Enjaymo
sutimlimab
Species
Monkey
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
Cynomolgus monkey only
“The cynomolgus monkey was the only nonclinical species demonstrated to be pharmacologically relevant, and the nonclinical program was conducted only in that species.”
Why that species
Comparable binding to monkey and human C1s (EC50 0.13 vs 0.15 nM) and similar hemolysis inhibition; no binding/inhibition in mouse, rat, rabbit, minipig, dog
“Sutimlimab binds cynomolgus monkey and human C1s with comparable affinity (EC50, 0.13 nM and 0.15 nM, respectively)”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“The cynomolgus monkey was the only nonclinical species demonstrated to be pharmacologically relevant, and the nonclinical program was conducted only in that species.”
Species: general tox
Cynomolgus monkey only
“The cynomolgus monkey was the only nonclinical species demonstrated to be pharmacologically relevant, and the nonclinical program was conducted only in that species.”
Species: DART
Cynomolgus monkey (ePPND, 60 and 180 mg/kg/week); no dedicated fertility study
“An enhanced pre- and post-natal developmental (ePPND) toxicity study was conducted in pregnant monkeys with intravenous administration of 60 and 180 mg/kg/week sutimlimab (during organogenesis to parturition) to evaluate the potential for embryo-fetal and pre/post-natal developmental toxicity.”
Species: carcinogenicity
Not conducted (weight-of-evidence assessment instead)
“The applicant’s non-clinical package did not include a traditional in vivo carcinogenicity assessment. Instead, the applicant provided a weight-of-evidence (WOE)-based assessment of carcinogenic potential (per ICH S6).”
Surrogate used in
No surrogate used; clinical antibody tested in cynomolgus monkeys
“The cynomolgus monkey was the only nonclinical species demonstrated to be pharmacologically relevant, and the nonclinical program was conducted only in that species.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“A 26-week toxicity study was conducted in cynomolgus monkeys intravenously administered sutimlimab at 60 and 180 mg/kg/week.”
Pivotal GLP studies
Cynomolgus monkey 5-week (up to 100 mg/kg/week) and 26-week (up to 180 mg/kg/week) IV studies with 8-week recovery
“Sutimlimab has been evaluated in repeat-dose studies in cynomolgus monkey for 5 (up to 100 mg/kg/week) and 26 weeks (up to 180 mg/kg/week) with 8 weeks of recovery.”
Route in tox
Intravenous (once weekly)
“The intravenous route of administration was utilized in the repeated toxicology studies and the enhanced pre and postnatal study to match the intended clinical administration route.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (monoclonal antibody, ICH S6)
“No genotoxicity studies were performed with sutimlimab, as monoclonal antibodies are generally considered devoid of mutagenic or clastogenic risk.”
Carcinogenicity
Not conducted; weight-of-evidence (no proliferative lesions in chronic monkey study, mechanism, literature): no significant tumorigenic potential; ECAC concurred
“Given the absence of proliferative lesions observed at either dose tested in the chronic monkey study and the lack of any identified tumorigenic risk based on the mechanism of action and a search of the relevant scientific literature, it is unlikely that sutimlimab possesses significant tumorigenic potential.”
Reproductive & developmental
Monkey ePPND up to 180 mg/kg/week (~4x clinical exposure): no adverse reproductive or developmental effects; no dedicated fertility study
“There were no adverse effects on reproductive or developmental outcomes at 180 mg/kg/week, which represents 4 times the human exposure at the 7.5 g clinical dose.”
Safety pharmacology
Incorporated into repeat-dose monkey study; no adverse cardiovascular, respiratory or CNS effects
“Safety pharmacology endpoints incorporated into the repeat-dose toxicology study in monkeys did not identify any sutimlimab-related adverse effects on cardiovascular, respiratory or central nervous system endpoints at either dose.”
Genotox: Ames
Not conducted (monoclonal antibody, ICH S6)
“No genotoxicity studies were performed with sutimlimab, as monoclonal antibodies are generally considered devoid of mutagenic or clastogenic risk.”
Genotox: in vitro mammalian
Not conducted (monoclonal antibody, ICH S6)
“No genotoxicity studies were performed with sutimlimab, as monoclonal antibodies are generally considered devoid of mutagenic or clastogenic risk.”
