Skyrizi (Abbvie, 150 mg, ..., 55 mg) 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 ........................................................................... 5

1. 1.

   Indications ....................................................................................................................... 5

   1.1. Pediatrics .................................................................................................................. 5

   1.2. Geriatrics .................................................................................................................. 6

2. 2. Contraindications ............................................................................................................ 6
3. 4.

   Dosage and Administration ............................................................................................. 6

   4.1. Dosing Considerations .............................................................................................. 6

   4.2. Recommended Dose and Dosage Adjustment ......................................................... 8

   4.3. Reconstitution .......................................................................................................... 9

   4.4. Administration ........................................................................................................ 10

   4.5. Missed Dose ........................................................................................................... 11

4. 5. Overdose ....................................................................................................................... 11
5. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................. 12
6. 7.

   Warnings and Precautions ............................................................................................. 14

   General ............................................................................................................................... 14

   Immune .............................................................................................................................. 15

   Reproductive Health ........................................................................................................... 15

   Sensitivity/Resistance ......................................................................................................... 15

   7.1. Special Populations ................................................................................................ 15

   7.1.1. Pregnancy ...................................................................................................... 15

   7.1.2. Breastfeeding ................................................................................................ 16

   7.1.3. Pediatrics ....................................................................................................... 16

   7.1.4. Geriatrics ....................................................................................................... 16

7. 8.

   Adverse Reactions ......................................................................................................... 16

   8.1. Adverse Reaction Overview .................................................................................... 16

   8.2. Clinical Trial Adverse Reactions .............................................................................. 17

   8.2.1. Clinical Trial Adverse Reactions – Pediatrics .................................................. 21

   8.3. Less Common Clinical Trial Adverse Reactions ....................................................... 21

   8.5. Post-Market Adverse Reactions ............................................................................. 21

8. 9.

   Drug Interactions ........................................................................................................... 21

   9.2. Drug Interactions Overview .................................................................................... 21

   9.3. Drug-Behaviour Interactions .................................................................................. 22

   9.4. Drug-Drug Interactions ........................................................................................... 22

   9.5. Drug-Food Interactions........................................................................................... 22

   9.6. Drug-Herb Interactions ........................................................................................... 22

   9.7. Drug-Laboratory Test Interactions ......................................................................... 22

9. 10.

   Clinical Pharmacology ................................................................................................... 23

   10.1. Mechanism of Action .............................................................................................. 23

   10.2. Pharmacodynamics ................................................................................................ 23

   10.3. Pharmacokinetics ................................................................................................... 23

   10.4. Immunogenicity ...................................................................................................... 26

10. 11. Storage, Stability, and Disposal ...................................................................................... 27
11. 12. Special Handling Instructions ......................................................................................... 27

Part 2: Scientific Information ................................................................................................ 28

1. 13. Pharmaceutical Information .......................................................................................... 28
2. 14.

   Clinical Trials .................................................................................................................. 28

   14.1. Clinical Trials by Indication ..................................................................................... 28

   Adult Plaque Psoriasis ......................................................................................................... 28

   Pediatric Plaque Psoriasis (6 to < 18 years of age) .............................................................. 37

   Adult Psoriatic Arthritis ....................................................................................................... 39

   Pediatric Psoriatic Arthritis (6 to < 18 years of age) ............................................................ 44

   Crohn’s Disease .................................................................................................................. 44

   Ulcerative Colitis ................................................................................................................. 49

3. 15. Microbiology ................................................................................................................. 54
4. 16. Non-Clinical Toxicology .................................................................................................. 54

Patient Medication Information (Plaque Psoriasis and Psoriatic Arthritis) ............................ 56

Patient Medication Information (Crohn’s Disease and Ulcerative Colitis) ............................. 62

Instructions for Use (150 mg Pre-filled Pen) .......................................................................... 72

Instructions for Use (150 mg and 55 mg Pre-filled Syringe) ................................................... 76

