Tecvayli
teclistamab
Species
MonkeyRabbit
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 (rabbit used for SC local tolerance only)
“The cynomolgus monkey was selected as the only pharmacologically relevant species for the nonclinical PK and toxicology assessments of teclistamab based on cross-species comparisons of sequence homology, relative target-binding affinities, and functional activity in cell-based assays.”
Why that species
Binds monkey CD3 and BCMA (BCMA ~36-fold lower affinity); no rodent CD3 binding, rabbit not expected to bind
“The parental CD3 monoclonal antibody did not bind rodent CD3, and teclistamab is not expected to bind rabbit CD3 or BCMA due to low sequence similarity; thus, the cynomolgus monkey was determined to be a pharmacologically relevant species for toxicology studies.”
Surrogate molecule
No surrogate; clinical molecule tested in monkey
“The toxicity and toxicokinetics (TK) of teclistamab were evaluated in a 5-week repeat-dose toxicity study in cynomolgus monkeys.”
Species: general tox
Cynomolgus monkey only (5-week repeat-dose)
“The toxicity and toxicokinetics (TK) of teclistamab were evaluated in a 5-week repeat-dose toxicity study in cynomolgus monkeys.”
Species: DART
Not conducted; weight-of-evidence assessment (no informative species)
“No reproductive and developmental toxicity studies were conducted for teclistamab.”
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted with teclistamab.”
Surrogate used in
No surrogate used; clinical molecule tested in cynomolgus monkey
“The toxicity and toxicokinetics (TK) of teclistamab were evaluated in a 5-week repeat-dose toxicity study in cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
5 weeks
“The toxicity and toxicokinetics (TK) of teclistamab were evaluated in a 5-week repeat-dose toxicity study in cynomolgus monkeys.”
Pivotal GLP studies
GLP 5-week weekly IV monkey study (1, 10, 30 mg/kg) with 8-week recovery; 3-month study waived; rabbit SC local tolerance
“Monkeys were administered teclistamab (0 [control], 1, 10, or 30 mg/kg/dose, IV) once weekly for five total doses followed by an 8-week recovery period.”
Route in tox
IV in monkey (clinical route SC); single SC dose in rabbit for local tolerance
“This study evaluated the IV route of administration, whereas the clinical route of administration is subcutaneous (SC).”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Genotoxicity studies were not conducted with teclistamab.”
Carcinogenicity
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted with teclistamab.”
Reproductive & developmental
Not conducted; weight-of-evidence assessment (BCMA biology, knockout mice); no reproductive tissue findings in 5-week study
“No reproductive and developmental toxicity studies were conducted for teclistamab.”
Safety pharmacology
Incorporated into 5-week GLP monkey study (CV, respiratory, observational CNS); no effects
“Separate safety pharmacology studies were not conducted with teclistamab; however, the 5-week GLP study in cynomolgus monkey incorporated cardiovascular, respiratory as well as observational CNS assessments (body temperature and clinical signs).”
Genotox: Ames
Not conducted (ICH S6(R1))
“Genotoxicity studies were not conducted with teclistamab.”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1))
“Genotoxicity studies were not conducted with teclistamab.”
Genotox: in vivo
Not conducted (ICH S6(R1))
“Genotoxicity studies were not conducted with teclistamab.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted with teclistamab. 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 agreed carcinogenicity studies not needed
“We agree that carcinogenicity studies are not needed to support the approval of BLA 761261.”
hERG / QT
No hERG assay; no cardiovascular effects in monkey up to 30 mg/kg/week
“There were no teclistamab-related effects on examined cardiovascular, respiratory, or CNS parameters associated with IV administration up to 30 mg/kg/week in cynomolgus monkey.”
