Ultomiris
ravulizumab
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
“the murine surrogate molecule BB5.1 was administered to mice due to lack of pharmacologic activity of ALXN1210 in mice.”
Why that species
No binding or pharmacologic activity against C5 of any non-human species, per epitope mapping, sequence alignment and in vitro assays
“Neither ALXN1210 nor eculizumab exhibit detectable pharmacological activity against any non‐human species tested, as was predicted by epitope mapping studies and sequence alignments of human and non‐human C5 molecules, and confirmed by in vitro binding and activity studies.”
Surrogate molecule
Yes: murine anti-mouse C5 antibody BB5.1, used for all mouse repeat-dose and reproductive toxicity studies
“the murine surrogate molecule BB5.1 was administered to mice due to lack of pharmacologic activity of ALXN1210 in mice.”
Species: general tox
CD-1 mouse with murine surrogate anti-C5 antibody BB5.1
“For the following studies in the toxicology package, the murine surrogate molecule BB5.1 was administered to mice due to lack of pharmacologic activity of ALXN1210 in mice.”
Species: DART
Mouse with surrogate BB5.1 (fertility, EFD, pre/postnatal)
“Animal reproductive toxicology studies have not been conducted with ravulizumab, but were conducted in mice with a murine surrogate complement inhibitory antibody, BB5.1.”
Species: carcinogenicity
Not conducted
“Long-term animal carcinogenicity studies of ravulizumab-cwvz have not been conducted.”
Surrogate used in
Yes: murine anti-mouse C5 BB5.1 for 26-week repeat-dose and all reproductive studies
“A GLP‐ compliant 26‐week repeat‐dose toxicity study, and GLP‐compliant reproductive and developmental toxicology studies, were performed in mice using a surrogate murine anti‐ mouse C5 mAb (BB5.1).”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The No Observed Adverse Effect Level (NOAEL) for BB5.1 mAb administered to CD‐1 mice via IV injection twice weekly for 26 weeks was determined to be 60 mg/kg/week, the highest dose tested.”
Pivotal GLP studies
GLP 26-week IV mouse study with surrogate antibody, once or twice weekly, 30 or 60 mg/kg/week
“In the 26‐week repeat‐dose study, mice were administered once or twice weekly by intravenous (IV) injection resulting in doses of 30 or 60 mg/kg/week.”
Route in tox
IV
“In the 26‐week repeat‐dose study, mice were administered once or twice weekly by intravenous (IV) injection resulting in doses of 30 or 60 mg/kg/week.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“In line with ICH S6 (R1), genotoxicity studies were not performed with ALXN1210.”
Carcinogenicity
Not conducted; carcinogenic potential unknown; hematopoietic neoplasms in one high-dose female in 26-week surrogate mouse study
“The carcinogenic potential of ALXN1210 in animals is unknown. However, in the 26‐week repeat dose toxicology study in mice with BB5.1, multiple hematopoietic neoplasms (lymphoma/lung/salivary glands/thymus) occurred in 1 high dose female (60 mg/kg/week)”
Reproductive & developmental
Surrogate mouse studies: no fertility effects; EFD retinal dysplasia (2) and umbilical hernia (1) among 230 offspring at high dose
“When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, 2 cases of retinal dysplasia and 1 case of umbilical hernia were observed among 230 offspring”
Safety pharmacology
No safety pharmacology studies; considered acceptable
“The lack of safety pharmacology studies is considered acceptable.”
Genotox: Ames
Not conducted (ICH S6)
“Genotoxicity studies have not been conducted with ravulizumab-cwvz.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genotoxicity studies have not been conducted with ravulizumab-cwvz.”
Genotox: in vivo
Not conducted (ICH S6)
“Genotoxicity studies have not been conducted with ravulizumab-cwvz.”
Carcinogenicity model
Not conducted; one high-dose female with hematopoietic neoplasms in 26-week surrogate mouse study
“The carcinogenic potential of ALXN1210 in animals is unknown. However, in the 26‐week repeat dose toxicology study in mice with BB5.1, multiple hematopoietic neoplasms (lymphoma/lung/salivary glands/thymus) occurred in 1 high dose female (60 mg/kg/week)”
Carcinogenicity timing
Not required: not generally relevant to biotechnology products (ICH S6(R1))
“No carcinogenicity studies were performed. The ICH S6 (R1) guideline indicates that nonclinical carcinogenicity studies are not generally considered relevant to biotechnology products.”
hERG / QT
Not conducted; no safety pharmacology studies
“In vitro safety pharmacology studies have not been performed (see discussion on non-clinical aspects).”