Instructions for Use (180 mg and 360 mg On-body Injector with Pre-filled Cartridge) ........... 80

Part 1: Healthcare Professional Information

1. Indications

SKYRIZI (risankizumab injection) is indicated for:

• the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
• the treatment of pediatric patients aged 6 to < 18 years of age with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
• the treatment of adult patients with active psoriatic arthritis. SKYRIZI can be used alone or in combination with a conventional non-biologic disease-modifying antirheumatic drug (cDMARD) (e.g., methotrexate).
• the treatment of pediatric patients aged 6 to < 18 years of age with active psoriatic arthritis. SKYRIZI can be used alone or in combination with a conventional non-biologic disease-modifying antirheumatic drug (cDMARD) (e.g., methotrexate).

SKYRIZI (risankizumab injection / risankizumab for injection) is indicated for:

• the treatment of adults with moderately to severely active Crohn's disease who have had an inadequate response, intolerance, or demonstrated dependence to corticosteroids; or an inadequate response, intolerance, or loss of response to immunomodulators or biologic therapies.
• 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.

1.1. Pediatrics

Pediatrics (< 18 years of age)

Plaque Psoriasis

Pediatrics (6 to < 18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of SKYRIZI in pediatric patients has been established. Therefore, Health Canada has authorized an indication for pediatric use (see 1. Indications, 4.1. Dosing Considerations, 14.1. Clinical Trials by Indication).

Pediatrics (< 6 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric patients < 6 years of age.

Psoriatic Arthritis

Pediatrics (6 to < 18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of SKYRIZI in pediatric patients has been established, supported by model-based extrapolation. Therefore, Health Canada has authorized an indication for pediatric use (see 1. Indications).

Pediatrics (< 6 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric patients < 6 years of age.

Ulcerative Colitis

The efficacy and safety of SKYRIZI have not been evaluated in patients with ulcerative colitis younger than 18 years of age.

Crohn’s Disease

Of the 1574 subjects with Crohn’s disease exposed to SKYRIZI in clinical trials, 12 were 16 to 17 years of age. The efficacy and safety of SKYRIZI have not been evaluated in pediatric patients with Crohn’s disease younger than 16 years of age.

1.2. Geriatrics

Geriatrics (≥ 65 years of age)

Limited data are available to Health Canada regarding this age group. Of the 2234 patients with plaque psoriasis exposed to SKYRIZI in clinical trials, 243 (11%) were 65 years or older, including 24 (1%) who were 75 years or older. Of the 1574 subjects with Crohn’s disease exposed to SKYRIZI in clinical trials, 72 (5%) were 65 years or older, including 5 (0.3%) who were 75 years or older. Of the 1512 subjects with ulcerative colitis exposed to SKYRIZI, 103 (7%) were 65 years or older, including 8 (0.5%) who were 75 years or older.

2. Contraindications

SKYRIZI is contraindicated in patients who are hypersensitive to risankizumab or to any ingredient in the formulation or component of the container. For a complete listing, see 6. Dosage Forms, Strengths, Composition and Packaging.

SKYRIZI should not be given to patients with any clinically important active infections until the infection resolves or is adequately treated (see 7. Warnings and Precautions).

4. Dosage and Administration

SKYRIZI should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of plaque psoriasis, psoriatic arthritis, Crohn’s disease or ulcerative colitis.

The AbbVie Care Patient Support Program has been established to facilitate patient access and administration of their treatment with SKYRIZI. AbbVie Care Nurses are qualified health care professionals specially trained to provide injection support services including medication delivery, injection training and ongoing personalized care for patients treated with SKYRIZI. AbbVie Care Support Program services are available across Canada. Information about the support services can be obtained by calling the AbbVie Care Support Program at 1-866-848-6472.

4.1. Dosing Considerations

Recommended Evaluations and Immunizations Prior to Treatment Initiation:

• Evaluate patients for tuberculosis (TB) infection according to the Canadian Tuberculosis Standards prior to initiating treatment with SKYRIZI (see 7. Warnings and Precautions).
• Complete all age-appropriate vaccinations as recommended by current Canadian immunization guidelines (see 7. Warnings and Precautions).

