Soliris
eculizumab
Species
Mouse
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 (surrogate antibody) only
“Toxicological studies were performed in mice using a surrogate murine anti-mouse C5 antibody (BB5.1 mAb).”
Why that species
Eculizumab binds only human C5; did not block hemolytic activity of any primate or non-primate serum tested
“Eculizumab did not effectively block haemolytic activity of sera from any primate or non-primate species tested, even at extremely high concentrations of antibody.”
Surrogate molecule
Yes: murine anti-mouse C5 antibody BB5.1, used for repeat-dose, fertility, embryo-fetal and pre/postnatal studies in mice
“Toxicological studies were performed in mice using a surrogate murine anti-mouse C5 antibody (BB5.1 mAb).”
Species: general tox
Mouse (CD-1), using surrogate murine anti-mouse C5 antibody BB5.1
“Toxicological studies were performed in mice using a surrogate murine anti-mouse C5 antibody (BB5.1 mAb).”
Species: DART
Mouse with murine anti-C5 surrogate (fertility, embryo-fetal, pre/postnatal)
“Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human SOLIRIS dose, based on a body weight comparison.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies have not been performed with eculizumab or any surrogate anti-C5 antibodies.”
Surrogate used in
Yes: murine anti-mouse C5 surrogate (BB5.1) for all toxicology studies in mice
“Toxicological studies were performed in mice using a surrogate murine anti-mouse C5 antibody (BB5.1 mAb).”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“A twenty-six week study evaluated the toxicity of BB5.1 mAb.”
Pivotal GLP studies
26-week IV study of surrogate BB5.1 in CD-1 mice, once or twice weekly (30 or 60 mg/kg/week)
“Crl:CD-1®(ICR) BR mice received by IV route BB5.1 mAb at 0 mg/kg twice weekly, 30 mg/kg once weekly, or 30 mg/kg twice weekly (resulting in dose levels of 0, 30 and 60 mg/kg/week respectively).”
Route in tox
IV
“Crl:CD-1®(ICR) BR mice received by IV route BB5.1 mAb at 0 mg/kg twice weekly, 30 mg/kg once weekly, or 30 mg/kg twice weekly”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Non-clinical genotoxicity studies are not generally considered relevant to biotechnology products (ICH S6 guideline).”
Carcinogenicity
Not conducted; 26-week surrogate study showed no cytotoxic or proliferative activity suggestive of carcinogenic risk
“The 26-week repeat dose toxicity study with a murine anti-mouse C5 antibody (BB5.1mAb) showed no cytotoxic or proliferative activities suggestive of carcinogenic risk at dose levels up to 60 mg/kg/week”
Reproductive & developmental
Mouse surrogate fertility, EFD, PPND: no fertility effects; retinal dysplasia and umbilical hernia at high dose; more male offspring deaths
“When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death.”
Safety pharmacology
No nonclinical safety pharmacology studies; justified by species specificity and clinical data
“No specific nonclinical safety pharmacology studies have been conducted.”
Genotox: Ames
Not conducted (ICH S6)
“Non-clinical genotoxicity studies are not generally considered relevant to biotechnology products (ICH S6 guideline).”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Non-clinical genotoxicity studies are not generally considered relevant to biotechnology products (ICH S6 guideline).”
Genotox: in vivo
Not conducted (ICH S6)
“Non-clinical genotoxicity studies are not generally considered relevant to biotechnology products (ICH S6 guideline).”
Carcinogenicity model
Not conducted; 26-week surrogate (BB5.1) mouse study showed no proliferative activity up to 60 mg/kg/week
“The 26-week repeat dose toxicity study with a murine anti-mouse C5 antibody (BB5.1mAb) showed no cytotoxic or proliferative activities suggestive of carcinogenic risk at dose levels up to 60 mg/kg/week, i.e. a dose level showing significant inhibition of C5 activation.”
Carcinogenicity timing
Not conducted with eculizumab or any surrogate anti-C5 antibody; no reason or waiver stated
“Carcinogenicity studies have not been performed with eculizumab or any surrogate anti-C5 antibodies.”
hERG / QT
Not conducted; no nonclinical safety pharmacology studies
“No specific nonclinical safety pharmacology studies have been conducted.”
