Talvey
talquetamab
Species
Monkey
Longest study
4 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 (tool molecule for pivotal tox); no rodent tox
“Toxicology studies were not conducted in rodents due to the lack of talquetamab or JNJ-64024701 cross reactivity in these species.”
Why that species
Talquetamab binds cyno CD3 but not cyno GPRC5D (~100-fold lower activity); tool molecule binds cyno GPRC5D and CD3
“Due to the lack of cross reactivity of talquetamab to cynomolgus monkey GPRC5D, the tool molecule (JNJ-64024701) was developed.”
Surrogate molecule
Yes: monkey-cross-reactive GPRC5DxCD3 tool molecule JNJ-64024701 (same CD3 arm, different GPRC5D arm)
“The tool molecule has the same CD3 binding arm but different GPRC5D binding arm as talquetamab, and binding and in vitro functional activity against cGPRC5D-expressing cells consistent with talquetamab against hGPRC5D-expressing cells.”
Species: general tox
Cynomolgus monkey only (pivotal 1-month GLP study with tool molecule JNJ-64024701)
“The toxicity and toxicokinetics (TK) of JNJ-64024701 were evaluated in a GLP-compliant 1-month repeatdose toxicity study in cynomolgus monkeys”
Species: DART
Not conducted: monkey EFD/enhanced PPND with talquetamab or tool molecule judged not feasible (weight-of-evidence)
“Based on a weight-of-evidence risk assessment (Mod2.6.6/Sec6.2), an embryo-fetal development or enhanced pre- and postnatal development study in cynomolgus monkeys with talquetamab or the tool molecule would not be feasible nor further inform pregnancy risk to multiple myeloma patients.”
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted with talquetamab. As indicated in the ICH S9 guidance, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
Surrogate used in
Yes: monkey-cross-reactive tool molecule JNJ-64024701 used for monkey toxicology
“Due to the lack of cross reactivity of talquetamab to cynomolgus monkey GPRC5D, the tool molecule (JNJ-64024701) was developed.”
Study lengthopen answer page →
Longest pivotal study
4 weeks
“The toxicity and toxicokinetics (TK) of JNJ-64024701 were evaluated in a GLP-compliant 1-month repeat”
Pivotal GLP studies
1-month GLP IV study of tool molecule in cynomolgus monkey (0, 10, 30 mg/kg weekly x4); non-GLP 4-week talquetamab tolerability study
“JNJ-64024701 (GCDB32 GPRC5DxCD3): A 1-Month GLP Intravenous Toxicity and Toxicokinetic Study in Cynomolgus Monkeys / Study T-2017-009”
Route in tox
IV in monkey tox (clinical route SC); SC local tolerance in rabbit
“This study evaluated the IV route of administration, whereas the intended clinical route of administration is SC injection.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6; biotechnology-derived product)
“Genotoxicity studies routinely conducted for pharmaceuticals have not been conducted and are not applicable to biotechnology-derived pharmaceuticals such as talquetamab per ICH S6.”
Carcinogenicity
Not conducted (ICH S9; advanced cancer)
“As indicated in the ICH S9 guidance, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
Reproductive & developmental
Not conducted (weight-of-evidence assessment; ADA limits exposure, no relevant species); reproductive organs examined in repeat-dose study
“We agree with the Applicant’s WOE-based approach for the assessment of reproductive and developmental toxicity.”
Safety pharmacology
Incorporated into 1-month GLP monkey study with tool molecule (CV, respiratory, CNS); no effects
“However, cardiovascular, respiratory, and observational CNS safety pharmacology endpoints were incorporated into the 1-month GLP repeat dose toxicity study conducted with the tool molecule in cynomolgus monkeys”
Genotox: Ames
Not conducted (ICH S6)
“Genotoxicity studies routinely conducted for pharmaceuticals have not been conducted and are not applicable to biotechnology-derived pharmaceuticals such as talquetamab per ICH S6.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genotoxicity studies routinely conducted for pharmaceuticals have not been conducted and are not applicable to biotechnology-derived pharmaceuticals such as talquetamab per ICH S6.”