Plaque Psoriasis and Psoriatic Arthritis

• Adult patients may self-inject SKYRIZI subcutaneously if their physician determines that it is appropriate and with medical follow-up, as necessary, after proper training in subcutaneous injection technique. Patients should read the Instructions for Use before administration.

  • In children and adolescents 10 to < 18 years of age, it is recommended that SKYRIZI is administered by or under the supervision of an adult.
  • In children 6 to < 10 years of age, SKYRIZI should be administered by an adult.

Crohn’s Disease

• The intravenous infusion with the SKYRIZI 600 mg vial and the subcutaneous injection with the 90 mg/1 mL (90 mg/mL) pre-filled syringe should be administered only by a healthcare professional.
• Patients may self-inject SKYRIZI subcutaneously with the 360 mg/2.4 mL (150 mg/mL) cartridge with on-body injector if their physician determines that it is appropriate and with medical follow-up, as necessary, after proper training in subcutaneous injection technique. Patients should read the Instructions for Use before administration.
• If using SKYRIZI 360 mg/2.4 mL (150 mg/mL) patients should be instructed to inject one pre-filled cartridge with on-body injector for the full 360 mg dose.
• If using SKYRIZI 90 mg/1 mL (90 mg/mL) healthcare professionals should inject 4 pre-filled syringes for the full 360 mg dose.
• Consider obtaining liver tests as per routine patient management prior to initiating treatment with SKYRIZI in Crohn’s disease patients (see 8.2. Clinical Trial Adverse Reactions, Adverse Reactions in Crohn’s Disease Trials).

Ulcerative Colitis

• The intravenous infusion with the SKYRIZI 600 mg vial and the subcutaneous injection with the 90 mg/1 mL (90 mg/mL) pre-filled syringe should be administered only by a healthcare professional.
• Patients may self-inject SKYRIZI subcutaneously with the 180 mg/1.2 mL (150 mg/mL) cartridge or the 360 mg/2.4 mL (150 mg/mL) cartridge with on-body injector if their physician determines that it is appropriate and with medical follow-up, as necessary, after proper training in subcutaneous injection technique. Patients should read the Instructions for Use before administration.
• For a 180 mg dose, patients should be instructed to inject one 180 mg/1.2 mL pre-filled cartridge with on-body injector.
• For a 360 mg dose, patients should be instructed to inject one 360 mg/2.4 mL pre-filled cartridge with on-body injector.
• If using SKYRIZI 90 mg/1 mL (90 mg/mL) healthcare professionals should inject 4 pre-filled syringes for the full 360 mg dose.
• Consider obtaining liver tests as per routine patient management prior to initiating treatment with SKYRIZI in ulcerative colitis patients (see 8.2. Clinical Trial Adverse Reactions, Adverse Reactions in Ulcerative Colitis Trials).

Each pre-filled pen, pre-filled syringe, pre-filled cartridge with on-body injector, and vial is for single use only.

4.2. Recommended Dose and Dosage Adjustment

Plaque Psoriasis

• The recommended dose of SKYRIZI for adult patients is 150 mg administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.

Psoriatic Arthritis

• The recommended dose of SKYRIZI for adult patients is 150 mg administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.

Crohn’s Disease

• The recommended dose is 600 mg administered by intravenous infusion at Week 0, Week 4, and Week 8, followed by 360 mg administered by subcutaneous injection at Week 12, and every 8 weeks thereafter.

Ulcerative Colitis

• The recommended dose is 1200 mg administered by intravenous infusion at Week 0, Week 4, and Week 8, followed by 180 mg or 360 mg administered by subcutaneous injection at Week 12, and every 8 weeks thereafter. Use the lowest effective dosage needed to maintain therapeutic response.

Pediatrics (< 18 years of age)

Plaque Psoriasis (6 to < 18 years of age)

The recommended dose for pediatric patients is based on body weight (Table 1) and administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.