Genotox: in vivo
Not conducted (monoclonal antibody, ICH S6)
“No genotoxicity studies were performed with sutimlimab, as monoclonal antibodies are generally considered devoid of mutagenic or clastogenic risk.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment (ICH S6)
“The applicant’s non-clinical package did not include a traditional in vivo carcinogenicity assessment. Instead, the applicant provided a weight-of-evidence (WOE)-based assessment of carcinogenic potential (per ICH S6).”
Carcinogenicity timing
Not required; ECAC concurred no additional carcinogenicity studies warranted
“CDER’s Executive Carcinogenicity Assessment Committee concurred with this assessment, and no additional studies of the carcinogenic potential of sutimlimab are warranted at this time.”
hERG / QT
No hERG assay; ECG, heart rate and respiration unremarkable in monkeys up to 180 mg/kg weekly for 26 weeks
“Cardiovascular and respiratory function testing included heart rate monitoring, body temperature, oxygen saturation, ECG testing and evaluation of respiration, which were unremarkable at doses up to 180 mg/kg weekly for 26 weeks”
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 Enjaymo 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: NOAEL 180 mg/kg/week (highest dose) in repeat-dose monkey study; no adverse findings despite near-complete classical complement inhibition (FDA pharmacology/toxicology review, p. 40)
NOAEL / key findings
NOAEL 180 mg/kg/week (highest dose) in repeat-dose monkey study; no adverse findings despite near-complete classical complement inhibition
“The no observed adverse effect level (NOAEL) in the repeat-dose toxicity study was 180 mg/kg weekly in male and female monkeys.”
Risksopen answer page →
Immune & cytokine safety
Minimally immunogenic: ADA in 2/10 animals at 60 and 1/10 at 180 mg/kg/week, increased clearance, no immune complex disease
“in 2/10 animals at 60 mg/kg/week and 1/10 animal at 180 mg/kg/week. However, while sutimlimab clearance was increased in these animals, no adverse impacts on the health of animals (e.g., immune complex deposition) were observed.”
Biodistribution & persistence
Human TCR: expected staining consistent with complement proteins, no unintended cross-reactivity; no tissue distribution or placental transfer studies
“Sutimlimab showed an expected staining pattern in human tissue line with other complement proteins. There was no obvious cross-reactivity staining to un-intended target(s).”
Modality-specific risk
Infection risk (especially encapsulated bacteria) from classical complement pathway inhibition; no infection signal in animals
“The classical complement pathway is an important defense against infections, especially encapsulated bacteria, but no signal for increased infections was observed in nonclinical studies.”
Anti-drug antibodies: animals
Minimal; sporadic ADA in three monkeys shortened duration (not magnitude) of complement inhibition via faster clearance
“The increase in serum ADA in these three animals did not affect the magnitude of sutimlimab-mediated inhibition of complement activity; however, duration of complement inhibition was shortened, due to faster clearance, indicated by a return to baseline activity before dosing in these animals.”
Anti-drug antibodies: patients
12% (8/66) in CARDINAL and CADENZA
“During the treatment period in CARDINAL and CADENZA, 8/66 (12%) ENJAYMO-treated patients developed anti-sutimlimab-jome antibodies (duration of exposure up to 177 weeks).”
Label warnings
- Serious Infections Including Those Caused by Encapsulated Bacteria
- Infusion-Related Reactions
- Risk of Autoimmune Disease
- Recurrent Hemolysis After ENJAYMO Discontinuation
InfectionsHypersensitivity & infusion reactionsImmune-mediated 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 Enjaymo 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: NOAEL 180 mg/kg/week (highest dose) in repeat-dose monkey study; no adverse findings despite near-complete classical complement inhibition (FDA pharmacology/toxicology review, p. 40)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey (IV) GLP study with 8-week recovery
“In a GLP-compliant chronic toxicology study, sutimlimab was administered to cynomolgus monkeys by 30-minute intravenous infusion at 2 doses (60 and 180 mg/kg/week) for 26 consecutive weeks with an 8-week treatment-free recovery period.”
Pivotal GLP studies
Cynomolgus monkey 5-week (up to 100 mg/kg/week) and 26-week (up to 180 mg/kg/week) IV studies with 8-week recovery
“Sutimlimab has been evaluated in repeat-dose studies in cynomolgus monkey for 5 (up to 100 mg/kg/week) and 26 weeks (up to 180 mg/kg/week) with 8 weeks of recovery.”
