Omvoh (Eli Lilly Canada, 100 mg, ..., 200 mL) Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ....................................................................................... 2

Table of Contents .......................................................................................................... 2

Part 1: Healthcare Professional Information ............................................................... 4

1. 1.

   Indications ............................................................................................................... 4

   1.1. Pediatrics ....................................................................................................... 4

   1.2. Geriatrics ....................................................................................................... 4

2. 2. Contraindications ................................................................................................... 4
3. 4.

   Dosage and Administration ................................................................................... 4

   4.2. Recommended Dose and Dosage Adjustment .............................................. 4

   4.2.1. Ulcerative Colitis ............................................................................... 4

   4.2.2. Crohn’s Disease ................................................................................ 5

   4.4. Administration ................................................................................................ 5

   4.5. Missed Dose .................................................................................................. 7

4. 5. Overdose ................................................................................................................. 7
5. 6. Dosage Forms, Strengths, Composition, and Packaging ................................... 8
6. 7.

   Warnings and Precautions ..................................................................................... 9

   General .......................................................................................................... 9

   Hepatic/Biliary/Pancreatic .............................................................................. 9

   Immune ........................................................................................................ 10

   Reproductive Health ..................................................................................... 10

   Sensitivity/Resistance .................................................................................. 10

   7.1. Special Populations ..................................................................................... 10

   7.1.1. Pregnancy ....................................................................................... 10

   7.1.2. Breastfeeding .................................................................................. 10

   7.1.3. Pediatrics ........................................................................................ 10

   7.1.4. Geriatrics ......................................................................................... 10

7. 8.

   Adverse Reactions................................................................................................ 11

   8.1. Adverse Reaction Overview ......................................................................... 11

   8.2. Clinical Trial Adverse Reactions .................................................................. 11

   8.3. Less Common Clinical Trial Adverse Reactions .......................................... 13

8. 9.

   Drug Interactions .................................................................................................. 13

   9.2. Drug Interactions Overview .......................................................................... 13

   9.4. Drug-Drug Interactions ................................................................................. 14

   9.5. Drug-Food Interactions ................................................................................ 14

   9.6. Drug-Herb Interactions ................................................................................. 14

   9.7. Drug-Laboratory Test Interactions ............................................................... 14

9. 10.

   Clinical Pharmacology ......................................................................................... 14

   10.1. Mechanism of Action.................................................................................... 14

   10.2. Pharmacodynamics ..................................................................................... 14

   10.3. Pharmacokinetics ........................................................................................ 14

   10.4. Immunogenicity ........................................................................................... 16

10. 11. Storage, Stability, and Disposal .......................................................................... 17
11. 12. Special Handling Instructions ............................................................................. 17

Part 2: Scientific Information ..................................................................................... 18

1. 13. Pharmaceutical Information ................................................................................. 18
2. 14.

   Clinical Trials ........................................................................................................ 19

   14.1. Clinical Trials by Indication .......................................................................... 19

   14.1.1. Ulcerative Colitis ............................................................................. 19

   14.1.2. Crohn’s Disease .............................................................................. 23

3. 15. Microbiology ......................................................................................................... 27
4. 16. Non-Clinical Toxicology ....................................................................................... 27

Patient Medication Information .................................................................................. 29

Part 1: Healthcare Professional Information

1. Indications

Ulcerative Colitis

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.

Crohn’s Disease

OMVOH is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease who have had an inadequate response, loss of response, or were intolerant to either conventional therapy or a biologic treatment.

1.1. Pediatrics

Pediatrics (< 18 years of age): OMVOH is not indicated in the pediatric population, as the efficacy and safety of OMVOH have not been evaluated in patients with moderately to severely active ulcerative colitis or Crohn’s disease less than 18 years of age.

1.2. Geriatrics

Geriatrics (≥ 65 years of age): Limited data are available to Health Canada regarding this age group. Of the 1362 subjects with ulcerative colitis exposed to OMVOH in clinical trials, 99 subjects were 65 years or older, including 11 subjects who were 75 years or older (see 10.3 Pharmacokinetics).

2. Contraindications

• OMVOH is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage Forms, Strengths, Composition, and Packaging.
• With clinically important active infections (see 7 Warnings and Precautions, Infections).

4. Dosage and Administration

4.2. Recommended Dose and Dosage Adjustment

4.2.1. Ulcerative Colitis

Induction Dosing

The recommended induction dosage regimen of OMVOH is 300 mg infused intravenously for at least 30 minutes at Week 0, Week 4, and Week 8 (see 4.4 Administration, Preparation and Administration of OMVOH for Intravenous Infusion).

Only the 300 mg / 15 mL Vial presentation of OMVOH should be used for Induction dosing.

Evaluate patients after the 12-week induction dosing, and if there is adequate therapeutic response, transition to maintenance dosing. If patients do not have adequate therapeutic response at Week 12 after induction dosing, consider extended induction dosing by administering 300 mg OMVOH by intravenous infusion at Weeks 12, 16, and 20 (see 14.1 Clinical Trials by Indication). If therapeutic response is achieved with the additional intravenous induction dosing, patients may initiate OMVOH subcutaneous maintenance dosing every 4 weeks. Discontinue OMVOH in patients who do not show evidence of therapeutic benefit to extended induction therapy by Week 24.

Maintenance Dosing

The recommended maintenance dosage regimen of OMVOH is 200 mg given by subcutaneous injection every 4 weeks after completion of induction dosing. It may be administered either as two prefilled syringes or two prefilled pens of 100 mg each, or as one prefilled syringe or one prefilled pen of 200 mg (see 4.4 Administration, Administration of OMVOH solution for Subcutaneous Injection by Prefilled Pen or Prefilled Syringe).

4.2.2. Crohn’s Disease

Induction Dosing

The recommended induction dosing regimen of OMVOH is 900 mg infused intravenously for at least 90 minutes at Week 0, Week 4, and Week 8 (see 4.4 Administration, Preparation and Administration of OMVOH for Intravenous Infusion).

Only the 300 mg / 15 mL Vial presentation of OMVOH should be used for Induction dosing.

Maintenance Dosing

The recommended maintenance dosing regimen of OMVOH is 300 mg (given as two consecutive subcutaneous injections of 100 mg and 200 mg in any order) every 4 weeks starting at Week 12 upon completion of induction dosing (see 4.4 Administration, Administration of OMVOH solution for Subcutaneous Injection by Prefilled Pen or Prefilled Syringe).

