Omvoh
mirikizumab
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 toxicology package submitted by the applicant comprised studies in a single species (cynomolgus monkey) using the intended clinical routes of administration (intravenous and subcutaneous).”
Why that species
Cynomolgus IL-23 binding similar to human (55 pM); rabbit >1000-fold lower; no mouse or rat binding
“Similar binding kinetics were demonstrated for cynomolgus monkey IL-23 with a calculated value of 55 pM, however, the binding affinity for rabbit IL-23 was > 1000 fold lower and no binding to mouse or rat IL-23 was detectable.”
Surrogate molecule
No surrogate in toxicology; the clinical antibody was tested in cynomolgus monkeys (mouse surrogate LSN2479016 used only in efficacy models)
“Neutralization of IL-23 using a surrogate mouse antibody, LSN2479016, demonstrated efficacy in two murine models of inflammatory bowel disease.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Two six-month toxicity studies were conducted in cynomolgus monkeys, one by IV (twice weekly) and the other by SC (once weekly) routes of administration.”
Pivotal GLP studies
GLP monkey 4-week IV/SC study, 6-month weekly SC study and 6-month twice-weekly IV study
“The pivotal studies included a 4-week repeat dose toxicity study which used both subcutaneous and intravenous routes of administration, and two 6-month repeat dose toxicity studies, one using weekly subcutaneous injections and the second using twice weekly intravenous injections.”
Route in tox
IV and SC
“Two six-month toxicity studies were conducted in cynomolgus monkeys, one by IV (twice weekly) and the other by SC (once weekly) routes of administration.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“Not conducted, in line with ICH S6(R1).”
Carcinogenicity
Not conducted; weight-of-evidence: IL-23 neutralization not expected to increase cancer risk
“In general, an overview of the published literature supports that neutralization of IL-23 would not be expected to increase cancer risk, but rather IL-23 increases tumor incidence and promotes tumor growth and progression.”
Reproductive & developmental
Monkey ePPND (300 mg/kg): embryo/fetal loss 26.7% vs 6.7% in controls, within historical control range
“However, incidences of embryo/fetal loss were higher in the treated groups compared to control (6.7% [1 of 15] in controls vs 26.7% [4 of 15] at 300 mg/kg) but were within the range of historical control data.”
Safety pharmacology
Incorporated into 4-week monkey study (IV up to 100 mg/kg, SC up to 30 mg/kg); no cardiovascular, CNS or respiratory findings
“No adverse cardiovascular, central nervous system, or respiratory findings were observed in monkeys as part of the 4-week toxicology study administered via both IV (doses up to 100 mg/kg) and SC (doses up to 30 mg/kg) routes.”
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 Omvoh 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: NOAEL 100 mg/kg/dose (twice-weekly IV monkey study); decreased RBC indices in one female at 300 mg/kg/dose (FDA multi-discipline review, p. 72)
NOAEL / key findings
NOAEL 100 mg/kg/dose (twice-weekly IV monkey study); decreased RBC indices in one female at 300 mg/kg/dose
“The NOAEL was 100 mg/kg/dose • Findings were limited to changes in hematology parameters which included mildly to moderately decreased red blood cell indices for one female monkey at 300 mg/kg/dose on day 180.”
Risksopen answer page →
Immune & cytokine safety
No effect on immunophenotyping, T-dependent antibody response or NK-cell cytotoxicity in monkeys
“In both six-month studies immunophenotyping, T-dependent antibody responses and NK cell cytotoxicity was assessed without any significant effect of mirikizumab on the parameters measured.”
Biodistribution & persistence
TCR in human and monkey tissues: no specific staining, low off-target binding potential
“Furthermore, a tissue cross-reactivity study performed with human and cynomolgus monkey tissues (see toxicology section) did not identify any specific mirikizumab staining suggesting a low potential for off-target binding and pharmacological effects.”
Modality-specific risk
Malignancy and immunosuppression from IL-23 blockade; no proliferative or immunosurveillance effects seen in monkeys
“No evidence of increased cellular proliferation or effects on immunosurveillance (circulating lymphocytes, natural killer cell function, primary immune response, lymphoid organ histopathology) have been observed in repeat dose toxicity studies in cynomolgus monkeys”