Mirikizumab-Mrkz

1 INDICATIONS AND USAGE OMVOH is indicated for the treatment of: moderately to severely active ulcerative colitis in adults. moderately to severely active Crohn's disease in adults. OMVOH TM is an interleukin-23 antagonist indicated for the treatment of: moderately to severely active ulcerative colitis in adults ( 1 ) moderately to severely active Crohn's disease in adults ( 1 )

2 DOSAGE AND ADMINISTRATION Prior to Treatment Initiation Evaluate patients for tuberculosis (TB) infection. ( 2.1 , 5.3 ) Obtain liver enzymes and bilirubin levels. ( 2.1 , 5.4 ) Complete all age-appropriate vaccinations according to current immunization guidelines. ( 2.1 , 5.5 ) Recommended Dosage for Ulcerative Colitis Induction Dosage : Week 0, Week 4, and Week 8: Infuse 300 mg intravenously over at least 30 minutes. ( 2.2 ) Maintenance Dosage : Week 12 and every 4 weeks thereafter: Inject 200 mg subcutaneously (given as either one injection of 200 mg or as two consecutive injections of 100 mg each). ( 2.2 ) Recommended Dosage for Crohn's Disease Induction Dosage : Week 0, Week 4, and Week 8: Infuse 900 mg intravenously over at least 90 minutes. ( 2.3 ) Maintenance Dosage : Week 12 and every 4 weeks thereafter: Inject 300 mg subcutaneously (given as two consecutive injections of 100 mg and 200 mg in any order). ( 2.3 ) Preparation and Administration Instructions See the full prescribing information for preparation, administration and storage information for intravenous infusion and subcutaneous injection. ( 2.2 , 2.3 , 2.4 , 2.5 ) 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 for Ulcerative Colitis Induction Dosage Week 0, Week 4, and Week 8: Infuse 300 mg intravenously over at least 30 minutes [see Dosage and Administration ( 2.4 )]. Maintenance Dosage Week 12 and every 4 weeks thereafter : Inject 200 mg subcutaneously (given as one injection of 200 mg or as two consecutive injections of 100 mg each) [see Dosage and Administration ( 2.5 ) and How Supplied/Storage and Handling ( 16 )] . 2.3 Recommended Dosage for Crohn's Disease Induction Dosage Week 0, Week 4, and Week 8 : Infuse 900 mg intravenously over at least 90 minutes [see Dosage and Administration ( 2.4 )]. Maintenance Dosage Week 12 and every 4 weeks thereafter : Inject 300 mg subcutaneously (given as two consecutive injections of 100 mg and 200 mg in any order) [see Dosage and Administration ( 2.5 ) and How Supplied/Storage and Handling ( 16 )] . 2.4 Preparation and Administration Instructions for Intravenous Infusion OMVOH for intravenous use is intended for administration by a healthcare provider using aseptic technique. 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. Prior to intravenous administration, determine the dose needed based on the patient's indication (see Table 1 below). For Crohn's disease, discard 45 mL of the infusion bag prior to adding vial contents. Withdraw the required amount of solution from the vial(s) using a 18 gauge to 21 gauge needle and transfer to an infusion bag containing 0.9% Sodium Chloride Injection or 5% Dextrose Injection (see Table 1 below). Do not mix with other drugs. Do not dilute or infuse through the same intravenous line with other solutions. Table 1: Intravenous Induction Dose and Volume of Diluent Required Indication Intravenous Induction Dose Number of OMVOH 300mg/15mL vials needed Volume of 0.9% Sodium Chloride or 5% Dextrose Injection Ulcerative colitis 300 mg 1 50 mL, 100 mL, or 250 mL Crohn's disease 900 mg 3 100 mL or 250 mL Gently invert the infusion bag to mix the contents. Do not shake the prepared infusion bag. Connect the intravenous administration set (infusion line) to the prepared infusion bag and prime the line. Infuse the diluted solution intravenously over a period of at least 30 minutes for the 300 mg dose; at least 90 minutes for the 900 mg dose. If stored refrigerated, allow the diluted solution in the infusion bag to warm to room temperature prior to the start of the intravenous infusion. 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. 2.5 Preparation and Administration Instructions for Subcutaneous Injection 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 pens or OMVOH prefilled syringes from the refrigerator, and leave at room temperature for 45 minutes. Do not shake the prefilled pens or prefilled syringes. 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, discolored, 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 (such as upper arms, thighs or any quadrant of abdomen) than the previous injection. Administration of OMVOH in the back of upper arm may only be performed by another person. 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.