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 Tecvayli 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: NOEL 30 mg/kg/week (highest dose); no PD activity or adverse effects in monkey (FDA multi-discipline review, p. 44)
NOAEL / key findings
NOEL 30 mg/kg/week (highest dose); no PD activity or adverse effects in monkey
“The no-observed-effect level for 5 weekly IV doses of teclistamab-treated monkeys was 30 mg/kg , the highest dose tested”
Risksopen answer page →
Immune & cytokine safety
ADA in 21/30 monkeys (7 with reduced exposure); in vitro whole-blood cytokine release of IL-8, IFN-γ, TNF-α
“Antidrug antibodies (ADAs) were detected in 21/30 teclistamab-treated animals, and seven of these animals exhibited lower teclistamab exposure after dosing on Day 22 or Day 29.”
Biodistribution & persistence
No distribution studies; IgG expected confined mainly to vascular space
“Due to its molecular size, teclistamab is expected to be primarily confined to the vascular space with only limited distribution to the extracellular space, which is typical for IgG-based mAbs.”
Modality-specific risk
Cytokine release/T-cell activation by MOA; monkey uninformative (low BCMA affinity, few target cells, ADA)
“Teclistamab is expected to cause cytokine release due to the mechanism of action (MOA).”
Anti-drug antibodies: animals
ADA in 21/30 monkeys; seven had lower exposure after Day 22 or 29 dosing
“Antidrug antibodies (ADAs) were detected in 21/30 teclistamab-treated animals, and seven of these animals exhibited lower teclistamab exposure after dosing on Day 22 or Day 29.”
Anti-drug antibodies: patients
0.5% ADA (1/186 monotherapy; 2/379 with daratumumab/hyaluronidase)
“Among patients treated with subcutaneous TECVAYLI at various dosages, anti-teclistamab-cqyv antibodies developed in 1/186 (0.5%) of patients who received monotherapy (up to 27 months) and in 2/379 (0.5%) of patients who received combination therapy with daratumumab and hyaluronidase-fihj (up to 43 months).”
Label warnings
Boxed warning: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY, including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME
- Cytokine Release Syndrome
- Neurologic Toxicity including Immune Effector Cell-Associated Neurotoxicity Syndrome
- TECVAYLI and TALVEY REMS
- Hepatotoxicity
- Infections
- Neutropenia
- Hypersensitivity and Other Administration Reactions
- Embryo-Fetal Toxicity
Cytokine release syndromeNeurotoxicityHepatotoxicityInfectionsCytopeniasHypersensitivity & infusion reactionsEmbryo-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, Canada, France, Germany, Italy, Netherlands, Spain, Sweden, UK): first-in-human study
“Trial Location: This study was conducted at 39 centers that treated at least 1 subject in Belgium (2), Canada (4), France (6), Germany (3), Italy (2), Netherlands (1), Spain (7), Sweden (3), the United Kingdom (3), and the United States (8).”
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 Tecvayli 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: NOEL 30 mg/kg/week (highest dose); no PD activity or adverse effects in monkey (FDA multi-discipline review, p. 44)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
5-week weekly IV cynomolgus monkey study with 8-week recovery
“Monkeys were administered teclistamab (0 [control], 1, 10, or 30 mg/kg/dose, IV) once weekly for five total doses followed by an 8-week recovery period.”
Pivotal GLP studies
GLP 5-week weekly IV monkey study (1, 10, 30 mg/kg) with 8-week recovery; 3-month study waived; rabbit SC local tolerance
“Monkeys were administered teclistamab (0 [control], 1, 10, or 30 mg/kg/dose, IV) once weekly for five total doses followed by an 8-week recovery period.”
DART package
Species: DART
Not conducted; weight-of-evidence assessment (no informative species)
“No reproductive and developmental toxicity studies were conducted for teclistamab.”
Reproductive & developmental
Not conducted; weight-of-evidence assessment (BCMA biology, knockout mice); no reproductive tissue findings in 5-week study
“No reproductive and developmental toxicity studies were conducted for teclistamab.”
PPND / ePPND: when
Not conducted: reproductive and developmental toxicity studies would not be meaningful and are not warranted
“Similarly, reproductive and developmental toxicity studies would not provide meaningful information and are not warranted to support a BLA.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted with teclistamab.”
