Summary Basis of Decision for Omvoh

Clinical Pharmacology

Mirikizumab, the medicinal ingredient in Omvoh, is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that binds with high affinity and specificity to the p19 subunit of human interleukin-23 (IL-23) and inhibits its interaction with the IL-23 receptor. Interleukin-23 affects the differentiation, expansion, and survival of T-cell subsets (e.g., T helper 17 [Th17] cells and T cytotoxic 17 [Tc17] cells) and innate immune cell subsets, which represent sources of effector cytokines that drive inflammatory disease.

The submitted clinical pharmacology data support the use of Omvoh for the recommended indication.

In healthy volunteers and patients with ulcerative colitis, mirikizumab exhibited linear elimination kinetics, with a half-life of approximately 10 days that was consistent across dose levels and routes of administration. A dose-proportional increase in exposure to mirikizumab was observed over a dose range of 5 mg to 2,400 mg administered intravenously and over a dose range of 120 mg to 400 mg administered subcutaneously. There was no apparent accumulation of mirikizumab when administered intravenously or subcutaneously every 4 weeks. The time to reach the maximum observed serum concentration after subcutaneous administration of mirikizumab was approximately 3 days.

The exposures to mirikizumab observed following single-dose subcutaneous administrations by the to-be-marketed prefilled syringe or autoinjector were within Health Canada’s prespecified boundaries for bioequivalence. An increase in exposure of approximately 10% was observed following subcutaneous administration into the thigh compared to the exposure measured after subcutaneous injection into the abdomen or upper arm; this increase in exposure was deemed not likely to be clinically meaningful in terms of the efficacy or safety profile of mirikizumab.

A population pharmacokinetic model was built based on data from the Phase II dose-ranging study AMAC, which evaluated the doses of 50 mg, 200 mg, and 600 mg mirikizumab administered intravenously every 4 weeks for induction treatment in patients with moderately to severely active ulcerative colitis. The model was subsequently updated (i.e., reparameterized) with data combined from the Phase III induction study AMAN and the Phase III maintenance study AMBG (both are described in the Clinical Efficacy section). A two-compartment model with linear clearance from the central compartment is the most parsimonious structural model (i.e., a model with the fewest number of estimated parameters to appropriately fit the observed data) to describe the population pharmacokinetics of mirikizumab in patients with ulcerative colitis. No consistent biases in model parameterization were evident. Model-predicted exposures suggest that the induction regimen of mirikizumab 300 mg administered intravenously every 4 weeks results in higher exposures compared with the maintenance regimen of mirikizumab 200 mg administered subcutaneously every 4 weeks, with geometric mean (percent coefficient of variation) steady-state maximum serum concentration (C_max) values of 99.7 µg/mL (22.7%) and 10.1 µg/mL (52.1%), respectively. Body weight was the main covariate on mirikizumab exposure. After both intravenous and subcutaneous administration, decreasing exposure to mirikizumab was observed with increasing body weight; however, these data do not indicate the need for dose adjustment of mirikizumab based on weight.

The relationship observed between the average serum concentration of mirikizumab and the proportion of patients who achieved clinical remission at Week 12 in the Phase II study AMAC suggests a flat exposure-response relationship at mirikizumab exposures corresponding to 200 mg or 600 mg intravenous dosing for induction treatment. However, when the data are broken down into exposure (i.e., average mirikizumab concentration) quartiles, a steep relationship between mirikizumab exposure and efficacy endpoints is observed at the 300 mg intravenous dose in study AMAN. The discrepancy between the exposure-response relationships observed in study AMAC and study AMAN is attributed to unaccounted confounding. Therefore, the true relationship between exposure to mirikizumab and efficacy endpoints remains uncertain at this time. No consistent exposure-response relationship for safety signals (injection/infusion site reactions, infections, and hypersensitivity) was observed during intravenous or subcutaneous dosing of mirikizumab.

Among 1,159 patients who received mirikizumab in the Phase III studies AMAN and AMBG, 210 (18.1%) developed treatment-emergent anti-drug antibodies (ADAs). Of these 210 patients, 198 (94.3%) had neutralizing treatment-emergent ADAs. The ADA titers were low in the majority of patients. Notably, lower mirikizumab serum concentrations were found in 10 of the 32 patients (31.3%) who had ADA titers of 1:160 or higher. Of these, 7 patients who were responders at Week 12 of Study AMAN had a reduced clinical response during study AMBG. No consistent differences in the frequency of hypersensitivity and injection/infusion site reactions were observed in patients with treatment-emergent ADAs compared to ADA-negative patients, irrespective of the antibody titer. Information pertaining to the observed immunogenicity of mirikizumab was included in the Omvoh Product Monograph.

