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.”
Species: general tox
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).”
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development); fertility assessed in 6-month monkey study
“For the assessment of male and female fertility, sexually mature monkeys were used in the 6-month repeat dose toxicity study (Report 20043324).”
Species: carcinogenicity
Not conducted: rodents not pharmacologically relevant
“Conventional rodent carcinogenicity studies were not conducted for the evaluation of the carcinogenic potential of mirikizumab as rodents are not a pharmacologically relevant species.”
Surrogate used in
Yes: mouse surrogate anti-IL-23 antibody LSN2479016 for murine IBD efficacy models only
“As LY3074828 does not bind to rodent IL-23, a surrogate mouse antibody (LSN2479016) was developed to neutralize mouse IL-23 for use in preclinical disease models.”
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.”
Genotox: Ames
Not conducted (ICH S6)
“Not conducted, in line with ICH S6(R1).”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Not conducted, in line with ICH S6(R1).”
Genotox: in vivo
Not conducted (ICH S6)
“Not conducted, in line with ICH S6(R1).”
Carcinogenicity model
Not conducted; weight-of-evidence assessment, rodents not pharmacologically relevant
“Conventional rodent carcinogenicity studies were not conducted for the evaluation of the carcinogenic potential of mirikizumab as rodents are not a pharmacologically relevant species.”
Carcinogenicity timing
Waived: CDER ECAC concurred a 2-year rodent study is not needed
“Concurrence has been received from the Executive Carcinogenicity Assessment Committee of CDER that a 2-year rodent carcinogenicity study is not needed.”
hERG / QT
No hERG assay; no adverse cardiovascular findings in 4-week monkey study (IV up to 100 mg/kg, SC up to 30 mg/kg)
“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
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 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”
Anti-drug antibodies: animals
7 monkeys ADA-positive in chronic IV study (100 and 300 mg/kg); reduced exposure in only one ADA-positive female
“ADAs were measured in this study with 7 animals (4 at 100 mg/kg, 3 at 300 mg/kg) testing positive for ADAs. Exposure at Day 176 was lower in one ADA-positive female, however, other ADA-positive animals did not exhibit any significant reduction in serum mirikizumab levels.”
Anti-drug antibodies: patients
23% (88/378) developed ADA over 52 weeks in UC studies
“During the 52-week treatment period in studies UC-1 and UC-2, 23% (88/378) of OMVOH-treated subjects at the recommended dosage and evaluable for assessment, developed anti-mirikizumab-mrkz antibodies (referred to as anti-drug antibodies (ADA)).”
Label warnings
- Hypersensitivity Reactions
- Infections
- Tuberculosis
- Hepatotoxicity
- Immunizations
Hypersensitivity & infusion reactionsInfectionsHepatotoxicity
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 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
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month cynomolgus monkey studies, IV (twice weekly) and SC (once weekly)
“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.”
DART package
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development); fertility assessed in 6-month monkey study
“For the assessment of male and female fertility, sexually mature monkeys were used in the 6-month repeat dose toxicity study (Report 20043324).”
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.”
PPND / ePPND: when
ePPND in cynomolgus monkey (IV 300 mg/kg twice weekly) completed before the marketing application
“An enhanced pre- and postnatal development study was conducted in cynomolgus monkeys administered mirikizumab by intravenous injection during organogenesis to parturition at a dose of 300 mg/kg twice weekly.”
Carcinogenicity
Species: carcinogenicity
Not conducted: rodents not pharmacologically relevant
“Conventional rodent carcinogenicity studies were not conducted for the evaluation of the carcinogenic potential of mirikizumab as rodents are not a pharmacologically relevant species.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment, rodents not pharmacologically relevant
“Conventional rodent carcinogenicity studies were not conducted for the evaluation of the carcinogenic potential of mirikizumab as rodents are not a pharmacologically relevant species.”
Carcinogenicity timing
Waived: CDER ECAC concurred a 2-year rodent study is not needed
“Concurrence has been received from the Executive Carcinogenicity Assessment Committee of CDER that a 2-year rodent carcinogenicity study is not needed.”
Safety marginopen answer page →
Safety margin at NOAEL
No adverse effects in monkeys up to 30x MRHD (300 mg Q4W IV), AUC-based
“No adverse effects were observed in monkeys at doses up to 30 times the MRHD (300 mg Q4W IV), based on AUC comparison.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse surrogate antibody LSN2479016 in two murine IBD models (CD4+ T-cell transfer colitis)
“Neutralization of IL-23 using a surrogate mouse antibody, LSN2479016, demonstrated efficacy in two murine models of inflammatory bowel disease.”
Why that model
Mirikizumab does not bind rodent IL-23, so a mouse surrogate was developed for proof-of-concept studies
“Considering the absence of binding to rodent IL-23, a mouse surrogate antibody, LSN2479016, was also developed to enable its use in proof of concept studies.”
Reviewer's view of the efficacy data
EMA: proof-of-concept studies limited, acknowledging limited nonclinical models of ulcerative colitis
“Whilst the proof-of-concept studies are limited, it is acknowledged the limitations on available nonclinical models of ulcerative colitis.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No rodent carcinogenicity study; weight-of-evidence assessment instead
Why: Rodents not pharmacologically relevant; no proliferative or immunotoxicity signals; CDER carcinogenicity committee concurred · Weight of evidence · No relevant species
“Conventional rodent carcinogenicity studies were not conducted for the evaluation of the carcinogenic potential of mirikizumab as rodents are not a pharmacologically relevant species. Concurrence has been received from the Executive Carcinogenicity Assessment Committee of CDER that a 2-year rodent carcinogenicity study is not needed.”
“The absence of proliferative signals in repeat dose toxicity studies also supports the lack of carcinogenic potential of mirkizumab as does the absence of any significant immunotoxicity or immunomodulatory activity in these studies. Thus, the applicant’s approach and conclusions are acceptable.”
DARTAcceptedBeyond the letter
Higher ePPND embryo/fetal loss 26.7% vs 6.7% in concurrent controls
Why: Atypically low concurrent control loss; treated incidence within historical control range · Weight of evidence
“The applicant has argued that the study is confounded by the atypically low level of embryo/fetal loss in the control group and that the levels seen in the mirikizumab treated group are within the bounds of historical control data and hence are not mirikizumab related.”
“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.”
Similar precedents
IlumyaAntibodies · tildrakizumab · IL-23 p19Monkey only · 39 wkSkyriziAntibodies · risankizumab · IL-23 p19Monkey only · 26 wkTremfyaAntibodies · guselkumab · IL-23 p19Monkey only · 24 wkAdbryAntibodies · tralokinumab · IL-13Monkey only · 26 wkAlhemoAntibodies · concizumab · TFPIMonkey only · 52 wkAvastinAntibodies · bevacizumab · VEGF-AMonkey only · 26 wk