Genotox: in vivo
Not conducted (ICH S6)
“Genotoxicity studies routinely conducted for pharmaceuticals have not been conducted and are not applicable to biotechnology-derived pharmaceuticals such as talquetamab per ICH S6.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted with talquetamab. As indicated in the ICH S9 guidance, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not required (FDA agrees not warranted)
“We agree that carcinogenicity studies are not warranted to support the approval of BLA 761342.”
hERG / QT
No hERG assay; tool molecule up to 30 mg/kg weekly had no effect on ECG, blood pressure, heart rate in monkeys
“The tool molecule (JNJ-64024701) at weekly IV doses up to 30 mg/kg had no effect on cardiovascular (electrocardiograms, blood pressure, heart rate), respiratory (respiration rate), or CNS (clinical observations and body temperature) parameters evaluated up to Week 4”
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 Talvey 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 adverse effects up to 30 mg/kg weekly (highest dose); transient lymphocyte decrease, increased globulins, fibrinogen, IL-10 (FDA multi-discipline review, p. 55)
NOAEL / key findings
No adverse effects up to 30 mg/kg weekly (highest dose); transient lymphocyte decrease, increased globulins, fibrinogen, IL-10
“No adverse effects on any toxicology or safety pharmacology parameter evaluated at up to the high dose of 30 mg/kg weekly”
Risksopen answer page →
Immune & cytokine safety
In vitro dose-dependent cytokine release (IL-6, IFN-g, TNF-a etc.); ADAs in 10/12 monkeys reduced exposure
“Antidrug antibodies (ADAs) were observed in 10/12 JNJ-64024701-treated monkeys, and ADA-positive animals exhibited decreased JNJ-64024701 exposure following repeated doses.”
Biodistribution & persistence
No distribution studies; IgG-like, confined mainly to vascular space; monkey half-life 9-12 days
“Traditional distribution studies were not conducted for talquetamab, which is an antibody with a molecular weight of 147 kDa.”
Modality-specific risk
On-target/off-tumor toxicity (GPRC5D in skin, hair follicles, tongue) and T-cell activation/cytokine release
“the purpose of this study was to assess the potential on-target/off-tumor toxicity of a CD3xGPRC5D bsAb.”
Anti-drug antibodies: animals
ADA in 10/12 tool-molecule-treated monkeys, with decreased exposure after repeated doses
“Antidrug antibodies (ADAs) were observed in 10/12 JNJ-64024701-treated monkeys, and ADA-positive animals exhibited decreased JNJ-64024701 exposure following repeated doses.”
Anti-drug antibodies: patients
ADA in 25% (0.4 mg/kg weekly) and 18% (0.8 mg/kg every 2 weeks) of patients
“45/177 (25%) patients treated with subcutaneous TALVEY 0.4 mg/kg weekly (median follow-up 5.7 months) and 24/130 (18%) patients treated with subcutaneous TALVEY 0.8 mg/kg every 2 weeks (median follow-up 3.1 months) developed anti-talquetamab-tgvs 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 ICANS
- TECVAYLI and TALVEY REMS
- Oral Toxicity and Weight Loss
- Infections
- Cytopenias
- Skin Toxicity
- Hepatotoxicity
- Embryo-Fetal Toxicity
Cytokine release syndromeNeurotoxicityInfectionsCytopeniasSkin reactionsHepatotoxicityEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
US and ex-US (Belgium, France, Germany, Israel, Netherlands, Poland, Korea, Spain): first-in-human dose escalation/expansion
“Study Location: This study was conducted at 47 centers that treated at least 1 participant in Belgium, France, Germany, Israel, the Netherlands, Poland, Republic of Korea, Spain, and the United States.”
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 Talvey 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 adverse effects up to 30 mg/kg weekly (highest dose); transient lymphocyte decrease, increased globulins, fibrinogen, IL-10 (FDA multi-discipline review, p. 55)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week (weekly x4) IV cynomolgus monkey study with tool molecule JNJ-64024701; no recovery period
“Monkeys were administered JNJ64024701 as a once weekly (QW x 4) IV bolus injection (0 [control], 10, or 30 mg/kg), followed by sacrifice and necropsy on Day 29; there was no recovery period.”
Pivotal GLP studies
1-month GLP IV study of tool molecule in cynomolgus monkey (0, 10, 30 mg/kg weekly x4); non-GLP 4-week talquetamab tolerability study
“JNJ-64024701 (GCDB32 GPRC5DxCD3): A 1-Month GLP Intravenous Toxicity and Toxicokinetic Study in Cynomolgus Monkeys / Study T-2017-009”
DART package
Species: DART
Not conducted: monkey EFD/enhanced PPND with talquetamab or tool molecule judged not feasible (weight-of-evidence)
“Based on a weight-of-evidence risk assessment (Mod2.6.6/Sec6.2), an embryo-fetal development or enhanced pre- and postnatal development study in cynomolgus monkeys with talquetamab or the tool molecule would not be feasible nor further inform pregnancy risk to multiple myeloma patients.”
Reproductive & developmental
Not conducted (weight-of-evidence assessment; ADA limits exposure, no relevant species); reproductive organs examined in repeat-dose study
“We agree with the Applicant’s WOE-based approach for the assessment of reproductive and developmental toxicity.”