For further details, please refer to the Omvoh Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Omvoh in adult patients with moderately to severely active ulcerative colitis was established in two Phase III, randomized, double-blind, placebo-controlled studies: AMAN (LUCENT-1), a 12-week study of induction therapy (induction study), and AMBG (LUCENT-2), a 40-week study of maintenance therapy (maintenance study with a withdrawal design). Together, the studies encompassed a 52-week treatment period.

Patients enrolled were 18 years of age or older and had a modified Mayo score of 4 or greater including an endoscopy subscore of 2 or 3. The modified Mayo score, ranging from 0 (normal) to 9 (most severe), is a composite endpoint for assessing the severity of ulcerative colitis in clinical trials and consists of three subscores, each scored from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, and centrally read endoscopic mucosal appearance. An endoscopy subscore of 2 is defined by marked erythema, absent vascular pattern, friability, and erosions, whereas an endoscopy subscore of 3 is defined by spontaneous bleeding and ulceration. All patients had a history of failed conventional therapy (i.e., corticosteroids, immunomodulators) or failed advanced therapy (i.e., biologics, Janus kinase inhibitors) for the treatment of ulcerative colitis. The studies were properly designed, with appropriately selected endpoints for assessing the efficacy of Omvoh in the intended patient population.

In study AMAN, 1,162 patients were randomized (3:1) to receive an induction dose regimen of Omvoh 300 mg (868 patients) or placebo (294 patients) administered by intravenous injection at Week 0, Week 4, and Week 8. In study AMBG, 544 patients who achieved clinical response to Omvoh induction therapy in study AMAN were randomized (2:1) to receive a maintenance dose regimen of Omvoh 200 mg (365 patients) or placebo (179 patients) administered by subcutaneous injection every 4 weeks for 40 weeks (i.e., the overall treatment period for these patients was 52 weeks). In comparison to clinical remission (defined below), clinical response was defined as a decrease of at least 2 points in the modified Mayo score, with a decrease from baseline of at least 30%, and either a decrease from baseline of at least 1 point in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.

The primary efficacy endpoint in study AMAN was the proportion of patients in clinical remission at Week 12. In study AMBG, the primary efficacy endpoint was the proportion of patients in clinical remission at Week 40 (i.e., Week 52 of continuous treatment). Clinical remission was based on the modified Mayo score defined by a stool frequency subscore of 0, or stool frequency subscore of 1 with a decrease from baseline of at least one point, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1.

Supportive secondary efficacy endpoints included the proportions of patients achieving clinical response, symptomatic remission, endoscopic mucosal improvement, histologic-endoscopic mucosal improvement, and bowel-movement urgency reduction, at Week 12 (study AMAN) or at Week 40 (study AMBG). Additional supportive secondary efficacy endpoints in study AMBG included the proportion of patients who achieved corticosteroid-free remission without surgery, and the proportion of patients with the maintenance of clinical remission at Week 40 among those who achieved clinical remission with Omvoh at Week 12 in study AMAN.

In study AMAN, a greater proportion of patients receiving an induction dosing regimen of Omvoh 300 mg intravenously achieved clinical remission at Week 12 compared with those receiving placebo (24.2% versus 13.3%, respectively; with an adjusted treatment difference of 11.1%; 99.875% confidence interval [CI]: 3.2%, 19.1%; p<0.00125). Similarly, the results of the key secondary efficacy endpoints favoured Omvoh over placebo, including the proportions of subjects who achieved clinical response, endoscopic improvement, symptomatic remission, or histologic-endoscopic mucosal improvement. Additionally, in both the conventional therapy-failed and the advanced therapy-failed study subpopulations, the efficacy results were in favour of Omvoh compared to placebo, consistent with the findings in the overall study population.

Study AMBG demonstrated that among patients who received Omvoh and achieved clinical response at Week 12 in study AMAN, a greater proportion of patients receiving maintenance dosing regimen of Omvoh 200 mg subcutaneously were in clinical remission at Week 40 (i.e., Week 52) compared with those receiving placebo (49.9% versus 25.1%, respectively; with an adjusted treatment difference of 23.2%; 95% CI: 15.2%, 31.2%; p<0.05). The results of the key secondary efficacy endpoints were also in favour of Omvoh compared to placebo, including the proportions of subjects who achieved endoscopic improvement, histologic-endoscopic mucosal improvement, corticosteroid-free remission, or reduction in bowel-movement urgency. Among patients who received Omvoh and achieved clinical remission at Week 12 in study AMAN, a greater proportion of patients receiving the maintenance regimen of Omvoh maintained clinical remission at Week 40 compared to those receiving placebo (adjusted treatment difference: 24.8% [95% CI: 10.4%, 39.2%]; p<0.05). Efficacy results in both the conventional therapy-failed and the advanced therapy-failed study subpopulations were consistent with the findings in the overall study population.

