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.”
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.”
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 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: 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.”
Similar precedents
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