Carcinogenicity model
Not conducted (ICH S9, advanced cancer)
“Carcinogenicity studies were not conducted with teclistamab. 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 agreed carcinogenicity studies not needed
“We agree that carcinogenicity studies are not needed to support the approval of BLA 761261.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOEL 30 mg/kg IV weekly: 22x AUCtau, 48x Cmax vs human 1.5 mg/kg SC weekly
“the safety margins (at NOEL 30 mg/kg IV weekly dosing) were adequate, i.e. 48 times the Cmax and 22 times the AUCtau compared to subjects with relapsed/refractory multiple myeloma in Phase 1/2 study MajesTEC-1 (at steady-state exposure at 1.5 mg/kg SC weekly, the recommended weight-based dose regimen).”
NOAEL / key findings
NOEL 30 mg/kg/week (highest dose); no PD activity or adverse effects in monkey
“The no-observed-effect level for 5 weekly IV doses of teclistamab-treated monkeys was 30 mg/kg , the highest dose tested”
Efficacy evidenceopen answer page →
Efficacy evidence
Human MM xenografts (H929, RPMI-8226) in human PBMC/T-cell-engrafted NSG mice
“Teclistamab conferred dose-dependent antitumor activity in both xenograft mouse models of MM.”
Why that model
No cross-reactivity with rodent CD3, weak rodent BCMA binding; humanized immunodeficient mice used
“Teclistamab binds only weakly to rodent BCMA and does not cross-react with rodent or rabbit CD3.”
Reviewer's view of the efficacy data
EMA: xenograft studies gave in vivo proof of concept
“Nevertheless, these studies provided the proof of concept for in vivo functionality for this bi-specific Mab.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAcceptedBeyond the letter
Only a 5-week repeat-dose monkey study; no 13-week study
Why: No findings and neutralizing ADAs in the 5-week study; a 13-week study would not provide meaningful information · Weight of evidence
“Given the dearth of findings and the induction of neutralizing ADAs in the 5-week repeat-dose toxicity study in cynomolgus monkeys, a 13-week repeat-dose toxicity study would not provide meaningful information and is not warranted to support a BLA.”
SpeciesCriticised but acceptedBeyond the letter
No pharmacodynamic activity in the monkey toxicity study (lower monkey BCMA affinity, few target cells, neutralizing ADAs)
Why: PD absence attributed to lower monkey BCMA affinity, few BCMA-expressing target cells and neutralizing ADAs · Pharmacology or kinetics
“Teclistamab was administered at dose levels expected to be pharmacologically active, but there was no evidence of pharmacodynamic (PD) activity or teclistamab-related adverse effects.”
“Lack of teclistamab PD activity may be attributed to the lower binding affinity of teclistamab to cynomolgus monkey BCMA, the paucity of BCMA-expressing target cells in healthy cynomolgus monkeys, and the decreased teclistamab systemic exposure in animals affected by neutralizing ADAs.”
DARTAccepted
No reproductive and developmental toxicity studies; weight-of-evidence assessment using BCMA biology and BCMA-deficient mice
Why: No BCMA expression in human reproductive organs, so on-target/off-tumor risk in these tissues relatively low · Weight of evidence · Within the guideline
“The Applicant’s Position: No reproductive and developmental toxicity studies were conducted for teclistamab. In accordance with ICH S5(R3) and S6(R1) and the US FDA Guidance for Oncology, a weight of evidence based on the intended patient population, BCMA target biology including data from genetically modified mice that lack BCMA,”
“The FDA’s Assessment: We agree with the Applicant’s WOE-based approach for the assessment of reproductive and developmental toxicity. There is no BCMA gene or protein expression in human reproductive organs; therefore, the risk of on-target/off-tumor toxicity in these tissues is relatively low.”
OtherVerdict not stated
Monkey toxicity study used IV dosing while the clinical route is subcutaneous
“This study evaluated the IV route of administration, whereas the clinical route of administration is subcutaneous (SC).”
Similar precedents
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