 and HuLuc63 were studied in xenograft mouse models with tumors grown from the human multiple myeloma cell lines L363 and OPM2.”
Why that model
Human tumour xenografts used; SLAMF7-mediated NK-cell stimulation is not possible with mouse NK cells
“Remarkably that this is true for mouse studies with human xenografts, indicating that the SLAMF7-mediated stimulation of NK-cell activity (not possible with mouse NK-cells) is not essential for the full activity of elotuzumab.”
Reviewer's view of the efficacy data
EMA: antitumour activity clearly shown in vitro and in vivo, with tumour eradication in mice
“The antitumour activity of elotuzumab has been clearly shown in vitro and in vivo. In vivo elotuzumab induced eradication of tumours in a number of mice, indicating its usefulness in this respect.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
No pharmacologically relevant species or valid transgenic mouse; no repeat-dose toxicity studies; safety program mainly in vitro with human cells and tissues
Why: No species-specific cross-reactivity · No relevant species · Within the guideline
“Due to the lack of species-specific cross-reactivity, no relevant animal species or valid transgenic mouse models were identified in which to conduct the nonclinical toxicology studies.”
Safety pharmacologyAcceptedBeyond the letter
No safety pharmacology studies
Why: SLAMF7 binding not expected to affect CNS or cardiovascular function · Pharmacology or kinetics
“Binding to SLAMF7 by elotuzumab is therefore not expected to have effects on CNS parameters or cardiovascular functioning. The absence of specific safety pharmacology studies is therefore acceptable.”
DARTVerdict not stated
No reproductive and developmental toxicity studies; risk assessment based on SLAMF7 tissue distribution and published literature instead
Why: Lack of a pharmacologically relevant animal species · No relevant species · Weight of evidence
“Safety pharmacology, repeat dose toxicity, and reproductive and developmental toxicity studies were not conducted due to the lack of a pharmacologically-relevant animal species. The Applicant submitted a risk assessment for the potential for reproductive and developmental toxicity for elotuzumab based on the tissue distribution of SLAMF7 and published literature.”
Similar precedents
BavencioAntibodies · avelumab · PD-L1Monkey only · 13 wkCampathAntibodies · alemtuzumab · CD52Monkey + rodent · 4 wkCyramzaAntibodies · ramucirumab · VEGFR2Monkey only · 39 wkDanyelzaAntibodies · naxitamab · GD2Rodent only · 13 wkDarzalexAntibodies · daratumumab · CD38Monkey only · 6 wkErbituxAntibodies · cetuximab · EGFRMonkey + rodent · 39 wk