Consideration should be given to discontinuing treatment in patients who have shown no evidence of therapeutic benefit by Week 24.

Pediatrics (< 18 years of age)

OMVOH is not indicated in the pediatric population, as the efficacy and safety of OMVOH have not been evaluated in patients younger than 18 years.

Geriatrics (≥ 65 years of age)

Limited data are available to Health Canada regarding this age group. No dosage adjustment is required (see 1.2 Geriatrics and 10.3 Pharmacokinetics).

Renal or Hepatic Impairment

No specific studies were conducted to assess the effect of hepatic or renal impairment on the pharmacokinetics of OMVOH (see 10.3 Pharmacokinetics).

4.4. Administration

Preparation and Administration of OMVOH for Intravenous Infusion

OMVOH solution for intravenous infusion must be diluted, prepared, and infused by a healthcare professional.

Dilution of OMVOH to prepare solution for infusion

• Each vial is for single use only.
• Prepare the infusion solution using aseptic technique to ensure the sterility of the prepared solution.
• Inspect the content of the vial. The solution should be a clear colourless to slightly yellow to slightly brown solution, and free of visible particles.

• Prepare the infusion bag for treatment of either ulcerative colitis or Crohn’s disease as specified below. Note that there are unique instructions and volumes specified for each indication.

  Ulcerative Colitis: One 15 mL vial (300 mg)

  Withdraw 15 mL from the OMVOH vial (300 mg) using an appropriately sized needle (18 to 21 gauge is recommended) and transfer to the infusion bag. OMVOH should be diluted only in intravenous infusion bags (bag size ranging from 50 – 250 mL) containing EITHER 0.9% sodium chloride solution for injection OR 5% dextrose solution for injection. Do not dilute the infusion solution with other solutions or co-infuse with other electrolytes or medications.

  Crohn’s Disease: Three 15 mL vials (300 mg); total dose = 45 mL (900 mg)

  First, using an appropriately sized needle (18 to 21 gauge is recommended), withdraw and discard 45 mL of diluent from the infusion bag. Next, using a separate appropriately sized needle (18 to 21 gauge is recommended), withdraw 15 mL from each of the three OMVOH vials for a total of 45 mL (900 mg) and transfer to the infusion bag. OMVOH should be diluted only in intravenous infusion bags (bag size ranging from 100 – 250 mL) containing EITHER 0.9% sodium chloride solution for injection OR 5% dextrose solution for injection. Do not dilute the infusion solution with other solutions or co-infuse with other electrolytes or medications.

• Gently invert the infusion bag to mix the contents. Do NOT shake the prepared bag.

Administration of OMVOH solution for infusion

• Connect the intravenous administration set (infusion line) to the prepared infusion bag and prime the line.

  • For ulcerative colitis, administer the infusion for at least 30 minutes.
  • For Crohn’s disease, administer the infusion for at least 90 minutes.
• At the end of the infusion, to ensure a full dose is administered, the infusion line should be flushed with 0.9% sodium chloride solution for injection or 5% dextrose solution for injection. The flush should be administered 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 (ulcerative colitis) or 90-minute (Crohn’s disease) infusion time.

Storage

It is recommended to start the infusion immediately after preparation. If not used immediately, store the diluted infusion solution in the refrigerator 2°C to 8°C. The diluted infusion solution must be used within 48 total hours, of which not more than 5 hours are permitted at nonrefrigerated temperatures not to exceed 25°C, 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 (see 11 Storage, Stability, and Disposal).

Administration of OMVOH solution for Subcutaneous Injection by Prefilled Pen or Prefilled Syringe

• A full maintenance dose for ulcerative colitis (200 mg) will require 2 prefilled pens or 2 prefilled syringes given as two consecutive injections of 100 mg each or 1 prefilled pen or 1 prefilled syringe given as a single injection of 200 mg.
• A full maintenance dose for Crohn’s disease (300 mg) will require 2 prefilled pens or 2 prefilled syringes given as two consecutive injections of 100 mg and 200 mg in any order.
• 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.
• Sites for injection include the abdomen, thigh, and back of the upper arm. Instruct patients to inject in a different injection site with each injection. For example, if the first injection was in the abdomen, the second injection – to complete a full dose – should be in another area of the abdomen, thigh, or back of the upper arm. Rotate injection sites.
• Patients and/or caregivers can inject OMVOH into the abdomen and thigh. Only caregivers can inject OMVOH into the back of the upper arm.
• Do not inject into areas where the skin is tender, bruised, erythematous, or indurated.
• Before injection, remove OMVOH prefilled pen or OMVOH prefilled syringe from the refrigerator.
• Ulcerative colitis: If using OMVOH 100 mg / mL + 100 mg / mL prefilled pens or prefilled syringes, leave at room temperature for 30 minutes. If using an OMVOH 200 mg / 2 mL prefilled pen or prefilled syringe, leave at room temperature for 45 minutes.
• Crohn’s disease: Leave OMVOH 100 mg / mL + 200 mg / 2 mL prefilled pens or prefilled syringes at room temperature for 45 minutes.
• Inspect OMVOH visually for particulate matter and discolouration prior to administration. Do not use OMVOH if it is cloudy or there are visible particles.
• OMVOH is preservative-free, therefore discard any unused product. Do not reuse.

4.5. Missed Dose

Patients who miss their scheduled infusion should be advised to contact their healthcare professional and to schedule another appointment as soon as possible.

If a maintenance dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regularly scheduled time.

5. Overdose

Mirikizumab doses up to 2400 mg intravenously and up to 500 mg subcutaneously have been administered in clinical trials without dose-limiting toxicity. In the event of overdosage, monitor the patient for signs or symptoms of adverse reactions and start appropriate symptomatic treatment immediately.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free-number, 1-844 POISON-X (1-844-764-7669).

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 1 - Dosage Forms, Strengths, and Composition

OMVOH for Intravenous Infusion

OMVOH solution for intravenous infusion after dilution is available as 15 mL solution in a type I glass vial. OMVOH is preservative-free; therefore, each vial is for single use only.

The vial is not made with dry natural rubber latex.

OMVOH 300 mg / 15 mL is available in cartons containing 1 vial.

OMVOH Prefilled Pens and Prefilled Syringes

100 mg / 1 mL

OMVOH prefilled pens and prefilled syringes each contain a 1 mL glass syringe with a fixed 27-gauge ½ inch needle.

200 mg / 2 mL

OMVOH prefilled pens and prefilled syringes each contain a 2 mL glass syringe with a fixed 27-gauge 8 mm needle.

