OMVOH is indicated for the treatment of moderately to severely active ulcerative colitis in adults.

2.1 Recommended Evaluations and Immunizations Prior to Treatment Initiation

• Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with OMVOH [see Warnings and Precautions (5.3)].
• Obtain liver enzymes and bilirubin levels prior to initiating treatment with OMVOH [see Warnings and Precautions (5.4)].
• Complete all age-appropriate vaccinations according to current immunization guidelines [see Warnings and Precautions (5.5)].

2.2 Recommended Dosage

2.3 Preparation and Administration of OMVOH for Intravenous Infusion

1. OMVOH for intravenous use is intended for administration by a healthcare provider using aseptic technique. Each vial is for single use only.
2. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be a clear to opalescent, colorless to slightly yellow to slightly brown solution, and free of visible particles. Do not use OMVOH if it is cloudy or there are visible particles.
3. Using an 18 to 21 gauge needle withdraw 15 mL of OMVOH solution from the vial and transfer to an infusion bag ranging in size from 50 mL to 250 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection. Do not mix with other drugs. Do not dilute or infuse through the same intravenous line with solutions other than 0.9% Sodium Chloride or 5% Dextrose Injection.
4. Gently invert the infusion bag to mix the contents. Do not shake the prepared infusion bag.
5. Connect the intravenous administration set (infusion line) to the prepared infusion bag and prime the line.
6. Administer the infusion over at least 30 minutes.
7. At the end of the infusion, flush the line with 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
   • Administer the flush at the same infusion rate as used for OMVOH administration.
   • The time required to flush OMVOH solution from the infusion line is in addition to the minimum 30-minute infusion time.

Storage of Diluted Solution

• Start the infusion immediately after preparation. If not used immediately, store the diluted infusion solution in the refrigerator at 2°C to 8°C (36°F to 46°F). Use the diluted infusion solution within 48 total hours, of which not more than 5 hours are permitted at non-refrigerated temperatures not to exceed 25°C (77°F), starting from the time of vial puncture.
• Keep drug product away from direct heat or light. Do not freeze the diluted solution in the prepared infusion bag.

2.4 Preparation and Administration of OMVOH for Subcutaneous Injection

• A full maintenance dose will require 2 prefilled pens.
• OMVOH is intended for use under the guidance and supervision of a healthcare professional. Patients may self-inject OMVOH after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of OMVOH according to the “Instructions for Use”, included with the packaged product.
• Before injection, remove OMVOH prefilled pen from the refrigerator and leave at room temperature for 30 minutes. Do not shake the prefilled pens.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution should be a clear to opalescent, colorless to slightly yellow to slightly brown solution, and free of visible particles. Do not use OMVOH if it is cloudy or there are visible particles.
• Sites for injection include the abdomen, thigh, and back of the upper arm. Instruct patients to inject in a different location every time. For example, if the first injection was in the abdomen, administer the second injection (to complete a full dose) in another area of the abdomen, or upper arm, or thigh.
• Do not inject into areas where the skin is tender, bruised, erythematous, or indurated.
• OMVOH does not contain preservatives; therefore, discard any unused product. Do not reuse.
• If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing every 4 weeks.

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis during intravenous infusion, have been reported with OMVOH administration. Infusion-related hypersensitivity reactions, including mucocutaneous erythema and pruritis, were reported during induction [see Adverse Reactions (6.1)]. If a severe hypersensitivity reaction occurs, discontinue OMVOH immediately and initiate appropriate treatment.

5.2 Infections

OMVOH may increase the risk of infection [see Adverse Reactions (6.1)].

Do not initiate treatment with OMVOH in patients with a clinically important active infection until the infection resolves or is adequately treated.

In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing OMVOH. Instruct patients to seek medical advice if signs or symptoms of clinically important acute or chronic infection occur. If a serious infection develops or an infection is not responding to standard therapy, monitor the patient closely and do not administer OMVOH until the infection resolves.

5.3 Tuberculosis

Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with OMVOH.

Do not administer OMVOH to patients with active TB infection. Initiate treatment of latent TB prior to administering OMVOH. Consider anti-TB therapy prior to initiation of OMVOH in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Monitor patients for signs and symptoms of active TB during and after OMVOH treatment.

In clinical trials, subjects were excluded if they had evidence of active TB, a past history of active TB, or were diagnosed with latent TB at screening.

5.4 Hepatotoxicity

A case of drug-induced liver injury (alanine aminotransferase [ALT] 18x the upper limit of normal (ULN), aspartate aminotransferase [AST] 10x ULN, and total bilirubin 2.4x ULN) in conjunction with pruritis was reported in a clinical trial subject following a longer than recommended induction regimen. OMVOH was discontinued. Liver test abnormalities eventually returned to baseline.

Evaluate liver enzymes and bilirubin at baseline and for at least 24 weeks of treatment. Monitor thereafter according to routine patient management.

Consider other treatment options in patients with evidence of liver cirrhosis. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. Interrupt treatment if drug-induced liver injury is suspected, until this diagnosis is excluded. Instruct patients to seek immediate medical attention if they experience symptoms suggestive of hepatic dysfunction.

5.5 Immunizations

Avoid use of live vaccines in patients treated with OMVOH. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines. Prior to initiating therapy with OMVOH, complete all age-appropriate vaccinations according to current immunization guidelines. No data are available on the response to live or non-live vaccines in patients treated with OMVOH.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

OMVOH was studied up to 12 weeks in subjects with moderately to severely active ulcerative colitis in a randomized, double-blind, placebo-controlled induction study (UC-1). In subjects who responded to induction therapy in UC-1, long term safety up to 52 weeks was evaluated in a randomized, double-blind, placebo-controlled maintenance study (UC-2) and a long-term extension study [see Clinical Studies (14)].