Indication

The New Drug Submission for Omvoh was filed by the sponsor with the following indication:

Omvoh (mirikizumab) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy, a biologic treatment, or a Janus kinase (JAK) inhibitor or have medical contraindications to such therapies.

Upon minor revisions, Health Canada approved the following indication:

Omvoh (mirikizumab) is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, loss of response, or were intolerant to conventional therapy, a biologic treatment, or a Janus kinase (JAK) inhibitor.

For more information, refer to the Omvoh Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety evaluation of Omvoh in adult patients with moderately to severely active ulcerative colitis was primarily based on data derived from two Phase III, randomized, double-blind, placebo-controlled studies, AMAN (LUCENT-1) and AMBG (LUCENT-2). As described in the Clinical Efficacy section, AMAN was a 12-week study of induction therapy with 300 mg Omvoh administered intravenously at Week 0, Week 4, and Week 8, whereas AMBG was a 40-week study of maintenance therapy with 200 mg Omvoh administered subcutaneously every 4 weeks. Together, the studies encompassed a 52-week treatment period.

Across the clinical studies of Omvoh in the setting of ulcerative colitis (including the Phase III studies AMAN and AMBG), 1,442 patients with ulcerative colitis were exposed to the drug. Of these patients, 926 were exposed to Omvoh for at least 52 weeks and 450 were exposed to Omvoh for at least 104 weeks. The data represented 2250.9 patient-years of exposure.

Throughout the 52-week placebo-controlled treatment period comprising the treatment periods of studies AMAN and AMBG, the most frequently reported adverse events (occurring in at least 10% of Omvoh-treated patients) were nasopharyngitis, worsening of ulcerative colitis, headache, upper respiratory tract infections, and arthralgia.

During the 12-week placebo-controlled induction period, adverse events more frequently reported in the Omvoh group compared to the placebo group were nasopharyngitis (4.1% versus 3.1%), upper respiratory tract infections (1.4% versus 0.6%), oral herpes (1% versus 0.6%), arthralgia (2.1% versus 1.2%), headache (3.3% versus 2.8%), pyrexia (1.5% versus 0.9%), fatigue (1.3% versus 0.6%). Hypertension also occurred with slightly higher frequency in patients receiving Omvoh.

During the 40-week placebo-controlled maintenance period, adverse events occurring in at least 3% of Omvoh-treated patients and at a higher incidence compared to the placebo group included nasopharyngitis, arthralgia, injection site pain, and headache. However, between-group differences were small, and most events were of mild to moderate intensity. Herpes zoster was the most frequently reported opportunistic infection.

The Warnings and Precautions section of the Omvoh Product Monograph highlights the risk of infections associated with the use of Omvoh. Furthermore, Omvoh is contraindicated in patients with any clinically important active infection, including, but not limited to, sepsis, hepatitis B, hepatitis C, human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS), and active tuberculosis.

One case of immune thrombocytopenia has been reported after an intravenous dose of Omvoh 300 mg and led to treatment discontinuation. Given that drug-induced immune thrombocytopenia could not be definitively ruled out, cases of immune thrombocytopenia will be monitored in the post-authorization setting through routine pharmacovigilance activities.

Three patients discontinued treatment with Omvoh due to hepatic adverse events, which included one case of autoimmune hepatitis and one case of potential drug-induced liver injury that could not be attributed to other causes or significant confounding risk factors. Abnormal hepatic laboratory results in patients treated with Omvoh were reported infrequently. Elevations in liver enzyme levels of 5 times or greater than the upper limit of normal and 10 times or greater than the upper limit of normal were reported at low frequencies. These elevations have been noted with and without concomitant elevations in total bilirubin. Information regarding the need to monitor liver function has been included in the Omvoh Product Monograph. Furthermore, if increases in alanine aminotransferase or aspartate aminotransferase are observed and drug-associated liver injury is suspected, the Omvoh Product Monograph recommends Omvoh discontinuation until this diagnosis is excluded.

Malignancies were reported in 16 patients (1.1%) exposed to Omvoh in the clinical development program for the ulcerative colitis indication. The most frequently reported malignancies were adenocarcinoma of colon (3 patients) and rectal cancer (3 patients). None of these events were considered related to Omvoh by the investigators.