Table 1 - Recommended Dose for Pediatric Patients 6 to < 18 Years of Age with Plaque Psoriasis

The safety and efficacy of SKYRIZI in patients with plaque psoriasis < 6 years of age have not been evaluated.

Psoriatic Arthritis (6 to < 18 years of age)

The recommended dose for pediatric patients is based on body weight (Table 2) and administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.

Table 2 - Recommended Dose for Pediatric Patients 6 to < 18 Years of Age with Psoriatic Arthritis

The safety and efficacy of SKYRIZI in patients with psoriatic arthritis < 6 years of age have not been evaluated.

Crohn’s Disease

Of the 1574 subjects with Crohn’s disease exposed to SKYRIZI, 12 subjects were 16 to 17 years of age.

Ulcerative Colitis

The safety and efficacy of SKYRIZI in patients with ulcerative colitis younger than 18 years of age have not been evaluated.

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 (≥ 65 years of age) 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 SKYRIZI (see 10.3. Pharmacokinetics).

4.3. Reconstitution

Instructions for dilution of the solution for intravenous infusion

1. 1.
2. 2. SKYRIZI medicinal product must be diluted before administration.
3. 3. Follow the instructions below to dilute SKYRIZI to a final drug concentration of approximately 1.2 mg/mL to 6 mg/mL:

1. 4. The solution in the vial and dilutions should not be shaken.
2. 5.

   Once diluted, the solution can be stored (protected from sunlight) at room temperature

   1. between 15 to 30°C (59 to 86°F) for administration within 8 hours or, refrigerated immediately for up to 20 hours between 2 and 8°C (36 and 46°F) for later administration. Storage time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within 8 hours after dilution in the infusion bag. Exposure to indoor light is acceptable during room temperature storage and administration. Do not freeze (see 11. Storage, Stability, and Disposal).
3. 6. Prior to the start of the intravenous infusion, the content of the infusion bag or glass bottle should be at room temperature.
4. 7. Infuse the diluted solution over a period of at least one hour for the SKYRIZI 600 mg dose or at least two hours for the SKYRIZI 1200 mg dose.
5. 8. SKYRIZI vial solution should not be administered concomitantly in the same intravenous line with other medicinal products.
6. 9. Each vial is for single use only and any unused medicinal product or waste material should be disposed of in accordance with local requirements.

4.4. Administration

Plaque Psoriasis and Psoriatic Arthritis

SKYRIZI is administered by subcutaneous injection. Patients should not inject into areas where the skin is tender, bruised, erythematous, indurated or affected by psoriasis. SKYRIZI is intended for use under the guidance and supervision of a physician.

In adult patients, SKYRIZI may be administered by a healthcare professional, or a patient or caregiver after proper training in subcutaneous injection technique.

In pediatric patients 6 to < 10 years of age, SKYRIZI should be administered by a healthcare professional, or a caregiver, after proper training in subcutaneous injection technique. In pediatric patients 10 to < 18 years of age, SKYRIZI should be administered by a healthcare professional, a caregiver, or by the patient under adult supervision.

SKYRIZI can be administered in the front of the thigh, in the abdomen at least 5 cm (2 inches) from the navel, or in the upper, outer arm. Administration of SKYRIZI in the upper, outer arm may only be performed by a healthcare professional or caregiver.

Preparation for Use

Before injecting, patients should remove the carton from the refrigerator and allow it to reach room temperature out of direct sunlight (15 to 30 minutes for the pre-filled syringe or 30 to 90 minutes for the pre-filled pen) without removing the pre-filled syringe or pre-filled pen from the carton.

Visually inspect SKYRIZI for particulate matter and discolouration prior to administration. The 150 mg/1 mL (150 mg/mL) and 55 mg/0.37 mL (150 mg/mL) solution is colourless to yellow and clear to slightly opalescent. It may contain a few translucent to white product-related particles. Do not use if the solution is cloudy or discoloured, or contains large particles.