6 ADVERSE REACTIONS The following topics are also discussed in detail in the Warnings and Precautions section: Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Infections [see Warnings and Precautions ( 5.2 )] Tuberculosis [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Most common adverse reactions are: Ulcerative colitis (≥2%) : Induction : upper respiratory tract infections and arthralgia. ( 6.1 ) Maintenance: upper respiratory tract infections, injection site reactions, arthralgia, rash, headache, and herpes viral infection. ( 6.1 ) Crohn's disease (≥5%) : upper respiratory tract infections, injection site reactions, headache, arthralgia, and elevated liver tests ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Ulcerative Colitis 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 ( 14.1 )] . 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 2 summarizes the adverse reactions reported in at least 2% of subjects and at a higher frequency than placebo during UC-1. Table 2: Adverse Reactions a in Subjects with Ulcerative Colitis through Week 12 in a Placebo-Controlled Induction Study (UC-1) a Reported in at least 2% of subjects and at a higher frequency than placebo. b OMVOH 300 mg as an intravenous infusion at Weeks 0, 4, and 8. c Upper respiratory tract infections includes related terms (e.g., COVID-19, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection). Adverse Reactions OMVOH 300 mg Intravenous Infusion b N=958 n (%) Placebo N=321 n (%) Upper respiratory tract infections c 72 (8%) 20 (6%) Arthralgia 20 (2%) 4 (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 3 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. Table 3: Adverse Reactions a in Subjects with Ulcerative Colitis through Week 40 In a Placebo-Controlled Maintenance Study (UC-2) a Reported in at least 2% of subjects and at a higher frequency than placebo b OMVOH 200 mg as a subcutaneous injection at Week 12 and every 4 weeks thereafter for up to an additional 40 weeks. c Upper respiratory tract infections includes related terms (e.g., COVID-19, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection). d Injection site reactions includes related terms (e.g., erythema, hypersensitivity, pain, reaction, and urticaria at the injection site). e Rash is composed of several similar terms. f Herpes viral infection includes related terms (e.g., herpes zoster, herpes simplex, and oral herpes). Adverse Reactions OMVOH 200 mg Subcutaneous Injection b N=389 n (%) Placebo N=192 n (%) Upper respiratory tract infections c 53 (14%) 23 (12%) Injection site reactions d 34 (9%) 8 (4%) Arthralgia 26 (7%) 8 (4%) Rash e 16 (4%) 2 (1%) Headache 16 (4%) 2 (1%) Herpes viral infection f 9 (2%) 1 (1%) 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. Hepatic Enzyme Elevations In UC-1 through Week 12, alanine aminotransferase (ALT) ≥5X ULN was reported by 1 (0.1%) subject treated with OMVOH 300 mg and 1 (0.3%) subject treated with placebo. Aspartate aminotransferase (AST) ≥5X ULN was reported by 2 (0.2%) subjects treated with OMVOH 300 mg and no subject treated with placebo. These elevations have been noted with and without concomitant elevations in total bilirubin. In UC-2 through Week 40 (a total of 52 weeks of treatment), 3 (0.8%) subjects treated with OMVOH 200 mg reported ALT ≥5X ULN and 3 (0.8%) subjects reported AST ≥5X ULN; with or without concomitant elevations in total bilirubin. No subjects treated with placebo experienced similar elevations [see Warnings and Precautions ( 5.4 )] . Crohn's Disease OMVOH was studied up to 52 weeks in subjects with moderately to severely active Crohn's disease in a randomized, double-blind, placebo-controlled study (CD-1). The safety population consisted of 630 subjects who received OMVOH 900 mg administered as an intravenous infusion during induction at Weeks 0, 4, and 8 followed by OMVOH 300 mg administered as a subcutaneous injection every 4 weeks and 211 subjects who received placebo [see Clinical Trials ( 14.2 )] . Eighty-five of the 211 placebo subjects in the safety population who did not achieve clinical response by patient-reported outcome at Week 12 were switched to blinded induction and maintenance treatment with OMVOH. Observed data from these 85 subjects are included in the placebo cohort up to Week 12 and in the OMVOH cohort after Week 12. In CD-1, OMVOH and placebo-treated