PPND / ePPND: when
Not conducted: monkey EFD or enhanced PPND with talquetamab or tool molecule judged not feasible and uninformative (weight of evidence)
“Based on a weight-of-evidence risk assessment (Mod2.6.6/Sec6.2), an embryo-fetal development or enhanced pre- and postnatal development study in cynomolgus monkeys with talquetamab or the tool molecule would not be feasible nor further inform pregnancy risk to multiple myeloma patients.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted with talquetamab. As indicated in the ICH S9 guidance, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted with talquetamab. As indicated in the ICH S9 guidance, carcinogenicity studies are not warranted to support marketing for therapeutics intended to treat patients with advanced cancer.”
Carcinogenicity timing
Not required (FDA agrees not warranted)
“We agree that carcinogenicity studies are not warranted to support the approval of BLA 761342.”
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
No adverse effects up to 30 mg/kg weekly (highest dose); transient lymphocyte decrease, increased globulins, fibrinogen, IL-10
“No adverse effects on any toxicology or safety pharmacology parameter evaluated at up to the high dose of 30 mg/kg weekly”
Efficacy evidenceopen answer page →
Efficacy evidence
Myeloma cell line xenografts (H929 prophylactic; MM.1S, RPMI 8226 established) in humanized immunodeficient mice
“The in vivo antitumor activity of talquetamab was evaluated in cell line-derived xenograft (CDX) mouse models. These studies evaluated the prevention of tumorigenesis in a prophylactic model (H929 cell line) and tumor growth inhibition (TGI) in established tumor models (MM.1S and RPMI 8226 cell lines).”
Why that model
No binding to murine CD3, so efficacy mice were humanized with human PBMCs or T-cells
“Talquetamab does not bind murine CD3; therefore, the CDX studies were conducted in immunodeficient mice that were humanized by intravenous (IV) implantation of human peripheral blood mononuclear cells (PBMCs) or human T-cells.”
Reviewer's view of the efficacy data
EMA: xenograft studies gave in vivo proof of concept despite failure in the second therapeutic model
“Although talquetamab failed in second therapeutic xenograft tumour model (other MM origin cells and use of human pan T-cell implantation), these studies provided the proof of concept for in vivo functionality for this bi-specific Mab.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
No cross-reactivity of talquetamab with monkey GPRC5D; pivotal monkey toxicology used a surrogate tool molecule (JNJ-64024701)
Why: Talquetamab lacks cross-reactivity to monkey GPRC5D
“Due to the lack of cross reactivity of talquetamab to cynomolgus monkey GPRC5D, the tool molecule (JNJ-64024701) was developed.”
Study lengthCriticised but acceptedBeyond the letter
No 13-week study; longest general toxicology study was 1 month with the tool molecule
Why: ADAs reduced tool molecule exposure, so longer studies would add no value; limited PD alone not accepted as a reason · Pharmacology or kinetics
“Exposure to JNJ-64024701 was compromised following the development of ADAs in the 1-month repeat-dose toxicity study in cynomolgus monkeys. Longer-duration general toxicology studies with JNJ-64024701 would not provide meaningful information and are not warranted to support a BLA.”
“The limited PD effect observed in healthy monkey was expected and is not considered as an acceptable argument to omit the 13-week study. However, considering the reduced exposure and/or faster elimination of JNJ-64024701 due to ADA presence in almost all animals at this end of the study, it is obvious that a longer animal study with the tool molecule will add no additional value”
DARTAcceptedBeyond the letter
No embryo-fetal or enhanced pre- and postnatal development study; weight-of-evidence assessment instead
Why: ADAs would prevent adequate exposure throughout organogenesis in a monkey developmental toxicity study · Weight of evidence · Pharmacology or kinetics
“The FDA’s Assessment: We agree with the Applicant’s WOE-based approach for the assessment of reproductive and developmental toxicity.”
“Adequate drug exposure would not be maintained throughout organogenesis in a cynomolgus monkey developmental toxicity study, based on the development of ADAs in cynomolgus monkeys that reduced exposure of talquetamab in the single-dose pharmacokinetic study (Mod4.2.2.2/CP2017PK002)”
Similar precedents
ColumviMultispecifics · glofitamab · CD20 x CD3Monkey only · 4 wkElrexfioMultispecifics · elranatamab · BCMA x CD3Monkey only · 13 wkEpkinlyMultispecifics · epcoritamab · CD20 x CD3Monkey only · 5 wkLunsumioMultispecifics · mosunetuzumab · CD20 x CD3Monkey only · 26 wkLynozyficMultispecifics · linvoseltamab · BCMA x CD3Monkey only · 14 wkOrdsponoMultispecifics · odronextamab · CD20 x CD3Monkey only · 16 wk