DART package
Species: DART
Cynomolgus monkey (ePPND, 60 and 180 mg/kg/week); no dedicated fertility study
“An enhanced pre- and post-natal developmental (ePPND) toxicity study was conducted in pregnant monkeys with intravenous administration of 60 and 180 mg/kg/week sutimlimab (during organogenesis to parturition) to evaluate the potential for embryo-fetal and pre/post-natal developmental toxicity.”
Reproductive & developmental
Monkey ePPND up to 180 mg/kg/week (~4x clinical exposure): no adverse reproductive or developmental effects; no dedicated fertility study
“There were no adverse effects on reproductive or developmental outcomes at 180 mg/kg/week, which represents 4 times the human exposure at the 7.5 g clinical dose.”
PPND / ePPND: when
ePPND in cynomolgus monkey completed before the marketing application
“An enhanced pre- and post-natal developmental (ePPND) toxicity study was conducted in pregnant monkeys with intravenous administration of 60 and 180 mg/kg/week sutimlimab (during organogenesis to parturition) to evaluate the potential for embryo-fetal and pre/post-natal developmental toxicity.”
Carcinogenicity
Species: carcinogenicity
Not conducted (weight-of-evidence assessment instead)
“The applicant’s non-clinical package did not include a traditional in vivo carcinogenicity assessment. Instead, the applicant provided a weight-of-evidence (WOE)-based assessment of carcinogenic potential (per ICH S6).”
Carcinogenicity model
Not conducted; weight-of-evidence assessment (ICH S6)
“The applicant’s non-clinical package did not include a traditional in vivo carcinogenicity assessment. Instead, the applicant provided a weight-of-evidence (WOE)-based assessment of carcinogenic potential (per ICH S6).”
Carcinogenicity timing
Not required; ECAC concurred no additional carcinogenicity studies warranted
“CDER’s Executive Carcinogenicity Assessment Committee concurred with this assessment, and no additional studies of the carcinogenic potential of sutimlimab are warranted at this time.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 26-week NOAEL 180 mg/kg: ~3- or 5-fold human AUC at 6.5 g or 7.5 g
“Sutimlimab was tolerated up to the highest dose of 180 mg/kg (exposure approximately 3- or 5-fold greater than that at 6.5 g or 7.5 g clinical dose, based on AUC) with no adverse effects on the health of the animals.”
NOAEL / key findings
NOAEL 180 mg/kg/week (highest dose) in repeat-dose monkey study; no adverse findings despite near-complete classical complement inhibition
“The no observed adverse effect level (NOAEL) in the repeat-dose toxicity study was 180 mg/kg weekly in male and female monkeys.”
Efficacy evidenceopen answer page →
Efficacy evidence
Near-complete classical complement inhibition (up to 98%) in cynomolgus monkeys at both dose levels
“Chronic administration of sutimlimab in monkeys led to nearly complete inhibition of classical complement activity (up to 98% reduced activity) at both dose levels.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: pharmacology evaluated in vitro and in vivo within the toxicology program; considered sufficient
“The pharmacology of sutimlimab was evaluated in vitro and in vivo in the general toxicology program. This program is considered sufficient.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted
No carcinogenicity studies for chronic therapy; weight-of-evidence assessment instead
Why: Weight-of-evidence assessment per ICH S6(R1) showed low risk; approved complement inhibitors had no carcinogenicity studies · Within the guideline · Weight of evidence
“The applicant’s claim that the weight-of-evidence assessment of carcinogenic potential was done in line with the ICH S6 (R1) and that it showed a low cancerogenic risk of sutimlimab is accepted.”
“CDER’s Executive Carcinogenicity Assessment Committee’s (ECAC) concurred with the reviewer’s assessment. Thus, further characterization of the carcinogenic potential for sutimlimab is not warranted at this time.”
DARTAccepted with a conditionBeyond the letter
No fertility study; male spermatogenic cycle not examined in sexually immature monkeys, so male fertility effects unknown
Why: Reproductive organs evaluated in repeat-dose studies; gap reflected in the SmPC · Weight of evidence
“Due to sexual immaturity of male animals, examination of the spermatogenic cycle was not conducted. Therefore, effects on male fertility remain unknown for sutimlimab. This has been adequately reflected in the SmPC.”
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