Crohn’s Disease and Ulcerative Colitis

The induction dose is administered by intravenous infusion after dilution (see 4.3. Reconstitution). Intravenous SKYRIZI infusion should be administered by a healthcare professional. For patients with Crohn’s disease, the 600 mg induction dose should be administered over at least one hour. For patients with ulcerative colitis, the 1200 mg induction dose should be administered over at least two hours.

The maintenance dose is administered by subcutaneous injection using the 180 mg/1.2 mL (150 mg/mL) or 360 mg/2.4 mL (150 mg/mL) pre-filled cartridge with on-body injector or the 90 mg/1 mL (90 mg/mL) pre-filled syringe.

Using the 180 mg/1.2 mL (150 mg/mL) or 360 mg/2.4 mL (150 mg/mL) pre-filled cartridge with on-body injector

Patients should not inject into areas where the skin is tender, bruised, erythematous, indurated or affected by any lesions. SKYRIZI may be administered subcutaneously by a healthcare professional or a patient or caregiver after proper training in subcutaneous injection technique.

Preparation for Use

Before using the on-body injector with a pre-filled cartridge, remove the carton from the refrigerator and allow to reach room temperature out of direct sunlight (45 to 90 minutes) without removing the on-body injector or pre-filled cartridge from the carton.

Using the 90 mg/1 mL (90 mg/mL) pre-filled syringe

SKYRIZI 90 mg/1 mL (90 mg/mL) pre-filled syringe should be prepared and administered by a healthcare professional. To administer SKYRIZI 360 mg subcutaneously, four 90 mg/1 mL (90 mg/mL) pre-filled syringes are required. Inject one pre-filled syringe after the other in different anatomic locations (such as thighs or abdomen). Do not inject into areas where the skin is tender, bruised, erythematous, indurated or affected by any lesions.

Preparation for Use

Before injecting, remove the carton from the refrigerator and without removing the pre-filled syringes from the carton, allow SKYRIZI to reach room temperature out of direct sunlight (15 to 30 minutes).

Visually inspect SKYRIZI for particulate matter and discolouration prior to administration. The 90 mg/1 mL (90 mg/mL) solution is colourless to slightly yellow and clear to slightly opalescent. It may contain a few translucent to white product-related particles. Do not use if the solution is cloudy or discoloured, or contains large particles.

4.5. Missed Dose

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

5. Overdose

In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted immediately.

Single intravenous doses up to 1800 mg and multiple subcutaneous doses up to 360 mg of risankizumab have been administered in clinical trials without dose-limiting toxicity.

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

Table 3 – Dosage Forms, Strengths, Composition and Packaging

Description

Subcutaneous Injection

SKYRIZI (risankizumab injection) 55 mg/0.37 mL (150 mg/mL)

SKYRIZI is supplied as a solution for injection in a pre-filled syringe with needle guard containing 55 mg risankizumab in 0.37 mL sterile solution. SKYRIZI does not contain preservatives; therefore, each pre-filled syringe is for single-use only.

SKYRIZI 55 mg/0.37 mL (150 mg/mL) is available in cartons containing one pre-filled syringe.

Not made with natural rubber latex.

SKYRIZI (risankizumab injection) 150 mg/1 mL (150 mg/mL)

SKYRIZI is supplied as a solution for injection in a pre-filled pen or pre-filled syringe with needle guard containing 150 mg risankizumab in 1 mL sterile solution. SKYRIZI does not contain preservatives; therefore, each pre-filled pen or pre-filled syringe is for single use only.

SKYRIZI 150 mg/1 mL (150 mg/mL) is available in cartons containing one pre-filled pen or one pre-filled syringe.

Not made with natural rubber latex.

SKYRIZI (risankizumab injection) 180 mg/1.2 mL (150 mg/mL)

SKYRIZI is supplied as a solution for injection in a pre-filled cartridge containing 180 mg risankizumab in 1.2 mL sterile solution. SKYRIZI does not contain preservatives; therefore, each pre-filled cartridge is for single use only.