In the induction study (UC-1), 1279 subjects were enrolled of whom 958 received OMVOH 300 mg administered as an intravenous infusion at Weeks 0, 4, and 8. In the maintenance study (UC-2), 581 subjects were enrolled of whom 389 received OMVOH 200 mg administered as a subcutaneous injection every 4 weeks.

Table 1 summarizes the adverse reactions reported in at least 2% of subjects and at a higher frequency than placebo during UC-1.

In the induction study (UC-1), infusion-related hypersensitivity reactions were reported by 4 (0.4%) subjects treated with OMVOH and 1 (0.3%) subject treated with placebo.

Table 2 summarizes the adverse reactions reported in at least 2% of subjects and at a higher frequency than placebo during the 40-week controlled period of UC-2.

Infections

In UC-1 through Week 12, infections were reported by 145 (15%) subjects treated with OMVOH 300 mg and 45 (14%) subjects treated with placebo. Serious infections were reported by less than 1% in both groups. Serious infections in the OMVOH group included intestinal sepsis, listeria sepsis, and pneumonia.

In the maintenance study (UC-2) through Week 40 (a total of 52 weeks of treatment), infections were reported by 93 (24%) subjects treated with OMVOH 200 mg and 44 (23%) subjects treated with placebo. A case of COVID-19 pneumonia was reported as a serious infection in the OMVOH group.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of OMVOH have not been established in pediatric patients.

8.5 Geriatric Use

Of the 795 OMVOH-treated subjects in the two clinical trials, 64 subjects (8%) were 65 years of age and older, while 10 subjects (1%) were 75 years of age and older. These clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger adult subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. No clinically meaningful differences in the pharmacokinetics of mirikizumab-mrkz were observed in subjects 65 years of age and older compared to younger adult subjects [see Clinical Pharmacology (12.3)].

OMVOH for Intravenous Infusion

OMVOH (mirikizumab-mrkz) injection is a sterile, preservative-free, clear to opalescent, colorless to slightly yellow to slightly brown solution in a single-dose vial for intravenous infusion after dilution. Each mL contains 20 mg of mirikizumab-mrkz, anhydrous citric acid (0.4 mg), polysorbate 80 (0.5 mg), sodium chloride (8.8 mg), sodium citrate (2.1 mg), and Water for Injection. The OMVOH solution has a pH range of 5.0 - 6.0.

OMVOH for Subcutaneous Injection

OMVOH (mirikizumab-mrkz) injection is a sterile, preservative free, clear to opalescent, colorless to slightly yellow to slightly brown solution for subcutaneous use available as 100 mg of mirikizumab-mrkz in a 1 mL single-dose prefilled pen. The prefilled pen contains a 1 mL glass syringe with a fixed 27-gauge ½ inch needle. The OMVOH 100 mg prefilled pen is manufactured to deliver 100 mg of mirikizumab-mrkz. Each mL is composed of mirikizumab-mrkz (100 mg), anhydrous citric acid (0.4 mg), polysorbate 80 (0.3 mg), sodium chloride (8.8 mg), sodium citrate (2.1 mg), and Water for Injection. The OMVOH solution has a pH range of 5.0 to 6.0.

12.1 Mechanism of Action

Mirikizumab-mrkz is a humanized IgG4 monoclonal antibody that selectively binds to the p19 subunit of human IL-23 cytokine and inhibits its interaction with the IL-23 receptor.

IL-23 is involved in mucosal inflammation and affects the differentiation, expansion, and survival of T cell subsets, and innate immune cell subsets, which represent sources of pro-inflammatory cytokines. Research in animal models has shown that pharmacologic inhibition of IL-23p19 can ameliorate intestinal inflammation.

Mirikizumab-mrkz inhibits the release of pro-inflammatory cytokines and chemokines.

12.2 Pharmacodynamics

In both study UC-1 (induction) and study UC-2 (maintenance), a positive relationship was observed between mirikizumab-mrkz average concentration and rates of clinical remission and clinical response [see Clinical Studies (14)].

12.3 Pharmacokinetics

Mirikizumab-mrkz exhibited linear pharmacokinetics with dose-proportional increase in exposure over a dose range of 60 to 2400 mg given as an intravenous injection or over a dose range of 200 to 400 mg given as a subcutaneous injection, in healthy volunteers. There was no apparent accumulation of mirikizumab-mrkz concentrations in serum over time when administered as a subcutaneous injection every 4 weeks to subjects with ulcerative colitis. The estimated exposure parameters of mirikizumab-mrkz at steady state are summarized in Table 3.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of mirikizumab-mrkz or of other mirikizumab products.

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)). Of those who developed ADA, 33/88 (38%) developed titers ≥1:160. Of these 33 OMVOH-treated subjects, 10 had reduced serum trough concentrations of mirikizumab-mrkz compared to subjects who did not develop anti-mirikizumab-mrkz antibodies, and 5 of these 10 subjects did not achieve clinical response at Week 52. There is insufficient data to assess whether the observed ADA-associated pharmacokinetic changes reduced effectiveness. There is no identified clinically significant effect of ADA on the safety of OMVOH over the treatment duration of 52-weeks.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of mirikizumab-mrkz.

No organ weight or histopathology effects were observed in the male or female reproductive tract in sexually mature cynomolgus monkeys that received subcutaneous mirikizumab-mrkz once weekly for 26 weeks, at a dose of 100 mg/kg (at least 7 times the MRHD of mirikizumab-mrkz, based on exposure comparisons).