Imaavy
nipocalimab
Species
Monkey
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Cynomolgus monkey only
“Toxicology studies evaluating weekly IV (15-minute infusion) administration of nipocalimab were conducted in cynomolgus monkeys.”
Why that species
Binds human and cynomolgus FcRn with similar picomolar affinity; no binding to mouse or rat FcRn
“and pH 7.4 with KD of ≤57.8 pM, 58 pM for human and cynomolgus monkey, respectively and did not bind to mouse or rat FcRn.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys (no rodent studies)
“No studies were conducted in rodents, based on the absence of pharmacologic activity.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In the 26-week study, weekly 15-minute IV infusions of 0, 20, 100, or 300 mg/kg (3/sex/group, main; 2/sex/group, recovery) resulted in transient tremors and reddened skin.”
Pivotal GLP studies
GLP cynomolgus monkey IV repeat-dose studies of 4 and 26 weeks, with recovery
“Pivotal GLP-compliant repeat-dose studies consisted of 4- and 26-week studies in which”
Route in tox
IV infusion
“Toxicology studies evaluating weekly IV (15-minute infusion) administration of nipocalimab were conducted in cynomolgus monkeys.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No genetic toxicology studies were conducted.”
Carcinogenicity
Not conducted (not active in rodents); weight-of-evidence: no increased carcinogenic risk
“Nipocalimab is a mAb which does not cross-react with rodent FcRn, precluding the conduct of traditional carcinogenicity studies. In line with ICH guideline S6(R1) and based on a WoE approach it was concluded that nipocalimab does not pose an increased carcinogenic risk.”
Reproductive & developmental
Monkey ePPND (100, 300 mg/kg weekly from GD45): placental infarcts with fetal loss at both doses; no direct fetal developmental effects
“These infarcts were associated with fetal loss (one stillborn fetus) at 100 mg/kg and 300 mg/kg (two aborted fetuses).”
Safety pharmacology
Incorporated into 4- and 26-week monkey IV studies: no cardiovascular, respiratory or CNS effects
“Safety pharmacology assessments were incorporated into the 4-week and 26-week IV toxicity studies in monkey; there were no effects of nipocalimab on cardiovascular, respiratory, or central nervous system parameters.”
First doseopen answer page →
First-in-human starting dose
First-in-human SAD in healthy volunteers started at 0.3 mg/kg IV, escalating to 60 mg/kg; derivation not stated
“In the SAD portion of the study, six groups received a single IV infusion of placebo (N=10) or escalating doses of nipocalimab at 0.3 mg/kg (N=3), 3 mg/kg (N=3), 10 mg/kg (N=6), 30 mg/kg (N=6), or 60 mg/kg (N=6).”
NOAEL / key findings
26-week NOAEL 100 mg/kg, as systemic lymphoproliferation in a euthanised high-dose monkey could not be excluded as drug-related
“As nipocalimab cannot be ruled out as involved in the mechanism of systemic lymphoproliferation in the euthanised monkey in the 26-week study, the NOAEL should be lowered to 100 mg/kg providing safety margins of 10.8 and 6.7 based on AUC0-last and Cmax, respectively.”
Risksopen answer page →
Immune & cytokine safety
KLH TDAR suppressed as expected from mechanism; tetanus toxoid response preserved during recovery in monkeys
“In the 8- and 26-week studies, nipocalimab inhibited the T-cell dependent antibody response to keyhole limpet hemocyanin, which is expected based on nipocalimab’s mechanism of action, but did not inhibit antibody response to tetanus toxoid challenge administered during the recovery periods.”
Biodistribution & persistence
Placental transfer of nipocalimab inhibited; very little fetal and neonatal exposure in monkey ePPND
“Nipocalimab also effectively inhibited placental transfer of itself and there was very little drug exposures to fetuses and neonates observed in the enhanced pre- and postnatal development (ePPND) study.”
Modality-specific risk
IgG lowering: impeded placental IgG transfer and reduced infant passive immunity
“Because IMAAVY reduces maternal serum IgG concentration and impedes placental IgG transfer to the fetus, passive immunity in the infant may be reduced for 6 months or more”