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.”
Species: general tox
Cynomolgus monkey only; no rodent studies (no pharmacologic activity)
“Toxicology studies evaluating weekly IV (15-minute infusion) administration of nipocalimab were conducted in cynomolgus monkeys. No studies were conducted in rodents, based on the absence of pharmacologic activity.”
Species: DART
Cynomolgus monkey (enhanced pre/postnatal development study); fertility from repeat-dose histopathology
“An enhanced ePPND study consisting of two distinct phases was conducted in cynomolgus monkeys.”
Species: carcinogenicity
Not conducted (not pharmacologically active in mouse or rat)
“Nipocalimab is not pharmacologically active in mouse or rat; therefore, carcinogenicity studies were not conducted.”
Surrogate used in
No surrogate; humanized FcRn transgenic (Tg32) mice used for in vivo pharmacology
“In vivo studies were performed using humanized FcRn mice (also called Tg32 mice,”
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.”
Genotox: Ames
Not conducted
“No genetic toxicology studies were conducted.”
Genotox: in vitro mammalian
Not conducted
“No genetic toxicology studies were conducted.”
Genotox: in vivo
Not conducted
“No genetic toxicology studies were conducted.”
Carcinogenicity model
Not conducted (not active in rodents); weight-of-evidence assessment
“Nipocalimab is not pharmacologically active in mouse or rat; therefore, carcinogenicity studies were not conducted.”
Carcinogenicity timing
Not required; weight-of-evidence accepted, carcinogenic potential unlikely
“Overall, the carcinogenic potential has been adequately addressed and it is considered that the WoE submitted by the applicant lends support to the conclusion that the carcinogenic potential of nipocalimab is unlikely.”
hERG / QT
No stand-alone studies; no cardiovascular, respiratory or CNS effects in 4- and 26-week monkey studies
“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”
Anti-drug antibodies: animals
ADA and neutralizing antibodies in most monkeys when serum nipocalimab <50 μg/mL, with decreased exposure
“ADAs were observed in most dosed animals after administration of nipocalimab when nipocalimab serum concentrations were less than 50 μg/mL, which tested positive for NAb and a corresponding decrease in exposure was observed.”
Anti-drug antibodies: patients
gMG: ADA 48% (49/102), 38.8% of these neutralizing; no clinically relevant effect
“In gMG clinical trials, antibodies to nipocalimab-aahu were detected in 49/102 (48%) adult and pediatric patients 12 years of age and older during 24-week treatment period. Out of the 49 patients who were positive for antibodies to nipocalimab-aahu, 19 (38.8%) patients had neutralizing antibodies to nipocalimab-aahu.”
Label warnings
- Infections
- Hypersensitivity Reactions
- Infusion-Related Reactions
InfectionsHypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
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
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).”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week GLP study (IV) with 8-week recovery
“Pivotal GLP-compliant repeat-dose studies consisted of 4- and 26-week studies in which reversibility was evaluated for 9 and 8 weeks, respectively.”
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”
DART package
Species: DART
Cynomolgus monkey (enhanced pre/postnatal development study); fertility from repeat-dose histopathology
“An enhanced ePPND study consisting of two distinct phases was conducted in cynomolgus monkeys.”
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).”
PPND / ePPND: when
ePPND in cynomolgus monkey (two phases): completed before the marketing application
“An enhanced ePPND study consisting of two distinct phases was conducted in cynomolgus monkeys.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not pharmacologically active in mouse or rat)
“Nipocalimab is not pharmacologically active in mouse or rat; therefore, carcinogenicity studies were not conducted.”
Carcinogenicity model
Not conducted (not active in rodents); weight-of-evidence assessment
“Nipocalimab is not pharmacologically active in mouse or rat; therefore, carcinogenicity studies were not conducted.”
Carcinogenicity timing
Not required; weight-of-evidence accepted, carcinogenic potential unlikely
“Overall, the carcinogenic potential has been adequately addressed and it is considered that the WoE submitted by the applicant lends support to the conclusion that the carcinogenic potential of nipocalimab is unlikely.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 26-week NOAEL lowered to 100 mg/kg by EMA: 10.8x (AUC) and 6.7x (Cmax) human exposure
“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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Nipocalimab in humanized FcRn Tg32 mice: collagen antibody-induced arthritis and immune thrombocytopenia models
“Improvement of the disease pathology was demonstrated in the collagen antibody-induced arthritis (CAIA) Tg32 mouse model and increasing platelet levels was shown in the immune thrombocytopenia (ITP) Tg32 mouse model.”
Why that model
No gMG animal model studied; human FcRn transgenic mice used in autoantibody-mediated disease models instead
“No proof-of-concept studies were conducted in gMG models; however, IV administration of nipocalimab to transgenic mice expressing human FcRn reduced autoantibody-mediated effects in models of collagen-induced arthritis and immune-mediated thrombocytopenia.”
Reviewer's view of the efficacy data
EMA: accepted as in vivo proof of concept for the mechanism, although not myasthenia gravis models
“These studies can nevertheless be accepted as non-clinical in-vivo proof of concept for the mechanism of action of nipocalimab, although they are not disease models for myasthenia gravis.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
No binding-affinity screen in non-rodent species other than monkey to select the toxicology species
Why: Cynomolgus monkey shown relevant by binding and functional data; addressed in scientific advice · No relevant species · Other reason
“Apparently, binding affinity studies for another non-rodent species than non-human primates (NHP) were not conducted, which would normally be expected in order to include/exclude relevant species.”
“However, as also addressed in a scientific advice (EMA/SA/0000049032), the lack of such assessment is accepted since the cynomolgus monkey, based on binding affinity and functional in vitro data, is considered an appropriate and relevant species for toxicology evaluation and studies in this species were already conducted.”
CarcinogenicityAccepted
No carcinogenicity studies for a chronic autoimmune therapy; weight-of-evidence assessment instead
Why: No cross-reactivity with rodent FcRn; WoE per ICH S6(R1) shows no increased carcinogenic risk · Within the guideline · No relevant species · Weight of evidence
“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.”
“Overall, the carcinogenic potential has been adequately addressed and it is considered that the WoE submitted by the applicant lends support to the conclusion that the carcinogenic potential of nipocalimab is unlikely.”
DARTCriticised but acceptedBeyond the letter
Fertility assessed in 26-week monkey study using sexually immature animals; no specialised fertility assessments
Why: Overall evidence does not indicate concerns regarding effects on fertility · Weight of evidence
“The used strategy is supported, but the monkeys used in the 26-week study were sexually immature (2-3 years of age) at study start which is not in line with the guideline.”
“The available evidence does not indicate any concerns regarding potential effects on fertility.”
DARTCriticised but acceptedBeyond the letter
Monkey ePPND dosing started on GD45, missing early organogenesis
Why: IgG transfer is limited during organogenesis and increases in the foetal period in monkeys and humans · Pharmacology or kinetics
“The late start of nipocalimab dosing on GD45 is not in accordance with current guidance and limits the opportunity to evaluate potential effects on early organogenesis.”
“In line with the applicant’s justification, dosing from GD45 is considered valid to assess the potential effects of nipocalimab on prenatal development because transfer of IgG is limited during organogenesis and increases during the foetal period through the end of gestation in both monkeys and humans.”
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