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 Soliris 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: Surrogate 26-week mouse study: no treatment effects on any toxicity parameter at either dose; no target organs (EMA assessment report, p. 9)
NOAEL / key findings
Surrogate 26-week mouse study: no treatment effects on any toxicity parameter at either dose; no target organs
“Treatment did not affect any of the toxicity parameters examined.”
Risksopen answer page →
Immune & cytokine safety
No lymph node findings with surrogate in 26-week mouse study; no dedicated immunotoxicity or cytokine studies
“There were no remarkable macroscopic observations or histomorphological findings in mandibular or mesenteric lymph nodes related to treatment with the surrogate antibody, BB5.1 mAb, in the twenty six week mouse study.”
Biodistribution & persistence
TCR: C5 staining of smooth/skeletal muscle, myoepithelium, myofibroblasts, renal tubular epithelium, reticulum cells; no distribution studies
“Eculizumab binds to C5 on smooth muscle (intrinsic/vascular) and skeletal muscle, myoepithelium, myofibroblasts, renal tubular epithelium, and reticulum cells.”
Modality-specific risk
Infections from terminal complement blockade, especially meningococcal; hemolysis after discontinuation
“Identified and potential risks are general infections, especially meningococcal infections, haemolysis after drug discontinuation and haematologic abnormalities.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
PNH: 2% (ELISA) and 3% (ECL); aHUS: 3%
“In the PNH population, antibodies to SOLIRIS were detected in 3/196 (2%) patients using the ELISA assay and in 5/161 (3%) patients using the ECL assay during the entire treatment period. In the aHUS population, antibodies to SOLIRIS were detected in 3/100 (3%) patients using the ECL assay during the entire treatment period.”
Label warnings
Boxed warning: Serious meningococcal infections
- Serious Meningococcal Infections
- ULTOMIRIS and SOLIRIS REMS
- Other Infections
- Monitoring Disease Manifestations after SOLIRIS Discontinuation
- Thrombosis Prevention and Management
- Infusion-Related Reactions
InfectionsThrombosis & embolismHypersensitivity & infusion reactions
US prescribing information, Boxed Warning and 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 Soliris 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: Surrogate 26-week mouse study: no treatment effects on any toxicity parameter at either dose; no target organs (EMA assessment report, p. 9)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week IV mouse study with surrogate anti-C5 antibody BB5.1, with 4-week recovery
“Serum analysis indicated that the extent of mean % haemolysis decreased from pre-treatment levels of 70-80 % to below 20 % in treated mice at weeks 12 and 25. Although results were similar for both treated mice groups, the mean % haemolysis was slightly less for the 60 mg/kg/week mice in most instances. Following a four-week recovery period, the mean % haemolysis approximated pre-study values for both treatment groups.”
Pivotal GLP studies
26-week IV study of surrogate BB5.1 in CD-1 mice, once or twice weekly (30 or 60 mg/kg/week)
“Crl:CD-1®(ICR) BR mice received by IV route BB5.1 mAb at 0 mg/kg twice weekly, 30 mg/kg once weekly, or 30 mg/kg twice weekly (resulting in dose levels of 0, 30 and 60 mg/kg/week respectively).”
DART package
Species: DART
Mouse with murine anti-C5 surrogate (fertility, embryo-fetal, pre/postnatal)
“Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human SOLIRIS dose, based on a body weight comparison.”
Reproductive & developmental
Mouse surrogate fertility, EFD, PPND: no fertility effects; retinal dysplasia and umbilical hernia at high dose; more male offspring deaths
“When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death.”
PPND / ePPND: when
PPND in CD-1 mouse with surrogate anti-C5 antibody BB5.1: completed before the marketing application
“Female Crl:CD-1®(ICR) BR mice received BB5.1 mAb at 30 mg/kg/dose once or twice weekly (groups 2 and 3, low and high dose, respectively) or vehicle.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies have not been performed with eculizumab or any surrogate anti-C5 antibodies.”