Twenty-eight cases of adjudicated major adverse cardiovascular events were reported in Omvoh-treated participants across studies investigating the use of Omvoh for different indications. Six of these cases were reported in patients with moderately to severely active ulcerative colitis and all of them were reported in the extended maintenance or long-term extension periods of studies. The incidence rates of major adverse cardiovascular events observed in the different analysis sets were comparable to the background rate reported in the literature. Nevertheless, taking into consideration that a causal relationship could not be ruled out, major adverse cardiovascular events will be further monitored during the use of Omvoh in the post-authorization setting.

The potential risks of serious infections, severe liver injury, immune thrombocytopenia, major adverse cardiovascular events, and malignancies will be further characterized in the post-authorization setting through routine pharmacovigilance activities and an observational secondary database study aiming to assess the long-term safety of Omvoh.

Appropriate warnings and precautions are in place in the approved Omvoh Product Monograph to mitigate the risks identified during the review of the submitted data.

For more information, refer to the Omvoh Product Monograph, approved by Health Canada and available through the Drug Product Database.

In vitro pharmacodynamic studies of mirikizumab, the medicinal ingredient in Omvoh, showed selective binding to human and cynomolgus monkey IL-23 and inhibition of IL-23 receptor pathway. In a murine model of inflammatory bowel disease, a mouse surrogate anti-IL-23 antibody (LSN2479016) attenuated disease progression, as determined by histopathology. The improvement in histopathological findings was moderate and did not demonstrate a clear dose-response relationship.

In the pivotal repeat-dose toxicity study, cynomolgus monkeys were administered mirikizumab at doses of 100 mg/kg or 300 mg/kg or a vehicle (vehicle control animals) by intravenous injection twice weekly for 6 months, without a recovery period. One female in the high-dose mirikizumab group exhibited hematologic, clinical chemistry, and morphologic changes indicative of immune-mediated hemolysis. This animal also exhibited an approximately 90% reduction in natural killer (NK) cell activity and an approximately 75% reduction in NK cell absolute counts. These findings were considered an off-target effect of mirikizumab. The no-observed-adverse-effect level (NOAEL) for the study was determined to be 100 mg/kg twice weekly, which resulted in a systemic exposure 30 times the human exposure achieved at the mirikizumab induction dose of 300 mg administered intravenously (based on area under the curve [AUC] comparisons).

In the pivotal enhanced prenatal and postnatal development study, pregnant cynomolgus monkeys were administered mirikizumab 300 mg/kg or a vehicle (vehicle control animals) by intravenous injection twice weekly starting on Day 21 of gestation until parturition. Embryo-fetal loss was observed in 27% (4 animals of 15) and 7% (1 animal of 15) of the mirikizumab-administered and vehicle control females, respectively. These values were within the range (an upper bound of 38.9%) of the historical control data for embryo-fetal loss at the testing facility. No other toxicological effects were observed in the mirikizumab-administered females and their offspring. Mirikizumab was quantifiable in the serum of the offspring up to Day 84 postnatally. The concentration of mirikizumab in maternal milk was not measured. A NOAEL of 300 mg/kg twice weekly was determined for maternal and gestational toxicity, which resulted in a systemic exposure 69 times higher than the human exposure at the mirikizumab induction dose of 300 mg administered intravenously (based on AUC comparisons).

The results of the non-clinical studies as well as the potential risks to humans have been included in the Omvoh Product Monograph. In view of the intended use of Omvoh, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Omvoh Product Monograph, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Mirikizumab, the medicinal ingredient in Omvoh, is a humanized immunoglobulin G4 (IgG4) monoclonal antibody that binds with high affinity and specificity to the p19 subunit of interleukin (IL)-23 and inhibits its interaction with the IL-23 receptor. It has no observed cross-reactivity to other members of the IL-12 cytokine family (i.e., IL-12, IL-27, and IL-35b). The monoclonal antibody is composed of two identical immunoglobulin kappa light chains and two identical immunoglobulin gamma heavy chains. It has a molecular weight of approximately 147 kDa. Amino acid substitutions have been introduced in the heavy chain to minimize the formation of half antibodies during production and reduce the Fc effector function of the monoclonal antibody.

Detailed characterization studies were performed to provide assurance that mirikizumab consistently exhibits the desired characteristic structure and biological activity.

The product- and process-related impurities that were reported and characterized were found to be within established limits.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

Mirikizumab is produced using a genetically engineered Chinese hamster ovary (CHO) cell line. The protein is expressed as a secreted product of the CHO cells.