OMVOH is preservative-free; therefore, each prefilled pen or prefilled syringe is for single use only.

The prefilled pen and prefilled syringe are not made with dry natural rubber latex.

OMVOH is available in the following carton presentations:

Ulcerative Colitis (200 mg total dose)

• 2 prefilled pens of 100 mg / 1 mL each or
• 2 prefilled syringes of 100 mg / 1 mL each or
• 1 prefilled pen of 200 mg / 2 mL or
• 1 prefilled syringe of 200 mg / 2 mL

Crohn’s Disease (300 mg total dose)

• 2 prefilled pens (1 x 100 mg / 1 mL and 1 x 200 mg / 2 mL) or
• 2 prefilled syringes (1 x 100 mg / 1 mL and 1 x 200 mg / 2 mL)

7. Warnings and Precautions

General

Infections

OMVOH may increase the risk of infection. Treatment with OMVOH should not be initiated in patients with any clinically important active infection (including, but not limited to, sepsis, hepatitis B, hepatitis C, HIV/AIDS, and active tuberculosis (TB)). Prior to initiating treatment, patients should be evaluated for active infections. Consider the risks and benefits of treatment prior to initiating use of OMVOH in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek immediate medical advice if signs or symptoms of clinically important acute or chronic infection occur. If a serious infection develops, consider discontinuation of OMVOH until the infection resolves.

No safety data are available in patients with HIV, hepatitis B or hepatitis C. Patients who screened positive for any of these infections were excluded from the clinical trials.

Tuberculosis

OMVOH should not be given to patients with active tuberculosis (TB). Evaluate patients for TB prior to initiating treatment with OMVOH. Consider anti-TB therapy prior to initiation of OMVOH in patients with a history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving OMVOH should be monitored closely for signs and symptoms of active TB during and after treatment.

Hepatic/Biliary/Pancreatic

Hepatic Enzyme Elevation

Elevations of aminotransferases have been reported in patients receiving OMVOH. Evaluate liver enzymes and bilirubin at baseline and every 1-4 months during induction (including extended induction period, if applicable) and thereafter, according to standard practice for patient management and as clinically indicated. If increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) are observed and drug-associated liver injury is suspected, discontinue OMVOH until this diagnosis is excluded (see 8.2 Clinical Trial Adverse Reactions).

Immune

Vaccinations

Prior to initiating therapy with OMVOH, consider completion of all immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with OMVOH. If necessary, live vaccines should be administered at least 4 weeks before initiating OMVOH treatment.

Reproductive Health

• Fertility

  The effect of OMVOH on human fertility has not been studied. In addition, no dedicated fertility studies have been conducted in animals (see 16 Non-Clinical Toxicology).

Sensitivity/Resistance

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, may occur with OMVOH administration. If serious hypersensitivity reactions occur, discontinue OMVOH immediately and initiate appropriate treatment (see 8 Adverse Reactions).

7.1. Special Populations

7.1.1. Pregnancy

The use of OMVOH in pregnant women has not been studied. Women of childbearing potential should use effective contraception during treatment and for a minimum of 12 weeks after the last administration. A developmental toxicity study in pregnant monkeys revealed no evidence of harm to the developing fetus or infant (see 16 Non-Clinical Toxicology). However, animal studies are not always predictive of human response; therefore, it is unknown whether OMVOH can cause fetal harm when administered to a pregnant woman.

7.1.2. Breastfeeding

There are no data on the presence of OMVOH in human milk, the effects on the breastfed infant, or the effects on milk production. Because human immunoglobulin G (IgG) is secreted into human milk, precaution should be exercised. The developmental and health benefits of breast-feeding should be considered, as well as any potential adverse effects on the breastfed infant.

7.1.3. Pediatrics

Pediatrics (< 18 years of age): OMVOH is not indicated in the pediatric population, as the efficacy and safety of OMVOH have not been evaluated in patients less than 18 years of age.

7.1.4. Geriatrics

Of the 1362 subjects with ulcerative colitis exposed to OMVOH in Phase 2 and Phase 3 studies, 99 subjects were 65 years or older and 11 subjects were 75 years or older. Thus, data in these age groups are limited.

8. Adverse Reactions

8.1. Adverse Reaction Overview

Ulcerative Colitis

The most frequently reported adverse reactions were injection site reactions (8.7%, maintenance period), upper respiratory tract infections (7.9%, frequently nasopharyngitis), headache (3.3%), arthralgia (2.1%), and rash (1.1%) (see Table 2).

The proportion of patients treated with OMVOH who discontinued treatment due to adverse events was 1.8% (7/389).

Crohn’s Disease

The most frequently reported adverse reactions were upper respiratory tract infections (12.1%), injection site reactions (10.8%, maintenance period), headache (3.0%), and rash (1.6%).

The proportion of patients treated with OMVOH who discontinued treatment due to adverse events was 5.1% (32/630).

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction frequencies observed in the clinical trials; therefore, may not reflect the frequencies observed in practice and should not be compared to the frequencies in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating frequencies of adverse drug reactions in real-world use.

Ulcerative Colitis

A total of 1442 subjects were treated with OMVOH in clinical development trials in UC.

In these trials, exposure to OMVOH in 1442 adult ulcerative colitis patients included 1208 exposed for at least 6 months, 926 exposed for at least one year, and 450 exposed for at least 2 years.

Clinical trials excluded patients who had an unstable or uncontrolled illness, including, but not limited to cerebrovascular, cardiovascular, respiratory, gastrointestinal (excluding UC), hepatic, renal, endocrine, hematologic or neurological disorders.

Table 2 summarizes the adverse drug reactions that occurred at a frequency of at least 1% in the OMVOH-treated patients and higher than the placebo group during the 12-week controlled period of LUCENT 1.

Table 2 – Adverse Drug Reactions through Week 12 from LUCENT-1 and through Week 40 from LUCENT-2 occurring in ≥ 1% of OMVOH-treated patients and higher than placebo

^a Upper respiratory tract infections contains the preferred terms: acute sinusitis, nasopharyngitis, oropharyngeal discomfort, oropharyngeal pain, pharyngitis, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, and viral upper respiratory tract infection.

^b Rash contains the preferred terms: rash, rash macular, rash maculo-papular, rash papular, and rash pruritic.

^c Injection site reactions contains the preferred terms: injection site pain, injection site reaction, injection site erythema, injection site bruising, injection site pruritus, injection site dermatitis, injection site hematoma, injection site hypersensitivity, injection site oedema, injection site paraesthesia, injection site rash, injection site urticaria.

