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.”
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.”
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 outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
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.”
Similar precedents
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