SKYRIZI 180 mg/1.2 mL (150 mg/mL) is available in cartons containing one pre-filled cartridge with one on-body injector.

Not made with natural rubber latex.

SKYRIZI (risankizumab injection) 360 mg/2.4 mL (150 mg/mL)

SKYRIZI is supplied as a solution for injection in a pre-filled cartridge containing 360 mg risankizumab in 2.4 mL sterile solution. SKYRIZI does not contain preservatives; therefore, each pre-filled cartridge is for single use only.

SKYRIZI 360 mg/2.4 mL (150 mg/mL) is available in cartons containing one pre-filled cartridge with one on-body injector.

Not made with natural rubber latex.

SKYRIZI (risankizumab injection) 90 mg/1 mL (90 mg/mL)

SKYRIZI is supplied as a solution for injection in a pre-filled syringe with needle guard. Each pre-filled syringe contains 90 mg risankizumab in 1 mL sterile solution. SKYRIZI does not contain preservatives; therefore, each pre-filled syringe is for single use only.

SKYRIZI 90 mg/1 mL (90 mg/mL) is available in cartons containing 4 pre-filled syringes.

Not made with natural rubber latex.

Intravenous Infusion

SKYRIZI (risankizumab for injection) 600 mg/10 mL (60 mg/mL)

SKYRIZI is supplied as a concentrate for solution for intravenous infusion in a vial containing 600 mg in 10 mL sterile solution. SKYRIZI does not contain preservatives; therefore, each vial is for single use only.

SKYRIZI 600 mg/10 mL (60 mg/mL) is available in cartons containing one vial.

7. Warnings and Precautions

General

Infections

SKYRIZI (risankizumab injection) may increase the risk of infections (see 8.2. Clinical Trial Adverse Reactions).

SKYRIZI should not be given to patients with any clinically important active infection until the infection resolves or is adequately treated (see 2. Contraindications). In patients with a chronic infection or a history of recurrent infection, the risks and benefits should be considered prior to prescribing SKYRIZI. Patients should be instructed to seek medical advice if signs or symptoms of a clinically important infection occur. If a patient develops such an infection or is not responding to standard therapy for the infection, the patient should be closely monitored and SKYRIZI should not be administered until the infection resolves.

In clinical trials in plaque psoriasis, infections were reported in 22% of patients in the SKYRIZI 150 mg group versus 15% of patients in the placebo group through 16 weeks of treatment. The most common type of infection reported in patients that received SKYRIZI 150 mg were upper respiratory tract infections (see 8.2. Clinical Trial Adverse Reactions).

Tuberculosis

SKYRIZI must not be given to patients with active tuberculosis (TB). Evaluate patients for TB infection according to the Canadian Tuberculosis Standards prior to initiating treatment with SKYRIZI. Initiate treatment of latent TB prior to initiating SKYRIZI. Consider anti-TB therapy prior to initiating SKYRIZI in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving SKYRIZI should be monitored for signs and symptoms of active TB during and after the treatment.

Hepatotoxicity

Crohn’s Disease

A serious adverse reaction of drug-induced liver injury was reported in a patient with Crohn’s disease following two intravenous doses of SKYRIZI 600 mg in conjunction with a rash that required hospitalization. The liver test abnormalities resolved following administration of steroids. SKYRIZI was subsequently discontinued.

If clinically indicated for the treatment of Crohn’s disease, evaluate liver enzymes and bilirubin at baseline, and consider monitoring 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.

Immune

Vaccinations

Prior to initiating therapy with SKYRIZI, completion of all appropriate immunizations should be considered according to current Canadian immunization guidelines, including live immunizations. SKYRIZI should not be used with live vaccines. Medications that interact with the immune system may increase the risk of infection following administration of live vaccines (see 9. Drug Interactions). No data are available on the response to live or inactive vaccines.