Carcinogenicity model
Not conducted; 26-week surrogate (BB5.1) mouse study showed no proliferative activity up to 60 mg/kg/week
“The 26-week repeat dose toxicity study with a murine anti-mouse C5 antibody (BB5.1mAb) showed no cytotoxic or proliferative activities suggestive of carcinogenic risk at dose levels up to 60 mg/kg/week, i.e. a dose level showing significant inhibition of C5 activation.”
Carcinogenicity timing
Not conducted with eculizumab or any surrogate anti-C5 antibody; no reason or waiver stated
“Carcinogenicity studies have not been performed with eculizumab or any surrogate anti-C5 antibodies.”
Safety marginopen answer page →
Safety margin at NOAEL
Surrogate mouse fertility study: no effect on mating or fertility at up to 4-8 times the clinical dose
“Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of SOLIRIS had no adverse effects on mating or fertility.”
NOAEL / key findings
Surrogate 26-week mouse study: no treatment effects on any toxicity parameter at either dose; no target organs
“Treatment did not affect any of the toxicity parameters examined.”
Efficacy evidenceopen answer page →
Efficacy evidence
Murine anti-rodent C5 surrogates in non-PNH mouse models (arthritis, lupus, airway inflammation, cardiac allograft)
“Due to the species specificity of eculizumab, potential pharmacological activities in vivo have been explored with murine antibodies targeting rodent C5. Since there are no murine models of PNH, studies targeting other therapeutic areas with potential involvement of C5 activation (arthritis, lupus, airway inflammation and cardiac allograft models) have been presented.”
Why that model
Eculizumab binds only human C5 (species specificity) and no murine PNH model exists
“Due to the species specificity of eculizumab, potential pharmacological activities in vivo have been explored with murine antibodies targeting rodent C5. Since there are no murine models of PNH, studies targeting other therapeutic areas with potential involvement of C5 activation (arthritis, lupus, airway inflammation and cardiac allograft models) have been presented.”
Reviewer's view of the efficacy data
CHMP: in vitro-only pharmacodynamic characterisation acceptable given species specificity
“As stated in the CHMP scientific advice and in accordance with ICH S7, the approach to characterize the pharmacodynamic properties of eculizumab by in vitro methods is considered as acceptable in the light of the species specificity.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesQuestioned
No relevant species for eculizumab; all toxicology in mice with surrogate anti-mouse C5 antibody BB5.1, cross-reactivity profile not compared
Why: Surrogate antibody specifically binds mouse C5
“Toxicological studies were performed in mice using a surrogate murine anti-mouse C5 antibody (BB5.1 mAb). BB5.1 mAb specifically binds to mouse C5 but there was no information on whether the cross-reactivity profile of BB5.1 mAb with normal mouse tissues is similar to the cross-reactivity profile of eculizumab with normal human tissues.”
Safety pharmacologyAccepted
No safety pharmacology studies; pharmacodynamics characterised in vitro only
Why: Species specificity; in vitro approach acceptable per CHMP scientific advice and ICH S7 · No relevant species · Within the guideline
“No specific nonclinical safety pharmacology studies have been conducted.”
“As stated in the CHMP scientific advice and in accordance with ICH S7, the approach to characterize the pharmacodynamic properties of eculizumab by in vitro methods is considered as acceptable in the light of the species specificity.”
CarcinogenicityVerdict not stated
No carcinogenicity studies for a chronic indication; reliance on absence of proliferative findings in the 26-week surrogate mouse study
Why: No proliferative activity in the 26-week surrogate study
“Carcinogenicity studies have not been performed with eculizumab or any surrogate anti-C5 antibodies. The 26-week repeat dose toxicity study with a murine anti-mouse C5 antibody (BB5.1mAb) showed no cytotoxic or proliferative activities suggestive of carcinogenic risk at dose levels up to 60 mg/kg/week, i.e. a dose level showing significant inhibition of C5 activation.”
GLPVerdict not stated
Mouse plasma clearance study with an eculizumab variant run non-GLP with unvalidated methods
“Methods used in the plasma clearance study were not validated. The plasma clearance study was performed as a non-GLP research study.”
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