In the first 12 weeks (LUCENT-1), infusion-related hypersensitivity reactions were reported by 4 (0.4%) OMVOH-treated patients compared to 1 (0.3%) patient in the placebo group.

Increases in alanine aminotransferase (ALT) were reported by 4 (0.4%) OMVOH-treated patients compared to 1 (0.3%) in the placebo group. Increases in aspartate aminotransferase (AST) were reported by 5 (0.5%) OMVOH-treated patients compared to 1 (0.3%) in the placebo group.

Safety in LUCENT-2 (Weeks 12 - 52)

Injection site reactions were reported by 8.7% OMVOH-treated patients compared to 4.2% patients in the placebo group. The most frequently reported events were injection site pain, injection site reaction, and injection site erythema.

Through Week 52, with the exception of injection site reactions, adverse drug reaction data were consistent with data observed in induction study LUCENT-1.

Over all treatment periods in the OMVOH ulcerative colitis clinical development program (including the placebo-controlled and open label induction and maintenance periods), there have been elevations of ALT to ≥ 3X ULN (2.0%), ≥ 5X ULN (0.7%) and ≥ 10X ULN (0.2%) and AST to ≥ 3X ULN (2.1%), ≥ 5X ULN (1.1%) and ≥ 10X ULN (0.1%) in patients receiving OMVOH (see Hepatic/Biliary/Pancreatic). These elevations have been noted with and without concomitant elevations in total bilirubin.

Crohn’s Disease

Overall, the safety profile observed in subjects with Crohn’s disease treated with OMVOH is generally consistent with the safety profile in adult patients with ulcerative colitis, with the exception of the frequency of injection site reactions (10.8%).

The result described above was obtained with the original formulation of OMVOH.

Hepatic Enzyme Elevations

Over all the treatment periods in the OMVOH Crohn's Disease clinical development program, there have been elevations of ALT to ≥ 3X ULN (2.2%) and ≥ 5X ULN (0.4%), and AST to ≥ 3X ULN (1.6%) and ≥ 5X ULN (0.3%) in patients receiving OMVOH. No subject had elevation of AST or ALT ≥ 10X ULN. No subject had a concomitant elevation in total bilirubin.

8.3. Less Common Clinical Trial Adverse Reactions

Adverse drug reactions from LUCENT-1, LUCENT-2, and VIVID-1 occurring in < 1% of OMVOH-treated patients:

Immune system disorders: infusion-related hypersensitivity reaction (LUCENT-1 and VIVID-1, weeks 1-12).

Hepatic and hepatobiliary disorders: alanine aminotransferase increased; aspartate aminotransferase increased.

9. Drug Interactions

9.2. Drug Interactions Overview

Specific drug interaction studies have not been conducted in ulcerative colitis or Crohn’s disease patients with OMVOH.

Population pharmacokinetic data analyses indicated that the clearance of OMVOH was not impacted by concomitant administration of Aminosalicyclic acid (5ASAs), corticosteroids or oral immunomodulators (6-mercaptopurine, azathioprine, methotrexate, tioguanine) in patients with ulcerative colitis or Crohn’s disease.

9.4. Drug-Drug Interactions

Live Vaccines

Avoid use of live vaccines in patients treated with OMVOH (see 7 Warnings and Precautions, Immune).

9.5. Drug-Food Interactions

Interactions with food have not been established.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

Mirikizumab is a humanized IgG4 monoclonal antibody that binds with high affinity and specificity to the p19 subunit of human IL-23 cytokine and inhibits its interaction with the IL-23 receptor. It has no observed cross-reactivity to other members of the IL-12 cytokine family (that is, IL-12, IL-27, and IL-35).

IL-23 is a naturally occurring cytokine that affects the differentiation, expansion, and survival of T cell subsets, (e.g., Th17 cells and Tc17 cells) and innate immune cell subsets, which represent sources of effector cytokines, that drive inflammatory disease.

10.2. Pharmacodynamics

No formal Pharmacodynamic studies have been performed with mirikizumab.

10.3. Pharmacokinetics

The pharmacokinetic properties of mirikizumab were similar in the adult ulcerative colitis and Crohn’s disease.

Mirikizumab exhibited linear pharmacokinetics with a dose-proportional increase in exposure over a dose range of 5 to 2400 mg given as an intravenous injection or over a dose range of 120 to 400 mg given as a subcutaneous injection, in patients with ulcerative colitis or in healthy volunteers. There was no apparent accumulation in serum mirikizumab concentration over time when given intravenously or subcutaneously every 4 weeks.

Table 3 – Summary of mirikizumab Pharmacokinetic Parameters in adult patients with Ulcerative Colitis^a

^a Abbreviations: AUC_{tau, ss} = area under concentration-time curve at a dosing interval at steady state; C_{max, ss} = peak concentration at steady state; CL = clearance; CL/F = apparent clearance; V = volume of distribution; V/F = apparent volume of distribution; t_1/2 = half life.

Parameter estimates following intravenous and subcutaneous administration are based on population PK analysis using data from phase 3 induction and maintenance study, respectively. Parameter estimates were reported as geometric mean (% coefficient variation).

Absorption

Following subcutaneous dosing of mirikizumab, peak serum concentrations were achieved approximately 3 days post dose. The absolute bioavailability was estimated to be 44% based on population PK modeling.

Injection site location had no clinically meaningful effect on mirikizumab exposure.

Distribution

The mean total volume of distribution of mirikizumab was 4.83 L.

Metabolism

Mirikizumab 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.

Elimination

Based on population pharmacokinetic analysis, the mean systemic clearance of mirikizumab was 0.0229 L / hr and the mean half-life was 9.3 days in patients with ulcerative colitis. Clearance was independent of dose.

Special Populations and Conditions

• Pediatrics

  The pharmacokinetics of mirikizumab in pediatric patients has not been evaluated.

• Geriatrics

  Of the 1362 subjects with ulcerative colitis exposed to mirikizumab in Phase 2 and Phase 3 studies, 99 subjects were 65 years or older and 11 subjects were 75 years or older. Population pharmacokinetic analysis showed no overall differences in mirikizumab exposure between older and younger subjects.

• Sex

  Population pharmacokinetic analysis showed that sex did not have a significant effect on the pharmacokinetics of mirikizumab.

• Ethnic origin

  Population pharmacokinetic analysis showed that race/ethnicity did not have a significant effect on the pharmacokinetics of mirikizumab.