If a patient has received live vaccination (viral or bacterial), it is recommended to wait at least four weeks prior to starting treatment with SKYRIZI.

Reproductive Health

• Fertility

  The effect of SKYRIZI on human fertility has not been studied.

Sensitivity/Resistance

Hypersensitivity

Serious hypersensitivity reactions, including anaphylaxis, have been reported with the use of SKYRIZI. If an anaphylactic or other serious allergic reaction occurs, immediately discontinue the administration of SKYRIZI and initiate appropriate medical treatment.

Inform patients/caregivers of the signs and symptoms of anaphylaxis and hypersensitivity reactions, and instruct them to seek immediate medical care if signs and symptoms occur.

7.1. Special Populations

7.1.1. Pregnancy

The use of SKYRIZI in pregnant women has not been studied.

In an enhanced pre- and post-natal developmental study conducted in cynomolgus monkeys, fetal losses and neonatal deaths were observed following weekly subcutaneous injections of risankizumab at 5 or 50 mg/kg to pregnant monkeys from the beginning of organogenesis until parturition at exposure values that were 0.6 and 5 times human exposure levels during induction at the maximum recommended human dose of 1200 mg intravenous every 4 weeks, and 4 and 32 times human exposure levels at the maximum recommended maintenance dose of 360 mg subcutaneous every 8 weeks based on AUC. No adverse developmental effects were observed in surviving monkey infants. In addition, risankizumab was detected in monkey infant serum (see 16. Non-Clinical Toxicology).

Animal studies are not always predictive of human response; therefore, it is unknown whether SKYRIZI can cause fetal harm when administered to a pregnant woman.

Women of childbearing potential should use adequate contraception while using SKYRIZI and for at least 20 weeks after the last SKYRIZI dose.

7.1.2. Breastfeeding

There are no data on the presence of risankizumab 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):

Plaque Psoriasis

Pediatrics (6 years to < 18 years of age): The safety and efficacy of SKYRIZI for the treatment of moderate-to-severe plaque psoriasis have been established in pediatric patients 6 years of age and older who are candidates for systemic therapy or phototherapy (see 8.2.1. Clinical Trial Adverse Reactions – Pediatrics, Adverse Reactions in Pediatric Plaque Psoriasis Trials, 14.1. Clinical Trials by Indication).

Pediatrics (< 6 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric patients < 6 years of age.

Psoriatic Arthritis

No clinical trials were conducted in pediatric patients with active juvenile psoriatic arthritis. The use of SKYRIZI in pediatric patients 6 to < 18 years of age with active psoriatic arthritis is supported by model-based extrapolation which relies on efficacy, safety, and pharmacokinetic evidence from clinical studies of SKYRIZI in adults with psoriatic arthritis and plaque psoriasis, and pediatric patients with moderate-to-severe plaque psoriasis (see 10.3. Pharmacokinetics, 14.1. Clinical Trials by Indication). The safety and efficacy of SKYRIZI in patients with psoriatic arthritis < 6 years of age have not been evaluated.

Ulcerative Colitis

SKYRIZI is not indicated in the pediatric population with ulcerative colitis, as the efficacy and safety of SKYRIZI have not been evaluated in patients younger than 18 years of age.

Crohn’s Disease

Of the 1574 subjects with Crohn’s disease exposed to SKYRIZI, 12 subjects were 16 to 17 years of age. The safety and efficacy of SKYRIZI in pediatric patients with Crohn’s disease younger than 16 years of age have not yet been evaluated (see 1.1. Pediatrics).

7.1.4. Geriatrics

Geriatrics (≥ 65 years of age): Limited data are available regarding this age group (see 1.2. Geriatrics (≥ 65 years of age) and 4.2. Recommended Dose and Dosage Adjustment).

8. Adverse Reactions

8.1. Adverse Reaction Overview

The most frequently reported (≥ 10%) adverse drug reactions were upper respiratory tract infections. Most of the reactions were mild or moderate in severity.

