Yartemlea
narsoplimab
Species
MonkeyMouse
Longest study
26 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
Mouse and cynomolgus monkey
“including safety pharmacology studies, repeat-dose toxicity studies in mice and monkeys for durations up to 4 and 26 weeks, respectively, reproductive toxicity studies in mice and rabbits”
Why that species
Functional lectin-pathway inhibition in mouse, rabbit and cynomolgus monkey (3.8-, 2.7-, 10-fold less potent than human); none in rat
“OMS721 displayed functional activity in mouse, rabbit, and cynomolgus monkey, with potencies 3.8, 2.7 and 10-fold less than human. No functional activity was observed in rats.”
Surrogate molecule
No surrogate; the clinical antibody was tested in mice, monkeys and rabbits
“including safety pharmacology studies, repeat-dose toxicity studies in mice and monkeys for durations up to 4 and 26 weeks, respectively, reproductive toxicity studies in mice and rabbits”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“A Repeat-Dose Toxicity and Toxicokinetic Study in Cynomolgus Monkeys Administered OMS721 by Subcutaneous and/or Intravenous Injection Once Weekly for 26 Weeks with a 10-Week Recovery”
Pivotal GLP studies
Repeat-dose studies in mice (up to 4 weeks) and cynomolgus monkeys (up to 26 weeks); mouse and rabbit reproductive studies
“including safety pharmacology studies, repeat-dose toxicity studies in mice and monkeys for durations up to 4 and 26 weeks, respectively, reproductive toxicity studies in mice and rabbits”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”
Carcinogenicity
Not conducted
“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”
Reproductive & developmental
Mouse and rabbit EFD (SC and IV): no adverse effects without maternal toxicity at up to 22- and 91-fold MRHD exposure
“In animal reproduction studies, narsoplimab-wuug was administered subcutaneously and intravenously twice weekly to pregnant mice and rabbits during organogenesis at dose exposures up to 22 and 91-fold, respectively, the human exposure at the maximum recommended human dose (MRHD) based on area under the concentration-time curve (AUC).”
Safety pharmacology
CV and respiratory endpoints in monkeys, CNS in mice; no effects
“Cardiovascular and respiratory safety pharmacology assessments in monkeys and a CNS safety pharmacology assessment in mice showed no OMS721-related effects.”
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 Yartemlea 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: Monkey 26-week NOAEL 300 mg/kg/week SC (38-fold MRHD); IV NOAEL not set due to irreversible protein/albumin decreases at 150 mg/kg (FDA integrated review, p. 180)
NOAEL / key findings
Monkey 26-week NOAEL 300 mg/kg/week SC (38-fold MRHD); IV NOAEL not set due to irreversible protein/albumin decreases at 150 mg/kg
“The no observed adverse effect level (NOAEL) identified in the 26-week monkey study was 300 mg/kg/week by the SC route (38-fold the maximum recommended human dose (MRHD)), while the NOAEL for the IV route was not established due to irreversible changes in protein and albumin levels at 150 mg/kg”
Risksopen answer page →
Immune & cytokine safety
ADA in 2 of 40 treated monkeys, with no effect on exposure
“Antidrug antibodies were observed in only 2 of 40 OMS721 treated monkeys. There was no effect of ADA status on serum OMS721 concentration.”
Biodistribution & persistence
Present in serum of mouse offspring, presumably via lactational transfer; milk levels not measured
“Narsoplimab was present in serum of F1 offspring, presumably via transfer during the lactation period. Levels of narsoplimab in maternal milk were not measured.”
Modality-specific risk
Lower potency in animal species than humans; pivotal studies still achieved near-complete lectin-pathway inhibition
“Note that functional potency of OMS721, measured as inhibition of C4 and C3 activation in serum, is lower in nonclinical species than in humans; however, exposures evaluated in the pivotal toxicology studies achieved near- to complete inhibition of lectin-mediated complement activation”