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”
Species: general tox
Mouse (up to 4 weeks) and cynomolgus monkey (up to 26 weeks)
“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”
Species: DART
Mouse and rabbit (reproductive toxicity); juvenile toxicity study in mice
“reproductive toxicity studies in mice and rabbits, a juvenile toxicity study in mice, and a local tolerance study in rabbits.”
Species: carcinogenicity
Not conducted
“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”
Surrogate used in
Yes: mouse anti-MASP-2 antibody AbD04211 in a mouse tail bleeding (hemostasis) assay only
“A recombinant mouse monoclonal antibody, AbD04211, which binds to mouse MASP-2 and blocks the lectin pathway of complement in mice, was used in this study.”
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.”
Genotox: Ames
Not conducted
“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”
Genotox: in vitro mammalian
Not conducted
“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”
Genotox: in vivo
Not conducted
“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”
Carcinogenicity model
Not conducted
“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”
Carcinogenicity timing
Not conducted; no reason stated
“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”
hERG / QT
No cardiovascular effects in monkey safety pharmacology
“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
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: 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”
Anti-drug antibodies: animals
ADA in 2 of 40 treated monkeys; no effect on serum drug concentration
“Antidrug antibodies were observed in only 2 of 40 OMS721 treated monkeys. There was no effect of ADA status on serum OMS721 concentration.”
Anti-drug antibodies: patients
11% (3 of 28 TA-TMA patients); 1 of 3 neutralizing
“treatment-emergent antibodies to narsoplimab-wuug were detected in 3 of 28 patients (11%) with TA-TMA. One of the 3 patients (33%) developed neutralizing antibodies.”
Label warnings
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 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
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey (SC and/or IV, once weekly) with 10-week recovery
“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”
DART package
Species: DART
Mouse and rabbit (reproductive toxicity); juvenile toxicity study in mice
“reproductive toxicity studies in mice and rabbits, a juvenile toxicity study in mice, and a local tolerance study in rabbits.”
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).”
PPND / ePPND: when
PPND in mouse (SC and IV, with postnatal behavioral/functional evaluation) completed before the marketing application
“NARSOPLIMAB: A Developmental and Perinatal/Postnatal Reproduction Study by Subcutaneous and Intravenous Injection in the Mouse, Including a Postnatal Behavioral/Functional Evaluation”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”
Carcinogenicity model
Not conducted
“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”
Carcinogenicity timing
Not conducted; no reason stated
“Genotoxicity and animal carcinogenicity studies of narsoplimab-wuug have not been conducted.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 26-week SC NOAEL 300 mg/kg/week: 38-fold the MRHD
“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))”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
In vivo mouse model of TMA and ex vivo aHUS patient serum on human endothelial cells
“Key pharmacodynamic effects of OMS721 were evaluated in an ex vivo model of aHUS and an in vivo mouse model of TMA.”
Why that model
Functionally active in mouse, rabbit and monkey (3.8-, 2.7-, 10-fold less potent than human); inactive 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.”
Reviewer's view of the efficacy data
FDA: partial C-activation mitigation and delayed thrombosis in models, but insufficient evidence of translation to clinical benefit
“Although there appears to be partial mitigation of C-activation and delay in thrombotic onset by narsoplimab in animal and in vitro models, the Applicant has not shown sufficient evidence that this is expected to translate into a measurable clinical benefit, either directly or indirectly.”
Flexibilityopen answer page →
Flexibility accepted
No departure named in the public reviews.
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