subjects had different lengths of exposure, therefore, exposure adjusted incidence rates (EAIRs) are also displayed in Table 4 to compare adverse reactions. Common Adverse Reactions Table 4 summarizes the frequencies and EAIRs per 100 person-years (PY) for adverse reactions reported in at least 5% of subjects treated with OMVOH and at a higher frequency than placebo during CD-1. Table 4: Adverse Reactions a in Subjects with Crohn's Disease through Week 52 In a Placebo-Controlled Study (CD-1) Abbreviations: EAIR, exposure-adjusted incidence rate; PY, person-years a Reported in at least 5% of subjects and at a higher frequency than placebo b Following OMVOH 900 mg as an intravenous infusion at Week 0, Week 4, and Week 8, subjects received OMVOH 300 mg as a subcutaneous injection at Week 12 and every 4 weeks thereafter for up to an additional 40 weeks. In addition, eighty-five placebo subjects who did not achieve clinical response by patient-reported outcome at Week 12 were switched to blinded induction and maintenance treatment with OMVOH. The observed data after Week 12 from these eighty-five subjects were included in the OMVOH cohort. c EAIRs are per 100 PY. The EAIR per 100 PY can be interpreted as an estimated number of first occurrences of the adverse reaction of interest if 100 subjects were treated for one year. d Upper respiratory tract infections includes related terms (e.g., COVID-19, nasopharyngitis, pharyngitis, rhinitis, sinusitis, and upper respiratory tract infection). e Injection site reactions includes related terms (e.g., erythema, hematoma, induration, pain, pruritus, and reaction at the injection site). f Headache includes related terms (i.e., headache and migraine). g Elevated liver tests include related terms (e.g., ALT increased, AST increased, alkaline phosphatase increased, bilirubin increased, and GGT increased) Adverse Reactions OMVOH b N=715, PY=655 n (%) [EAIR c ] Placebo N=211, PY=120 n (%) [EAIR c ] Upper respiratory tract infections d 199 (28) [37] 47 (22) [47] Injection site reactions e 69 (10) [11] 8 (4) [7] Headache f 45 (6) [7] 9 (4) [8] Arthralgia 44 (6) [7] 11 (5) [10] Elevated liver tests g 36 (5) [6] 8 (4) [7] Hepatic Enzyme Elevations Of the subjects with reported adverse reactions of elevated liver tests ( see Table 4 ), 3 subjects treated with OMVOH reported ALT ≥5X ULN and 2 subjects reported AST ≥5X ULN. Neither subject had a concomitant elevation in total bilirubin. No subjects treated with placebo experienced similar elevations. Less Common Adverse Reactions (<5%) In CD-1 through Week 52, urticaria was reported by 13 (2%, 2 per 100 PY) subjects treated with OMVOH and no subjects treated with placebo. Infections In CD-1 through Week 52, infections were reported by 282 (39%, 58 per 100 PY) subjects treated with OMVOH and 73 (35%, 81 per 100 PY) subjects treated with placebo. Serious infections in the OMVOH group included abscess (including abdominal abscess, anal abscess, gluteal abscess, and perineal abscess), cellulitis, pneumonia, and sepsis.

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 or Crohn's disease. The estimated exposure parameters of mirikizumab-mrkz at steady state are summarized in Tables 5 for ulcerative colitis and 6 for Crohn's disease. Table 5: Mirikizumab-mrkz Estimated Systemic Exposure at Steady State in Subjects with Ulcerative Colitis a OMVOH 300 mg as an intravenous infusion over at least 30 minutes at Weeks 0, 4, and 8. b OMVOH 200 mg as 2 subcutaneous injections (100 mg/mL each) at Week 12 and every 4 weeks thereafter for up to an additional 40 weeks. c AUC tau, ss = area under the concentration-versus-time curve over one dosing interval at steady state; C max, ss = maximum concentration at steady state; C trough, ss = concentration at the end of the dosing interval at steady state; CV = geometric coefficient of variation. OMVOH 300 mg Intravenous Infusion a Geometric mean (CV%) OMVOH 200 mg Subcutaneous Injection b Geometric mean (CV%) C max, ss (μg/mL) c 99.7 (22.7%) 10.1 (52.1%) AUC tau, ss (μg*day/mL) c 538 (34.4%) 160 (57.6%) C trough, ss (μg/mL) c 2.75 (101%) 1.70 (83.3%) Table 6: Mirikizumab-mrkz Estimated Systemic Exposure at Steady State in Subjects with Crohn's Disease a OMVOH 900 mg as an intravenous infusion over at least 90 minutes at Weeks 0, 4, and 8. b OMVOH 300 mg as 2 subcutaneous injections (100 mg/mL and 200 