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.”
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”
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)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“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.”