Monjuvi
tafasitamab
Species
Monkey
Longest study
13 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey only
“The safety of tafasitamab was evaluated in GLP-compliant 8- and 13-week general toxicology studies in cynomolgus monkeys.”
Why that species
Comparable binding to human, cynomolgus and rhesus CD19+ lymphocytes; low binding in rat and mouse, none in dog and rabbit
“Binding of tafasitamab-FITC to human, cynomolgus monkey and rhesus monkey lymphocytes was comparable. Tafasitamab showed lower binding to rat and mouse, and no binding to dog and rabbit lymphocytes.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“The studies were all conducted in cynomolgus monkeys (Macaca fascicularis), due to lack of tafasitamab antibody binding to lymphocytes in other common laboratory animal species.”
Species: general tox
Cynomolgus monkey only
“The safety of tafasitamab was evaluated in GLP-compliant 8- and 13-week general toxicology studies in cynomolgus monkeys.”
Species: DART
Not conducted: given with lenalidomide, a known teratogen (prior FDA agreement)
“Based on a prior agreement with the FDA, the Applicant did not conduct reproductive and developmental toxicity studies with tafasitamab since tafasitamab is administered in combination with lenalidomide, a known teratogen and embryo-fetal toxicant.”
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“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; all studies in cynomolgus monkeys
“The studies were all conducted in cynomolgus monkeys (Macaca fascicularis), due to lack of tafasitamab antibody binding to lymphocytes in other common laboratory animal species.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“The safety of tafasitamab was evaluated in GLP-compliant 8- and 13-week general toxicology studies in cynomolgus monkeys.”
Pivotal GLP studies
Cynomolgus monkey 8-week IV study (2, 10, 50 mg/kg every 2 weeks) and 13-week IV study (10, 30, 100 mg/kg weekly)
“once every two weeks at 2, 10 or 50 mg/kg in the 8-week study, or once every week at 0, 10, 30 or 100 mg/kg in the 13-week study.”
Route in tox
Intravenous infusion
“All general toxicology studies performed used the intended route for human use (i.e., intravenous administration via infusion) and included concomitant toxicokinetics”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Genotoxicity studies are generally not necessary to support marketing of biotechnology-derived pharmaceuticals such as tafasitamab as discussed in the ICH S6 guidance document.”
Carcinogenicity
Not conducted (advanced cancer, ICH S9)
“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
No DART studies (given with teratogen lenalidomide); weight-of-evidence: possible neonatal B-cell depletion; no reproductive-organ effects in 13-week monkey study
“Based on a prior agreement with the FDA, the Applicant did not conduct reproductive and developmental toxicity studies with tafasitamab since tafasitamab is administered in combination with lenalidomide, a known teratogen and embryo-fetal toxicant.”
Safety pharmacology
Incorporated into 8- and 13-week monkey studies (CV, respiratory, CNS); no findings of concern
“Monitoring of safety pharmacology parameters for vital organ functions (cardiovascular, respiratory and central nervous system) was incorporated into the 8-week and 13-week repeat-dose toxicology studies in cynomolgus monkeys”
Genotox: Ames
Not conducted (ICH S6)
“Genotoxicity studies are generally not necessary to support marketing of biotechnology-derived pharmaceuticals such as tafasitamab as discussed in the ICH S6 guidance document.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genotoxicity studies are generally not necessary to support marketing of biotechnology-derived pharmaceuticals such as tafasitamab as discussed in the ICH S6 guidance document.”
Genotox: in vivo
Not conducted (ICH S6)
“Genotoxicity studies are generally not necessary to support marketing of biotechnology-derived pharmaceuticals such as tafasitamab as discussed in the ICH S6 guidance document.”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“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)
“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
No ECG, arrhythmia or blood pressure effects in pivotal monkey toxicity studies
“Administration of tafasitamab was not associated with electrocardiographic evidence of cardiotoxicity, arrhythmogenesis, or effects on blood pressure when evaluated as part of the pivotal toxicity studies.”