mg/2 mL) at Week 12 and every 4 weeks thereafter up to Week 52. c AUC tau, ss = area under the concentration-versus-time curve over one dosing interval at steady state; C max, ss = maximum concentration at steady state; C trough, ss = concentration at the end of the dosing interval at steady state; CV = geometric coefficient of variation. OMVOH 900 mg Intravenous Infusion a Geometric mean (CV%) OMVOH 300 mg Subcutaneous Injection b Geometric mean (CV%) C max, ss (μg/mL) c 332 (21%) 13.6 (48%) AUC tau, ss (μg*day/mL) c 1820 (38%) 220 (56%) C trough, ss (μg/mL) c 10.4 (108%) 2.52 (88%) Absorption Following subcutaneous dosing of OMVOH for ulcerative colitis median (range) T max was 5 (3.08 to 6.75) days post dose and geometric mean (CV%) absolute bioavailability was 44% (34%). Following subcutaneous dosing of OMVOH for Crohn's disease, median (range) T max was 5 (3 to 6.83) days post dose and geometric mean (CV%) absolute bioavailability was 36.3% (31%). Injection site location (abdomen, upper arm, or thigh) did not significantly influence bioavailability of mirikizumab-mrkz following subcutaneous injection. Distribution In subjects with ulcerative colitis, the geometric mean (CV%) total volume of distribution was 4.83 L (21%). In subjects with Crohn's disease, the geometric mean (CV%) total volume of distribution was 4.4 L (14%). Metabolism/Elimination Mirikizumab-mrkz is a humanized IgG4 monoclonal antibody and is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. In subjects with ulcerative colitis, the geometric mean (CV%) clearance was 0.0229 L/hours (34%) and the geometric mean (CV%) elimination half-life was 9.3 days (40%). Clearance is independent of dose. In subjects with Crohn's disease, the geometric mean (CV%) clearance was 0.0202 L/hours (38%) and the geometric mean (CV%) elimination half-life was 9.3 days (26%). Clearance is independent of dose. Specific Populations There were no clinically significant differences in the pharmacokinetics of mirikizumab-mrkz based on age (18 to 79 years), sex, race (White or Asian), or mild and moderate renal impairment (i.e., estimated creatinine clearance by Cockcroft-Gault equation: 30 to 89 mL/min). Body Weight Following intravenous administration of 300 mg, the recommended induction dose, in subjects with ulcerative colitis weighing 90 kg or greater, the estimated geometric mean mirikizumab-mrkz average concentration (C avg ) was 20% lower compared with subjects weighing less than 90 kg. Following subcutaneous administration of 200 mg, the recommended maintenance dose, in subjects with ulcerative colitis weighing 90 kg or greater, the estimated geometric mean C avg was 38% lower compared with subjects weighing less than 90 kg. In Study UC-2 (maintenance), the rate of clinical remission and clinical response did not differ significantly between subjects weighing 90 kg or greater and subjects weighing less than 90 kg. Following intravenous administration of 900 mg, the recommended induction dose, in subjects with Crohn's disease weighing 90 kg or greater, the estimated geometric mean mirikizumab-mrkz C avg was 13% lower compared with subjects weighing less than 90 kg. Following subcutaneous administration of 300 mg, the recommended maintenance dose, in subjects with Crohn's disease weighing 90 kg or greater, the estimated geometric mean C avg was 34% lower compared with subjects weighing less than 90 kg. The rate of clinical remission and clinical response in Crohn's disease did not differ significantly between subjects weighing 90 kg or greater and subjects weighing less than 90 kg. Drug Interaction Studies Population pharmacokinetic analyses indicated that the clearance of OMVOH was not impacted by concomitant administration of aminosalicylates, corticosteroids, or oral immunomodulators (6-MP, AZA, MTX, tioguanine) in subjects with ulcerative colitis or Crohn's disease. No drug-drug interaction studies were conducted in subjects with ulcerative colitis or Crohn's disease at the recommended dosage. Based on a clinical drug-drug interaction study conducted in subjects with another condition, multiple subcutaneous doses of 250 mg every 4 weeks of mirikizumab-mrkz did not result in changes in the exposure of midazolam (CYP3A substrate), warfarin (CYP2C9 substrate), dextromethorphan (CYP2D6 substrate), omeprazole (CYP2C19 substrate), or caffeine (CYP1A2 substrate).