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 Ultomiris 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 mouse 26-week study: NOAEL 60 mg/kg/week, the highest dose tested (FDA multi-discipline review, p. 40)
NOAEL / key findings
Surrogate mouse 26-week study: NOAEL 60 mg/kg/week, the highest dose tested
“The No Observed Adverse Effect Level (NOAEL) for BB5.1 mAb administered to CD‐1 mice via IV injection twice weekly for 26 weeks was determined to be 60 mg/kg/week, the highest dose tested.”
Risksopen answer page →
Immune & cytokine safety
Repeat SC dosing in rabbits caused severe systemic immune-complex (type III) hypersensitivity; ADA in monkeys and rabbits
“Repeated SC injection of ALXN1210 caused a severe immunological reaction in rabbits, indicative of a systemic, type III hypersensitivity response with an immune complex etiology.”
Biodistribution & persistence
Human TCR: staining of proteinaceous material plus cytoplasmic staining, considered likely inaccessible in vivo
“However, with the exception of the staining of proteinaceous material, all staining observed in this study was cytoplasmic in nature, and it is unlikely that the cytoplasm and cytoplasmic structures would be accessible to the test article in vivo.”
Modality-specific risk
Serious meningococcal infection risk from terminal complement inhibition, as with eculizumab
“There is a serious risk of meningococcal infections with eculizumab and there is an ongoing REMS program for eculizumab.”
Anti-drug antibodies: animals
ADA in 75-100% of treated monkeys; less than dose-proportional AUC likely from ADA-driven clearance
“Cmax increased in a dose proportional manner, whereas AUC increased in a less than proportional manner, probably due to the presence of anti-human antibodies that could increase the clearance. ADAs were found in 75-100% of the ALXN1210 treated animals.”
Anti-drug antibodies: patients
Treatment-emergent ADA in 1/219 (0.5%) PNH and 1/71 (1.4%) aHUS patients; non-neutralizing
“In clinical studies with ULTOMIRIS, treatment-emergent antibodies to ravulizumab-cwvz were detected in 1 of 219 (0.5%) patients with PNH [see Clinical Studies (14.1) ] and 1 of 71 (1.4%) patients with aHUS [see Clinical Studies (14.2) ] . In these 2 patient populations, the observed ADA were non-neutralizing with no apparent impact on PK, safety, or efficacy.”
Label warnings
Boxed warning: Serious meningococcal infections
- Serious Meningococcal Infections
- ULTOMIRIS and SOLIRIS REMS
- Other Infections
- Monitoring Disease Manifestations after ULTOMIRIS Discontinuation
- Thromboembolic Event 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 Ultomiris 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 mouse 26-week study: NOAEL 60 mg/kg/week, the highest dose tested (FDA multi-discipline review, p. 40)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week mouse study with surrogate antibody BB5.1 (IV, once or twice weekly) with 4-week recovery
“A twenty-six week study evaluated the toxicity of BB5.1 mAb when administered once or twice weekly by IV injection to mice for 26 weeks followed by a 4-week recovery period (15-25 mice/sex/group).”
Pivotal GLP studies
GLP 26-week IV mouse study with surrogate antibody, once or twice weekly, 30 or 60 mg/kg/week
“In the 26‐week repeat‐dose study, mice were administered once or twice weekly by intravenous (IV) injection resulting in doses of 30 or 60 mg/kg/week.”
DART package
Species: DART
Mouse with surrogate BB5.1 (fertility, EFD, pre/postnatal)
“Animal reproductive toxicology studies have not been conducted with ravulizumab, but were conducted in mice with a murine surrogate complement inhibitory antibody, BB5.1.”
Reproductive & developmental
Surrogate mouse studies: no fertility effects; EFD retinal dysplasia (2) and umbilical hernia (1) among 230 offspring at high dose
“When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, 2 cases of retinal dysplasia and 1 case of umbilical hernia were observed among 230 offspring”
PPND / ePPND: when
PPND in mouse with surrogate BB5.1 completed before the marketing application
“BB5.1 was intravenously administered to pregnant mice (37/group) at 30 or 60 mg/kg/week from GD6 to LD18 (lactation day).”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Long-term animal carcinogenicity studies of ravulizumab-cwvz have not been conducted.”
