Gamifant
emapalumab
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
“In in vitro studies, emapalumab (NI-0501) bound to human (hIFNγ) and cynomolgus monkey IFNγ with similar affinity, but did not bind to rodent IFNγ, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”
Why that species
Binds cynomolgus and rhesus IFN-γ; no binding to dog, rat or mouse IFN-γ; no neutralization of rodent IFN-γ
“Emapalumab was cross-reactive to both cynomolgus and rhesus monkey, but no binding was detected in the dog, rat, or mouse.”
Surrogate molecule
Yes: rat IgG1 anti-mouse IFN-γ antibody XMG1.2, used for mouse embryo-fetal development study and HLH disease models
“The Applicant characterized a commercially available rat IgG1 anti-mouse IFNγ monoclonal antibody (mAb), XMG1.2, and used it as a surrogate of emapalumab to conduct studies in murine HLH models, as well as in their assessments of potential effects on embryofetal development.”
Species: general tox
Cynomolgus monkey
“The Applicant evaluated the safety of emapalumab in GLP-compliant repeat-dose toxicology studies in cynomolgus monkeys.”
Species: DART
Mouse (EFD, with surrogate XMG1.2); no standalone fertility study
“Standalone fertility assessments were not conducted as they are not needed to support the marketing of this product for the intended treatment indication. No adverse effects on male or female reproductive organs were observed in the repeat-dose toxicity studies in cynomolgus monkeys. Embryo-fetal developmental toxicology studies were conducted in mice, with XMG1.2 used as surrogate for emapalumab.”
Species: carcinogenicity
Not conducted (ICH S6)
“No carcinogenicity studies were conducted with emapalumab as per International Conference on Harmonisation S6.”
Surrogate used in
Yes: rat anti-mouse IFN-γ antibody XMG1.2 for murine HLH models and mouse EFD
“The Applicant characterized a commercially available rat IgG1 anti-mouse IFNγ monoclonal antibody (mAb), XMG1.2, and used it as a surrogate of emapalumab to conduct studies in murine HLH models, as well as in their assessments of potential effects on embryofetal development.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“In a 13-week study, monkeys received weekly intravenous (IV) doses up to 200 mg/kg.”
Pivotal GLP studies
Cynomolgus monkey 8-week and 13-week repeat-dose toxicity studies
“No adverse effects on male or female reproductive organs were observed in the 8- or 13-week repeat-dose toxicity studies in cynomolgus monkeys.”
Route in tox
IV (weekly)
“In a 13-week study, monkeys received weekly intravenous (IV) doses up to 200 mg/kg.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“No genotoxicity studies were conducted with emapalumab as per International Conference on Harmonisation S6.”
Carcinogenicity
Not conducted (ICH S6)
“No carcinogenicity studies were conducted with emapalumab as per International Conference on Harmonisation S6.”
Reproductive & developmental
Mouse EFD with surrogate: antibody in maternal and fetal plasma; no maternal toxicity, teratogenicity or embryo-fetal effects
“The surrogate antibody was detected in the plasma of all treated pregnant mice and their corresponding fetuses. No maternal toxicity occurred and there was no evidence of teratogenicity or effects on embryo-fetal survival or growth.”
Safety pharmacology
ECG assessed in repeat-dose monkey studies; no effects on ECG intervals or arrhythmias
“All electrocardiograms were qualitatively and quantitatively within normal limits; no NI-0501-related effects on the RR, PR, QRS, or QTc intervals were found comparing pre-dose and post-dose group average values.”
Genotox: Ames
Not conducted (ICH S6)
“No genotoxicity studies were conducted with emapalumab as per International Conference on Harmonisation S6.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“No genotoxicity studies were conducted with emapalumab as per International Conference on Harmonisation S6.”
Genotox: in vivo
Not conducted (ICH S6)
“No genotoxicity studies were conducted with emapalumab as per International Conference on Harmonisation S6.”
Carcinogenicity model
Not conducted (ICH S6)
“No carcinogenicity studies were conducted with emapalumab as per International Conference on Harmonisation S6.”
Carcinogenicity timing
Not required for the proposed indication
“Neither genetic toxicology or carcinogenicity studies were conducted or are required to support the use of emapalumab in the proposed indication.”
hERG / QT
No hERG assay; no effects on ECG intervals (RR, PR, QRS, QTc) in monkey repeat-dose studies
“All electrocardiograms were qualitatively and quantitatively within normal limits; no NI-0501-related effects on the RR, PR, QRS, or QTc intervals were found comparing pre-dose and post-dose group average values.”
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 Gamifant 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: Tolerated up to 30 mg/kg/week (highest dose) in the follow-up monkey study (FDA multi-discipline review, p. 39)
NOAEL / key findings
Tolerated up to 30 mg/kg/week (highest dose) in the follow-up monkey study
“NI-0501 was tolerated in monkeys up to 30 mg/kg/week, the highest dose tested.”
Risksopen answer page →
Immune & cytokine safety
Transient impairment of primary anti-KLH IgG response (TDAR) in monkeys; robust response after second challenge
“Emapalumab transiently impaired monkey’s capacity to mount a primary anti-Keyhole Limpet Hemocyanin (KLH) IgG response 14 days after the first KLH challenge; however, a robust IgG response was observed in all monkeys 21 days after the second KLH challenge.”
Biodistribution & persistence
No cross-reactivity with the human tissues tested
“Emapalumab did not induce in vitro antibody-dependent cell cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) activity and it did not cross-react with a variety of human tissues tested.”