• Hepatic Insufficiency

  Specific clinical pharmacology studies to evaluate the effects of hepatic impairment on the pharmacokinetics of mirikizumab have not been conducted. Population pharmacokinetic analysis showed that total bilirubin (range of 1.5 to 29 µmol / L) was not identified as a clinically relevant covariate on mirikizumab pharmacokinetics.

• Renal Insufficiency

  Specific clinical pharmacology studies to evaluate the effects of renal impairment on the pharmacokinetics of mirikizumab have not been conducted.

  Population pharmacokinetic analysis showed that creatinine clearance (range of 36.2 to 291 mL / min) was not identified as a clinically relevant covariate on mirikizumab pharmacokinetics.

• Obesity

  Population pharmacokinetic analysis showed that weight was a covariate on mirikizumab exposure; however, no clinically meaningful effects of weight were observed.

10.4. Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity with OMVOH. Immunogenicity tests are generally product-specific and are highly dependent on the sensitivity and specificity of the assay. Comparison of incidence of antibodies between products by different tests may be misleading.

Ulcerative Colitis

By Week 52, 23% (88/378) of subjects treated with OMVOH at the recommended dose developed antibodies to mirikizumab. Of the 88 subjects who developed antibodies to mirikizumab, 82 subjects (93.1%) had antibodies that were characterized as neutralizing. The antibody titers detected in OMVOH-treated subjects were mostly low. Higher antibody titers (≥ 1:160) were detected in approximately 9% of subjects treated with OMVOH, and these ADA titers were associated with lower serum mirikizumab concentrations and reduced clinical response in 2% of subjects treated with OMVOH.

Crohn’s Disease

By Week 52, 12.7% (79/622) of subjects treated with OMVOH at the recommended dose developed antibodies to mirikizumab, most of which were low titer and tested positive for neutralizing activity. There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics or effectiveness of mirikizumab.

No association was found between anti-mirikizumab antibodies and hypersensitivity or injection-related events in either the ulcerative colitis or Crohn’s disease studies.

1. 11.

   Storage, Stability, and Disposal

   • Store refrigerated at 2°C to 8°C.
   • Do NOT freeze. Do not use OMVOH if it has been frozen.
   • Do NOT shake.
   • Keep OMVOH in the original carton to protect from light until the time of use.
   • If needed, the prefilled syringe or prefilled pen may be stored outside of refrigeration at not more than 30°C for up to 2 weeks in the original carton to protect from light. Once OMVOH has been stored at room temperature, do not return to the refrigerator. If these conditions are exceeded, OMVOH must be discarded.

12. Special Handling Instructions

OMVOH is sterile and preservative-free. Discard any unused portion.

The prefilled syringe and prefilled pen should be disposed of in a puncture-resistant container for syringes and needles. Patients or caregivers should be instructed in the technique as well as proper syringe and needle disposal, and not to reuse these items.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of

the drug substance: mirikizumab

Chemical name: Immunoglobulin G4, anti-(human interleukin 23 p19 subunit) (human monoclonal LY3074828 γ4-chain), disulfide with human monoclonal LY3074828 κ-chain, dimer

Molecular formula: C₆₃₈₀H₉₈₄₂N₁₆₈₆O₂₀₀₄S₄₈ (protein backbone without pyroglutamation, tetramer)

Molecular mass: The overall molecular weight is approximately 147 kDa

Structure: Mirikizumab is a humanized immunoglobulin G4 (IgG4) isotype monoclonal antibody composed of two identical immunoglobulin kappa light chains and two identical immunoglobulin gamma heavy chains.

Physicochemical properties: Mirikizumab is clear to opalescent, colourless to slightly yellow to slightly brown solution.

Pharmaceutical standard: Professed

Product Characteristics:

Mirikizumab drug substance manufacture begins with the thawing of the working cell bank, that is scaled-up prior to seeding a production bioreactor. The culture is harvested, clarified, and purified via a downstream purification process. Mirikizumab drug product is formulated, sterile filtered and filled into vials or syringes prior to final packaging.

Mirikizumab for Injection, 300 mg / 15 mL is supplied as a sterile, non-pyrogenic, preservative-free solution in a 20-mL glass vial intended for single use. The mirikizumab drug product is diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection prior to administration by intravenous infusion.

Mirikizumab Injection, 100 mg / mL is supplied as a 100 mg/mL prefilled syringe and prefilled pen, non-pyrogenic parenteral solution for subcutaneous administration, intended for single use. The prefilled pen and prefilled syringe each contain a 1 mL-long, clear, Type I glass syringe barrel with a small round flange, 27G special thin wall x 1/2" staked needle, and closed with a barrier film laminated elastomeric plunger.

Mirikizumab Injection, 200 mg / 2 mL is supplied as a 200 mg / 2 mL prefilled syringe and prefilled pen, non-pyrogenic parenteral solution for subcutaneous administration, intended for single use.

The prefilled pen and prefilled syringe each contain a 2.25 mL, clear, Type I glass syringe barrel with a small round flange, 27G special thin wall x 8 mm staked needle and closed with a rigid needle shield and a barrier film laminated elastomeric plunger.

14. Clinical Trials

14.1. Clinical Trials by Indication

14.1.1. Ulcerative Colitis

The efficacy and safety of OMVOH in adult subjects with moderately to severely active ulcerative colitis were evaluated in two multicentre, randomized, double-blind, placebo-controlled clinical studies (LUCENT-1 and LUCENT-2). LUCENT-1 was a 12-week induction phase study that evaluated the ability of OMVOH administered by intravenous (IV) injection to achieve clinical remission. LUCENT-2 was a subsequent 40-week withdrawal maintenance phase study (52 weeks of continuous treatment) that evaluated the ability of OMVOH administered by subcutaneous (SC) injection to achieve clinical remission in subjects who achieved clinical response after 12 weeks of OMVOH treatment in the induction study. All subjects had previously had an inadequate response, loss of response, or failed to tolerate corticosteroids, immunomodulators (i.e., 6-mercaptopurine, azathioprine), biologic therapy (i.e., TNF blocker, vedolizumab), or a Janus Kinase inhibitor (i.e., tofacitinib).

Enrolled subjects were 18 years of age or older with a modified Mayo score (mMS) ≥ 4 including an endoscopy subscore (ES) ≥ 2. The mMS is a composite endpoint scored from 0 (normal) to 9 (most severe) consisting of three subscores each scored from 0 (normal) to 3 (most severe), including stool frequency, rectal bleeding, and findings on centrally read endoscopy. An ES of 2 was defined by marked erythema, absent vascular pattern, friability, and erosions; an ES of 3 was defined by spontaneous bleeding and ulceration.