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 Monjuvi 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: NOAEL 100 mg/kg/week (13-week); reversible B-cell depletion, reduced germinal center cellularity; tremors and body temperature changes at high dose (EMA assessment report, p. 40)
NOAEL / key findings
NOAEL 100 mg/kg/week (13-week); reversible B-cell depletion, reduced germinal center cellularity; tremors and body temperature changes at high dose
“In general, tafasitamab was well tolerated in single-dose studies up to 10 mg/kg and in repeat-dose studies up to 100 mg/kg, supporting the NOAEL of 100 mg/kg determined based on the 13-week”
Risksopen answer page →
Immune & cytokine safety
B-cell depletion with reduced serum IgG and reduced TDAR (KLH primary, tetanus toxoid secondary response)
“The findings correlated with reduced IgG concentration in serum and a reduction in primary and secondary antibody response to keyhole limpet haemocyanin (KLH) and tetanus toxoid (TT) respectively, in an assessment of the T-cell dependent antibody response (TDAR).”
Biodistribution & persistence
TCR (human, monkey): binding to B-lineage mononuclear leukocytes, blood lymphocytes and marrow precursors; no off-target binding
“There was no off-target binding of tafasitamab detected in tissue panels from the human and cynomolgus monkey.”
Modality-specific risk
B-cell depletion with immune dysfunction, including potential neonatal B-cell depletion after in utero exposure
“Based on the WOE risk assessment, treatment of pregnant women with tafasitamab may result in depletion of B cells and thus dysfunction of immune response in a newborn.”
Anti-drug antibodies: animals
Monkey ADA in 8/10 (2 mg/kg), 3/10 (10 mg/kg), 3/10 (50 mg/kg); ADA-mediated clearance lowered exposure with B-cell recovery
“This response was greatest at 2 mg/kg (8 of 10 animals), less at 10 mg/kg (3 of 10 animals) and at 50 mg/kg (3 of 10 animals). There was a relationship between tafasitamab antibody-mediated clearance and decline in tafasitamab concentrations and concomitant recovery of B-cells, especially at the low dose.”
Anti-drug antibodies: patients
ADA in 2.5% (2/81) of DLBCL patients (L-MIND) and 0.9% (3/327) of FL patients (inMIND)
“Following MONJUVI treatment, anti-tafasitamab-cxix antibodies developed in 2.5% (2/81) of patients with DLBCL in Study L-MIND (up to 23 cycles) and 0.9% (3/327) of patients with FL in Study inMIND (up to 12 cycles)”
Label warnings
- Infusion-Related Reactions
- Myelosuppression
- Infections
- Embryo-Fetal Toxicity
Hypersensitivity & infusion reactionsCytopeniasInfectionsEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
United States: first-in-human dose escalation in 27 patients with relapsed/refractory CLL/SLL at 3 centers
“27 R/R CLL or SLL 3 centers; 1 country (US)”
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 Monjuvi 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: NOAEL 100 mg/kg/week (13-week); reversible B-cell depletion, reduced germinal center cellularity; tremors and body temperature changes at high dose (EMA assessment report, p. 40)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey IV study (weekly) with 132-day recovery
“Monkeys were observed for 90 days and 132 days for recovery following the dosing periods in the 8-week and 13-week studies, respectively.”
Pivotal GLP studies
Cynomolgus monkey 8-week IV study (2, 10, 50 mg/kg every 2 weeks) and 13-week IV study (10, 30, 100 mg/kg weekly)
“once every two weeks at 2, 10 or 50 mg/kg in the 8-week study, or once every week at 0, 10, 30 or 100 mg/kg in the 13-week study.”
DART package
Species: DART
Not conducted: given with lenalidomide, a known teratogen (prior FDA agreement)
“Based on a prior agreement with the FDA, the Applicant did not conduct reproductive and developmental toxicity studies with tafasitamab since tafasitamab is administered in combination with lenalidomide, a known teratogen and embryo-fetal toxicant.”