The production of mirikizumab starts with the thawing of a single vial of the working cell bank. Cells are expanded through series of flasks and bioreactors and subsequently transferred into a fed-batch production bioreactor. After completion of the cell culture process in the production bioreactor, cells and cellular debris are removed by centrifugation and filtration steps to produce a clarified cell culture harvest containing mirikizumab. The downstream purification process employs a series of viral inactivation, chromatography, and filtration steps. Finally, the purified bulk drug substance is filtered, dispensed in either high-density polyethylene containers or polycarbonate containers, and stored at or below -65 °C.

The commercial drug substance manufacturing process was validated by manufacturing three consecutive process performance qualification batches. Results demonstrated that the proposed manufacturing process consistently produced drug substance batches of acceptable quality. All three process performance qualification batches met established release specifications. In addition, all critical process parameters were maintained within their acceptable ranges, and all critical in-process tests and non-critical controls met their acceptance criteria. The downstream purification process demonstrated consistent ability to reduce process-related impurities to acceptable levels. The results of ancillary validation studies further supported the commercial drug substance manufacturing process. In the future, the manufacturing process will be monitored through a continuous process verification protocol to assure that the drug substance manufacturing process remains in a validated state of control.

The manufacturing of the drug product is initiated by thawing of the drug substance batches, which are then pooled and mixed with excipient buffer solution to obtain the specified drug product strengths and formulations. The resulting drug product solution undergoes sterile filtration prior to the aseptic filling into vials or semi-finished syringes. These semi-finished syringes are subsequently assembled with device components to form either the prefilled syringes or prefilled pens. Each single-use vial of Omvoh contains 300 mg of mirikizumab in 15 mL of solution (20 mg/mL) for intravenous infusion after dilution, whereas the single-use prefilled syringe or prefilled pen contains 100 mg of mirikizumab in 1 mL of solution (100 mg/mL) for subcutaneous administration.

The commercial drug product manufacturing processes for vials and semi-finished syringes were validated by manufacturing three process performance qualification batches for each presentation. All results met their acceptance criteria for release and stability testing, the critical process parameters were maintained within their acceptable ranges, and the results of in-process sampling met their acceptance criteria. Overall, the results demonstrated that the proposed manufacturing processes consistently produced drug products of appropriate quality. In addition, suitable data were provided to demonstrate that the commercial drug product presentations manufactured using the commercial processes at the commercial site are comparable to the material used during the clinical trials.

Control of the Drug Substance and Drug Product

The quality of the drug substance and drug product is ensured by suitable specifications for identity, purity, potency, and relevant characteristics of the dosage forms and presentations. The corresponding analytical methods were adequately validated. Of note, in response to a Health Canada’s request, the sponsor tightened the drug product release and stability specifications for purity. Due to several manufacturing site changes, multiple transfers of the analytical methods were conducted throughout the product development. Overall, the information provided demonstrates a successful transfer of the analytical methods to the proposed testing sites.

A two-tiered reference standard system has been implemented and comprises well-characterized reference standards. In addition, an appropriate program has been established to qualify future primary and working reference material.

Omvoh is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered satisfactory.

The stability data support the proposed shelf life of 24 months for Omvoh (vials, prefilled syringes, and prefilled pens), when the drug product is stored protected from light at 2 °C to 8 °C. If needed, the prefilled syringe or prefilled pen may be stored unrefrigerated at a temperature not higher than 30 °C for up to 2 weeks, in the original carton to protect from light. If these conditions are exceeded, the prefilled syringe or prefilled pen must be discarded. The solution for intravenous infusion should be used immediately after preparation. If not used immediately, it must be stored in the refrigerator at 2 °C to 8 °C and used within an overall period of 48 hours, starting at the time of vial puncture. Within this in-use period, no more than 5 hours are permitted outside of refrigerated conditions at a temperature not exceeding 25 °C.

The compatibility of the drug product with the container closure system was demonstrated through long-term stability studies and extractables/leachables studies.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured.

Based on risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary.

Both sites involved in production are compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The manufacturing process of mirikizumab incorporates adequate control measures to prevent contamination and maintain microbial control.

Extensive testing of the master cell bank, working cell bank, and pre-harvest cell culture fluid provides confirmation that the cell substrate and starting materials for the drug substance manufacturing process are free of detectable adventitious agents (bacteria, fungi, mycoplasma, and viruses). The cell culture process includes in-process tests to monitor for bioburden, mycoplasma, and viruses. Scaled-down viral clearance studies demonstrate that the downstream purification process is capable of inactivating or removing model viruses with a broad range of biochemical and biophysical properties.

No animal-derived and human-derived raw materials are used in the manufacture of the drug substance and drug product. In addition, the excipients in the drug product formulation are not of animal or human origin.