Table 4 - Summary of subject demographics for clinical trials in ulcerative colitis

IV = intravenous; SC = subcutaneous; Q4W = every 4 weeks.

Induction Phase Study: LUCENT-1

In LUCENT-1, 1162 subjects were randomized 3:1 to receive 300 mg OMVOH or placebo by intravenous infusion at Week 0, Week 4, and Week 8. Randomization was stratified by (a) biologic-failed status (yes/no), (b) baseline corticosteroid use (yes/no), (c) baseline disease activity (mMS: [4-6, moderate] or [7-9, severe]), and (d) region (North America/Europe/Other). Subjects who were on concomitant ulcerative colitis therapies prior to enrollment continued on stable doses during the study, including 39.9% of subjects receiving oral corticosteroids, 24.1% receiving immunomodulators and 74.3% receiving aminosalicylates.

At baseline, 57.1% of subjects were biologic and Janus Kinase inhibitor (JAKi) naive, 41.0% had failed at least one biologic and 3.4% had failed a JAKi. An additional 1.7% had previously received but had not failed a biologic or JAKi.

Subjects had a median mMS of 7.0 and 53.2% had severely active disease (mMS ≥ 7).

The primary efficacy endpoint was the proportion of subjects in clinical remission at Week 12. Key secondary endpoints included the proportion of subjects in clinical response, endoscopic improvement, and histologic-endoscopic mucosal improvement.

Study Results

The results of the primary and key secondary endpoints are shown in Table 5.

Table 5 - Proportion of Patients Meeting Efficacy Endpoints at Week 12 in LUCENT-1^a

^a Abbreviations: CI = confidence interval; ES = endoscopic subscore; IV = intravenous; MMS = modified Mayo score; RB = rectal bleeding; SF = stool frequency; UC = ulcerative colitis.

^b Treatment difference (99.875% CI) adjusted for randomization stratification factors.

^c Clinical remission is based on the MMS defined as an SF subscore = 0, or an SF subscore = 1 with a ≥ 1-point decrease from baseline; and an RB subscore = 0; and an ES = 0 or 1 (excluding friability).

^d p < 0.00125 based on the Cochran-Mantel-Haenszel chi-square test adjusted for randomization stratification factors. Non-responder imputation was used to impute missing data.

^e An additional 5 patients on placebo and 15 patients on OMVOH were previously exposed to but did not fail a biologic or JAKi.

^f Prior biologic or JAKi failed is defined as loss of response, inadequate response or intolerance to biologic therapy (TNF blocker or vedolizumab), or tofacitinib.

^g Clinical response is defined as a decrease in the MMS of ≥ 2 points with ≥ 30% decrease from baseline, and either a decrease of ≥ 1 point in the RB subscore from baseline or an RB subscore of 0 or 1.

^h Endoscopic improvement is defined as an ES = 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern), excluding friability.

ⁱ Histologic-endoscopic mucosal improvement is defined as achieving both endoscopic improvement (ES = 0 or 1, excluding friability) and histologic improvement (Geboes scoring system with neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue).

Symptomatic Remission Subscore

Symptomatic remission (defined as a rectal bleeding subscore = 0 and a stool frequency subscore = 0 or a stool frequency subscore = 1 with a ≥1 point decrease from baseline) was observed at Week 12 in 45.5% of subjects receiving OMVOH and 27.9% of subjects receiving placebo. Symptomatic remission was observed at Week 4 in 21.8% of subjects receiving OMVOH and 12.9% of subjects receiving placebo.

Maintenance Phase Study: LUCENT-2

LUCENT-2 was a randomized withdrawal maintenance study in which 544 subjects who received OMVOH and achieved clinical response at Week 12 in study LUCENT-1 were randomized 2:1 to receive 200 mg OMVOH or placebo subcutaneously every 4 weeks for 40 weeks (i.e., 52 weeks of continuous treatment in LUCENT-1 and LUCENT-2 in total). Randomization was stratified by (a) biologic-failed status (yes/no), (b) baseline corticosteroid use (yes/no), (c) baseline disease activity (mMS: [4-6, moderate] or [7-9, severe]), and (d) region (North America/Europe/Other). Subjects who were on concomitant ulcerative colitis therapies during LUCENT-1 were required to continue on stable doses during the study; subjects who were receiving corticosteroids at LUCENT-1 baseline and who achieved clinical response in study LUCENT-1 required corticosteroid tapering at start of LUCENT-2.

The primary endpoint was the proportion of subjects in clinical remission at Week 40 (52 weeks of continuous treatment in LUCENT-1 and LUCENT-2). Key secondary endpoints included the proportion of subjects achieving endoscopic improvement, histo-endoscopic mucosal remission, corticosteroid-free clinical remission without surgery, and bowel urgency response at Week 40. An additional key secondary endpoint was maintenance of clinical remission at Week 40 of LUCENT-2 among subjects who achieved clinical remission at Week 12 in LUCENT-1.

Study Results

The results of primary and key secondary endpoints are provided in Table 6.

Table 6 – Proportion of Patients Meeting Efficacy Endpoints in LUCENT-2 at Week 40 (52 weeks of continuous treatment)^a

^a Abbreviations: CI = confidence interval; ES = endoscopic subscore; MMS = modified Mayo score; RB = rectal bleeding; SC = subcutaneous; SF = stool frequency.

^b The placebo arm includes those patients who received OMVOH during the induction study (LUCENT-1) and were randomized to receive placebo through Week 40.

^c Treatment difference (95% CI) adjusted for randomization stratification factors.

^d Among patients who achieved clinical response with OMVOH induction treatment.

^e Clinical remission is based on the MMS defined as an SF subscore = 0, or an SF subscore = 1 with a ≥ 1-point decrease from UC-1 baseline; and an RB subscore = 0; and an ES = 0 or 1 (excluding friability).

^f p < 0.05 based on the Cochran-Mantel-Haenszel chi-square test adjusted for randomization stratification factors. Non-responder imputation was used to impute missing data.

^g An additional 1 patient on placebo and 8 patients on OMVOH were previously exposed to but did not fail a biologic or JAKi.

^h Prior biologic or JAKi failed is defined as loss of response, inadequate response or intolerance to biologic therapy (TNF blocker or vedolizumab), or tofacitinib.