Modality-specific risk
Increased infection susceptibility from IFN-γ neutralization
“An increase in susceptibility to infection as consequence of an exaggerated immunomodulating (pharmacological) effect of emapalumab can’t be ruled out, since IFNγ neutralization favors infections.”
Anti-drug antibodies: animals
Not detected in the 13-week monkey study; inconclusive due to possible drug interference
“Anti-drug antibodies were not detected; however, the results are inconclusive due possible interference of the drug itself.”
Anti-drug antibodies: patients
Treatment-emergent ADA in 3% (1/33) of primary HLH patients (neutralizing) and 14% (5/35) in HLH/MAS trials (non-neutralizing)
“Treatment-emergent anti-drug antibodies (ADAs) were detected in 1/33 (3%) of patients in the primary HLH clinical trial. The ADAs in this patient were found to have neutralizing ability. Treatment-emergent ADAs were detected in 5/35 patients (14%) in the two HLH/MAS clinical trials. None of the ADAs in these 5 patients were found to have neutralizing ability.”
Label warnings
- Infections
- Increased Risk of Infection with Use of Live Vaccines
- 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
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Gamifant 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 monoclonal antibodies
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
This product's starting point
NOAEL / key findings: Tolerated up to 30 mg/kg/week (highest dose) in the follow-up monkey study (FDA multi-discipline review, p. 39)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week cynomolgus monkey (IV) with 8-week recovery
“NI-0501 13 Week Intravenous Infusion Toxicity Study in Cynomolgus Monkeys with an 8 Week Recovery Period”
Pivotal GLP studies
Cynomolgus monkey 8-week and 13-week repeat-dose toxicity studies
“No adverse effects on male or female reproductive organs were observed in the 8- or 13-week repeat-dose toxicity studies in cynomolgus monkeys.”
DART package
Species: DART
Mouse (EFD, with surrogate XMG1.2); no standalone fertility study
“Standalone fertility assessments were not conducted as they are not needed to support the marketing of this product for the intended treatment indication. No adverse effects on male or female reproductive organs were observed in the repeat-dose toxicity studies in cynomolgus monkeys. Embryo-fetal developmental toxicology studies were conducted in mice, with XMG1.2 used as surrogate for emapalumab.”
Reproductive & developmental
Mouse EFD with surrogate: antibody in maternal and fetal plasma; no maternal toxicity, teratogenicity or embryo-fetal effects
“The surrogate antibody was detected in the plasma of all treated pregnant mice and their corresponding fetuses. No maternal toxicity occurred and there was no evidence of teratogenicity or effects on embryo-fetal survival or growth.”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6)
“No carcinogenicity studies were conducted with emapalumab as per International Conference on Harmonisation S6.”
Carcinogenicity model
Not conducted (ICH S6)
“No carcinogenicity studies were conducted with emapalumab as per International Conference on Harmonisation S6.”
Carcinogenicity timing
Not required for the proposed indication
“Neither genetic toxicology or carcinogenicity studies were conducted or are required to support the use of emapalumab in the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
NOAEL / key findings
Tolerated up to 30 mg/kg/week (highest dose) in the follow-up monkey study
“NI-0501 was tolerated in monkeys up to 30 mg/kg/week, the highest dose tested.”
Efficacy evidenceopen answer page →
Efficacy evidence
Perforin-deficient mice infected with LCMV (HLH model) treated with surrogate antibody XMG1.2
“For the disease model, perforin-deficient (pfp-/-) mice were infected with lymphocytic choriomeningitis virus and received single injections of XMG1.2 at 3, 10, 30 or 100 mg/kg on day 6 post-infection.”
Why that model
Emapalumab does not neutralize mouse or rat IFN-γ
“Emapalumab neutralized human IFNγ in a dose dependent manner, with an IC50 of 0.9 μg/mL (equivalent to 6 nM), but was not active in mice or rats.”
Reviewer's view of the efficacy data
FDA: nonclinical pharmacology and toxicology data adequate to support approval
“The nonclinical pharmacology and toxicology data submitted to this BLA are adequate to support the approval of emapalumab for the proposed indication.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted with a conditionBeyond the letter
Embryo-fetal development tested in mice with the rodent surrogate antibody XMG1.2 instead of emapalumab
“Embryo-fetal developmental toxicology studies were conducted in mice, with XMG1.2 used as surrogate for emapalumab.”
“The pharmacology/toxicology team recommends including in the label of emapalumab a statement regarding the experimental design of the study with the surrogate antibody and the presence of the antibody in maternal and fetal plasma.”
DARTAcceptedBeyond the letter
No standalone fertility studies; reproductive organs assessed in repeat-dose monkey studies
Why: Not needed for the intended treatment indication; no reproductive organ effects in repeat-dose monkey studies · Other reason
“Standalone fertility assessments were not conducted as they are not needed to support the marketing of this product for the intended treatment indication. No adverse effects on male or female reproductive organs were observed in the repeat-dose toxicity studies in cynomolgus monkeys.”
Similar precedents
AlhemoAntibodies · concizumab · TFPIMonkey only · 52 wkCabliviAntibodies · caplacizumab · von Willebrand factor (A1 domain)Monkey only · 26 wkEnjaymoAntibodies · sutimlimab · Complement C1sMonkey only · 26 wkPiaskyAntibodies · crovalimab · Complement C5Monkey only · 26 wkHympavziAntibodies · marstacimab · TFPIMonkey + rodent · 26 wkSolirisAntibodies · eculizumab · Complement C5Rodent only · 26 wk