Carcinogenicity model
Not conducted; one high-dose female with hematopoietic neoplasms in 26-week surrogate mouse study
“The carcinogenic potential of ALXN1210 in animals is unknown. However, in the 26‐week repeat dose toxicology study in mice with BB5.1, multiple hematopoietic neoplasms (lymphoma/lung/salivary glands/thymus) occurred in 1 high dose female (60 mg/kg/week)”
Carcinogenicity timing
Not required: not generally relevant to biotechnology products (ICH S6(R1))
“No carcinogenicity studies were performed. The ICH S6 (R1) guideline indicates that nonclinical carcinogenicity studies are not generally considered relevant to biotechnology products.”
Safety marginopen answer page →
Safety margin at NOAEL
Mouse surrogate fertility study: no effects at up to 0.8-2.2x the clinical dose equivalent
“Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility.”
NOAEL / key findings
Surrogate mouse 26-week study: NOAEL 60 mg/kg/week, the highest dose tested
“The No Observed Adverse Effect Level (NOAEL) for BB5.1 mAb administered to CD‐1 mice via IV injection twice weekly for 26 weeks was determined to be 60 mg/kg/week, the highest dose tested.”
Efficacy evidenceopen answer page →
Efficacy evidence
NOD-scid mice given human C5: >3-fold longer half-life and prolonged haemolysis inhibition vs eculizumab; no disease model
“The findings from this study suggest that in the presence of human C5, ALXN1210 showed more than three-fold extension in half-life compared with eculizumab. In addition, the serum half-life of ALXN1210 relative to eculizumab resulted in increased PD, as evidenced by prolonged haemolytic inhibition.”
Why that model
No pharmacological activity against C5 of any non-human species (epitope mapping, sequence alignment, in vitro assays)
“Neither ALXN1210 nor eculizumab exhibit detectable pharmacological activity against any non‐human species tested, as was predicted by epitope mapping studies and sequence alignments of human and non‐human C5 molecules, and confirmed by in vitro binding and activity studies.”
Reviewer's view of the efficacy data
EMA: mouse PK/PD study used an unvalidated assay, so its PK results are not usable
“However, since the analytical method used in this study was not validated, the PK results from this study cannot be regarded as usable for the evaluation of ravulizumab.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
No toxicity studies with ravulizumab (no relevant species); reliance on surrogate BB5.1 mouse studies from the eculizumab application
Why: No anti-C5 activity in nonhuman species; surrogate studies already assessed in the Soliris application · No relevant species · Class precedent
“No repeat dose toxicity studies were performed with ALXN1210 because it does not display detectable anti-C5 activity in nonhuman serum and therefore no relevant species for toxicity testing exist. Instead, a repeat-dose toxicity study in mice was performed using BB5.1, a murine anti-mouse C5 surrogate antibody.”
“General toxicity and reproductive toxicity studies were submitted and assessed in the Soliris (eculizumab) MAA and they were conducted with CD-1 mice using BB5.1, a murine anti-mouse surrogate antibody; therefore, the relevance of these studies is limited. This is considered acceptable due to the lack of cross-reactivity with non-human tissues of ALXN1210.”
CarcinogenicityAccepted
No carcinogenicity studies for a chronic indication despite haematopoietic neoplasms in one high-dose female in the 26-week surrogate mouse study
Why: ICH S6(R1): carcinogenicity studies not generally relevant to biotechnology products; no anti-C5 activity in rodents · Within the guideline · No relevant species
“The carcinogenic potential of ALXN1210 in animals is unknown. However, in the 26‐week repeat dose toxicology study in mice with BB5.1, multiple hematopoietic neoplasms (lymphoma/lung/salivary glands/thymus) occurred in 1 high dose female (60 mg/kg/week), lymphoid or lymphoreticular hyperplasia in mandibular lymph node and thymus occurred in another high dose female.”
“The lack of these studies is acceptable as ICH S6 (R1) guideline indicates that nonclinical carcinogenicity studies are not generally considered relevant to biotechnology products. ALXN1210 does not display detectable anti-C5 activity in serum from species normally used for such testing (mice and rats)”
OtherAcceptedBeyond the letter
Nonclinical PK data limited and largely unusable (unvalidated assays); PK characterisation left to human studies
Why: Lack of cross-reactivity with non-human tissues; PK to be assessed in humans per EMA scientific advice · No relevant species · Human data
“However, since the analytical method used in this study was not validated, the PK results from this study cannot be regarded as usable for the evaluation of ravulizumab.”
“Overall, the PK data available with ALXN1210 are limited; however, as highlighted in the EMA scientific advice (EMA/CHMP/SAWP/403560/2016), given the lack of cross-reactivity with non-human tissues, the PK profile evaluation of ALXN1210 should be adequately assessed in humans.”
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