ⁱ Endoscopic improvement is defined as a modified Mayo ES = 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern) excluding friability.

^j Among patients who achieved clinical remission at week 12 in LUCENT-1 with OMVOH induction treatment.

^k Corticosteroid free remission is defined as clinical remission at Week 40; and symptomatic remission at Week 28; and no corticosteroid use for ≥ 12 weeks prior to Week 40.

^l Histo-endoscopic mucosal remission is defined as both endoscopic improvement (ES = 0 or 1, excluding friability); and histologic remission [Geboes scoring system with subscores of 0 for grades: 2b (lamina propria neutrophils), and 3 (neutrophils in epithelium), and 4 (crypt destruction), and 5 (erosion or ulceration)].

^m Bowel urgency response is defined as NRS 0 or 1 in patients with urgency NRS ≥ 3 at baseline in LUCENT-1.

OMVOH Extended Induction

Subjects who did not achieve clinical response after induction with OMVOH in LUCENT-1 were eligible to receive extended induction with OMVOH by intravenous infusion at Weeks 0, 4, and 8 of LUCENT-2. Of these subjects, 146/272 (53.7%) achieved clinical response at Week 12 (24 weeks total induction including LUCENT-1) and were eligible to receive maintenance OMVOH subcutaneously every 4 weeks during LUCENT-2. At Week 40, of the subjects who achieved clinical response after extended induction and transitioned to maintenance regimen, 72.2% maintained clinical response, including 36.1% who achieved clinical remission.

14.1.2. Crohn’s Disease

The efficacy and safety of OMVOH were evaluated in a randomized, double-blind, placebo- and active controlled treat-through design clinical study VIVID-1 in adult patients with moderately to severely active Crohn’s disease who had an inadequate response with, loss of response, or intolerance to corticosteroids, immunomodulators (e.g. azathioprine, 6-mercaptopurine), or a biologic treatment (e.g. TNFα antagonist or integrin receptor antagonist). This study included an OMVOH 12-week intravenous infusion induction period followed by a 40-week subcutaneous injection maintenance period. This study also included an ustekinumab comparator arm in the induction and maintenance periods.

In VIVID-1, efficacy was evaluated in 1065 subjects who were randomized 6:3:2 to receive 900 mg OMVOH by intravenous infusion (IV) at Week 0, Week 4, and Week 8 followed by a maintenance dose of 300 mg by subcutaneous injection (SC) at Week 12 and then every 4 weeks (Q4W) for 40 weeks, ustekinumab approximately 6 mg/kg by IV administration at Week 0 followed by 90 mg SC administration every 8 weeks (Q8W) starting at Week 8, or placebo. Subjects randomised to placebo at baseline who achieved clinical response by Patient-Reported Outcome (PRO) at Week 12 (defined as at least a 30% decrease in stool frequency (SF) and/or abdominal pain (AP) with neither score worse than baseline) remained on placebo. Patients randomized to placebo at baseline who did not achieve clinical response by PRO at Week 12 received 900 mg OMVOH by IV infusion at Week 12, Week 16, and Week 20 followed by a maintenance dose of 300 mg Q4W SC at Week 24 through Week 48.

Disease activity at baseline was assessed by (1) the unweighted daily average of SF (2), the unweighted daily average AP (ranging from 0 to 3) and (3) Simple Endoscopic Score for Crohn’s disease (SES-CD) (ranging from 0 to 56).

Moderately to severely active CD was defined by SF ≥ 4 and/or AP ≥ 2 and SES-CD ≥ 7 (centrally read) for patients with ileal-colonic and isolated colonic disease or ≥ 4 for patients with isolated ileal disease. At baseline patients had a median SF of 6, AP of 2 and SES-CD of 12.

Subjects had a mean age of 36 years (range 18 to 76 years); 45% were female; and 72% identified as White, 25% as Asian, 1% as American Indian or Alaska Native, 2% as Black or African American, and < 1% as another racial group or did not report their racial group. Subjects were permitted to use stable doses of oral corticosteroids, immunomodulators (e.g., 6-mercatopurine, azathioprine, or methotrexate) and/or aminosalicylates. At baseline, 31% of subjects were receiving oral corticosteroids, 27% were receiving immunomodulators, and 43% were receiving aminosalicylates.

At baseline, 49% had a loss of response, inadequate response, or intolerance to one or more biologic therapy (prior biologic failure).

Table 7 – Summary of subject demographics for clinical trials in Crohn’s disease

The co-primary endpoints were (1) clinical response by PRO at Week 12 and endoscopic response at Week 52 versus placebo and (2) clinical response by PRO at Week 12 and clinical remission by Crohn’s Disease Activity Index (CDAI) at Week 52 versus placebo; the results for the co-primary endpoints and the major secondary endpoints at Week 52 versus placebo are provided in Table 8. The major secondary endpoints at Week 12 versus placebo are provided in Table 9.

Table 8 – Proportion of patients with Crohn’s disease meeting efficacy endpoints in VIVID-1 at Week 52^a

Abbreviations: AP = abdominal pain; CDAI = Crohn’s Disease Activity Index; CI = confidence interval; PRO = 2 of the patient-reported items of the CDAI (SF and AP); SES-CD = Simple Endoscopic Score for Crohn’s Disease; SF = stool frequency.

^a To control the type I error rate of the primary and major secondary endpoint comparisons between OMVOH and placebo at a family wise error rate of 0.005, a graphical multiple testing procedure was used.

^b Following OMVOH 900 mg as an IV infusion at Week 0, Week 4, and Week 8 patients received OMVOH 300 mg as a SC injection at Week 12 and every 4 weeks thereafter for up to an additional 40 weeks.

^c For binary endpoints adjusted treatment difference was based on Cochran-Mantel-Haenszel method adjusted for baseline covariates.

^d Clinical response by PRO is defined as at least a 30% decrease in SF and/or AP and neither score worse than baseline.

^e Endoscopic response is defined as ≥ 50% reduction from baseline in SES-CD total score, based on central reading.

^f p < 0.000001

^g Prior biologic failure includes loss of response, inadequate response, or intolerance to one or more biologic therapy (e.g. TNFα antagonist or integrin receptor antagonist).

^h Clinical remission by CDAI is defined as CDAI total score < 150.

ⁱ Placebo sample size includes all patients randomized to placebo at baseline. Placebo patients that did not achieve clinical response by PRO at Week 12 were considered non-responders at Week 52.