Reproductive & developmental
No DART studies (given with teratogen lenalidomide); weight-of-evidence: possible neonatal B-cell depletion; no reproductive-organ effects in 13-week monkey study
“Based on a prior agreement with the FDA, the Applicant did not conduct reproductive and developmental toxicity studies with tafasitamab since tafasitamab is administered in combination with lenalidomide, a known teratogen and embryo-fetal toxicant.”
PPND / ePPND: when
No PPND or other DART studies: given with lenalidomide, a known teratogen (prior FDA agreement)
“Based on a prior agreement with the FDA, the Applicant did not conduct reproductive and developmental toxicity studies with tafasitamab since tafasitamab is administered in combination with lenalidomide, a known teratogen and embryo-fetal toxicant.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“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)
“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)
“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
Monkey NOAEL 100 mg/kg/week ~9x human AUC at 12 mg/kg/week
“In the 13-week repeat-dose general toxicity study in cynomolgus monkeys, no adverse effects on male and female reproductive organs were observed up to the highest dose tested, 100 mg/kg/week (approximately 9 times the human exposure based on AUC at the clinical dose of 12 mg/kg/week).”
NOAEL / key findings
NOAEL 100 mg/kg/week (13-week); reversible B-cell depletion, reduced germinal center cellularity; tremors and body temperature changes at high dose
“In general, tafasitamab was well tolerated in single-dose studies up to 10 mg/kg and in repeat-dose studies up to 100 mg/kg, supporting the NOAEL of 100 mg/kg determined based on the 13-week”
Efficacy evidenceopen answer page →
Efficacy evidence
SCID mouse subcutaneous xenografts of human Raji and RAMOS lymphoma; reduced tumor growth
“The in vivo antitumor activity of tafasitamab monotherapy was evaluated using subcutaneous xenograft models in severe combined immunodeficiency (SCID) mice engrafted with human Raji and RAMOS lymphoma cells. Tafasitamab treatment resulted in reduction in tumor growth.”
Why that model
Tafasitamab binds mouse Fc-gamma receptors with greater affinity than native IgG1, so human xenograft mouse models can test its efficacy
“Finally, tafasitamab binds with substantially greater affinity to mouse FcγRs compared to the native human IgG1 antibody. Hence, human xenograft mouse tumour models allow for testing of the antitumour efficacy of tafasitamab in vivo.”
Reviewer's view of the efficacy data
EMA: in vitro and in vivo proof of concept for tafasitamab with lenalidomide in lymphoma established
“Hence, non-clinical in vitro and in vivo proof of concept of tafasitamab in combination with lenalidomide for the treatment of lymphomas appear established.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies, including none in the pharmacologically relevant monkey; weight-of-evidence assessment instead
Why: Given in combination with lenalidomide, a known teratogen; waiver supported by prior FDA agreement and CHMP scientific advice · Other reason
“Based on a prior agreement with the FDA, the Applicant did not conduct reproductive and developmental toxicity studies with tafasitamab since tafasitamab is administered in combination with lenalidomide, a known teratogen and embryo-fetal toxicant.”
“This is considered acceptable for the present indication with treatment in combination with Lenalidomide, a drug known to be teratogenic or causing embryo-fetal lethality.”
CarcinogenicityAccepted
No carcinogenicity studies; carcinogenic potential, raised by secondary malignancies in the pivotal trial, addressed by comparison with rituximab
Why: Similar B-cell-depleting mode of action to rituximab; rituximab data show no increased risk of secondary malignancies · Class precedent · Within the guideline
“A comparison with rituximab was provided, which is considered acceptable due to the similar mode of action to deplete B-cells via ADCC and ADCP. Based on available rituximab data, no increased risk for SPMs induced by tafasitamab was expected.”
Similar precedents
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