^j Clinical remission by PRO is defined as SF ≤ 3 and not worse than baseline (according to the Bristol Stool Scale Category 6 or 7) and AP ≤ 1 and not worse than baseline.

^k Endoscopic remission is defined as SES-CD Total Score ≤ 4 and at least a 2-point reduction versus baseline and no subscore > 1 in any individual variable, based on central reading.

^l Corticosteroid-free is defined as patients who were corticosteroid-free from Week 40 to Week 52.

Bowel urgency response

The proportion of patients with a baseline urgency numeric rating scale (NRS) weekly average score ≥ 3 who achieved clinical response by PRO at Week 12 and an urgency NRS weekly average score of ≤ 2 at Week 52 was 33% in the OMVOH group and 11% in the placebo group.

Table 9 – Proportion of patients with Crohn’s disease meeting efficacy endpoints in VIVID-1 at Week 12^a

Abbreviations: CI = confidence interval; PRO = 2 of the patient-reported items of the CDAI (SF and AP); CDAI = Crohn’s Disease Activity Index; FACIT-fatigue = Functional Assessment of Chronic Illness Therapy – fatigue; LS Mean = Least Square Mean; SE = Standard Error.

^a To control the type I error rate of the primary and major secondary endpoint comparisons between OMVOH and placebo at a family wise error rate of 0.005, a graphical multiple testing procedure was used.

^b OMVOH 900 mg as an intravenous infusion at Week 0, Week 4, and Week 8.

^c For binary endpoints, adjusted treatment difference was based on Cochran-Mantel-Haenszel method adjusted for baseline covariates. For change from baseline in FACIT-Fatigue, the least square mean treatment difference was based on ANCOVA model adjusted for baseline FACIT-Fatigue and other covariates.

^d Clinical response by PRO is defined as at least a 30% decrease in SF and/or AP and neither score worse than baseline.

^e p-value < 0.000001.

^f Prior biologic failure includes loss of response, inadequate response, or intolerance to one or more biologic therapy (e.g. TNF blocker or integrin receptor antagonist).

^g Clinical remission by CDAI is defined as CDAI < 150.

^h p-value < 0.005.

ⁱ Endoscopic response is defined as ≥50% reduction from baseline in SES-CD Total Score, based on central reading.

^j Endoscopic remission is defined as SES-CD Total Score ≤ 4 and at least a 2-point reduction versus baseline and no subscore > 1 in any individual variable, based on central reading.

^k Least square mean values adjusted for baseline FACIT-Fatigue and other covariates reported. At baseline, mean FACIT- Fatigue values were similar across treatment groups and ranged from 32.3-31.5.

Improvements in clinical remission were observed as early as Week 4 in patients treated with OMVOH.

The efficacy and safety profile of OMVOH was consistent across subgroups, i.e. age, gender, body weight, disease activity severity at baseline and region. The effect size may vary.

Histologic outcome

Improvements in histologic outcomes were observed at Week 12 and Week 52 in patients treated with OMVOH.

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

General toxicology: Cynomolgus monkeys were administered mirikizumab two times per week at IV doses of 100 or 300 mg/kg (i.e., 200 or 600 mg/kg/week), formulated in 10 mM sodium citrate, 150 mM sodium chloride, 0.03% polysorbate 80, pH 5.5, or vehicle control, for 6 months. One animal in the 300 mg/kg/dose group exhibited hematologic, clinical chemistry, and morphologic changes indicative of immune-mediated hemolytic effect of mirikizumab administration. This animal also exhibited a ~90% reduction in NK cell activity and a ~75% reduction in NK cell absolute counts. The no observed adverse effect level (NOAEL) was 100 mg/kg/dose. For the UC indication, exposure at this dose corresponds to 30X and 100X the human exposure based on AUC at the mirikizumab induction dose (300 mg IV) and the mirikizumab maintenance dose (200 mg SC), respectively. For the CD indication, exposure at this dose corresponds to 9X and 73X the human exposure based on AUC at the mirikizumab induction dose (900 mg IV) and the mirikizumab maintenance dose (300 mg SC), respectively.

Sexually mature cynomolgus monkeys were administered mirikizumab once per week at SC doses of 10 and 100 mg/kg formulated in 10 mM sodium citrate, 150 mM sodium chloride, 0.02% polysorbate 80, pH 6.0, or vehicle control, for 6 months. No organ weight or histopathology effects were observed in the male or female reproductive tract. The NOAEL was 100 mg/kg. For the UC indication, exposure at this dose corresponds to 6.6X and 22X the human exposure based on AUC at the mirikizumab induction dose of 300 mg IV and maintenance dose of 200 mg SC, respectively. For the CD indication, exposure at this dose corresponds to 2X and 16X the human exposure based on AUC at the mirikizumab induction dose (900 mg IV) and the mirikizumab maintenance dose (300 mg SC), respectively.

Carcinogenicity: Carcinogenicity studies have not been conducted with mirikizumab.

Genotoxicity: Genotoxicity studies have not been conducted with mirikizumab.

Reproductive and Developmental Toxicology: A developmental toxicity study in pregnant monkeys revealed no adverse developmental effects to the fetus or infant. Pregnant cynomolgus monkeys were administered mirikizumab two times per week at an IV dose of 300 mg/kg (i.e., 600 mg / kg / week), formulated in 10 mM sodium citrate, 150 mM sodium chloride, 0.03% polysorbate 80, pH 5.5, or vehicle control, from gestation day 21 ± 1 until birth. There were no mirikizumab-related adverse effects in mothers, fetuses, or infants followed for 6 months after birth. Mirikizumab was detected in all infants for at least 28 days after birth. The overall incidence of embryo/fetal loss was 6.7% (1/15) in the control group and was 26.7% (4/15) at 300 mg/kg mirikizumab, with both values within the range of historical control data at the Testing Facility. The NOAEL for developmental effects was 300 mg/kg/dose, with a corresponding maternal AUC of 127000 µg∙hr/mL. For the UC indication, this exposure corresponds to 69X and 232X the human exposure based on AUC at the mirikizumab induction dose of 300 mg IV and the mirikizumab maintenance dose of 200 mg SC, respectively. For the CD indication, this exposure corresponds to 20X and 168X the human exposure based on AUC at the mirikizumab induction dose of 900 mg IV and the mirikizumab maintenance dose of 300 mg SC, respectively. The concentration of mirikizumab in maternal milk was not determined. Animal studies are not always predictive of human response, therefore, it is unknown whether mirikizumab could cause fetal harm when administered to a pregnant woman.