In the placebo-controlled period of the phase 3 studies, the proportion of patients who discontinued treatment due to adverse events was 0.5% in SKYRIZI 150 mg-treated patients and 3.0% in placebo-treated patients in plaque psoriasis studies, and 0.7% in SKYRIZI 150 mg-treated patients and 1.4% in placebo-treated patients in psoriatic arthritis studies. Serious adverse events were reported in 2.4% of SKYRIZI 150 mg-treated patients and 4.0% of placebo-treated patients in plaque psoriasis studies, and 3.0% of SKYRIZI 150 mg-treated patients and 4.4% of placebo-treated patients in psoriatic arthritis studies.

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Adverse Reactions in Adult Plaque Psoriasis Trials

A total of 2234 patients were treated with SKYRIZI in clinical development studies in plaque psoriasis, representing 2167 patient years of exposure. Of these, 1208 (54%) patients with psoriasis were exposed to SKYRIZI for at least one year. Safety results from 111 patients exposed to SKYRIZI for 104 weeks in the IMMHANCE study were consistent with the safety profile of SKYRIZI in other psoriasis studies.

Data from placebo- and active-controlled studies were pooled to evaluate the safety of SKYRIZI for up to 16 weeks. In total, 1306 patients were evaluated in the SKYRIZI 150 mg group.

Table 4 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the SKYRIZI group than the placebo group during the 16-week controlled period of pooled clinical studies.

Table 4 – Adverse Reactions Occurring in ≥ 1% of Patients with Plaque Psoriasis through Week 16

Plaque Psoriasis of the Scalp or Genital Area

The UNLIMMITED study evaluated the safety of SKYRIZI treatment in patients with moderate to severe plaque psoriasis specifically impacting the scalp (N=51) or genital area (N=54). During the 16-week placebo-controlled period of UNLIMMITED, the safety profile of SKYRIZI was generally consistent with that demonstrated during the 16-week controlled periods of the previous studies conducted in subjects with plaque psoriasis (see 14.1 Clinical Trials by Indication, Plaque Psoriasis).

Adverse Reactions in Adult Psoriatic Arthritis Trials

Overall, the safety profile observed in patients with psoriatic arthritis treated with SKYRIZI was consistent with the safety profile observed in patients with plaque psoriasis. The safety profile of SKYRIZI with up to 52 weeks of exposure was consistent with the profile observed up to 24 weeks.

A total of 1,407 patients were treated with SKYRIZI in Phase 3 clinical development studies in psoriatic arthritis. Data from two placebo- controlled studies, KEEPSAKE1 and KEEPSAKE2, were pooled to evaluate the safety of SKYRIZI for up to 24 weeks.

Table 5 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the SKYRIZI group than the placebo group during the 24-week controlled period of pooled studies KEEPSAKE1 and KEEPSAKE2.

Table 5 – Adverse Reactions Occurring in ≥ 1% of Patients with Psoriatic Arthritis through Week 24

Adverse Reactions in Crohn’s Disease Trials

The adverse drug reaction profile observed in patients with Crohn’s disease treated with SKYRIZI was generally consistent with the adverse drug reaction profile observed in patients with plaque psoriasis. Elevated liver enzymes have been reported in patients with Crohn’s disease during induction. Consider monitoring liver enzymes as clinically indicated.

Adverse Reactions in Ulcerative Colitis Trials

The adverse drug reaction profile observed in patients with ulcerative colitis treated with SKYRIZI was consistent with the adverse drug reaction profile observed in patients across indications. No new adverse drug reactions were identified in SKYRIZI ulcerative colitis studies. Elevated liver enzymes have been reported in patients with ulcerative colitis. Consider monitoring liver enzymes as clinically indicated. Eczema, rash, and urticaria have been reported in patients with ulcerative colitis.

Infections

Plaque Psoriasis

In the first 16 weeks, infections occurred in 22.1% (288/1306) of the SKYRIZI 150 mg group (90.8 events per 100 patient-years) compared with 14.7% (44/300) of the placebo group (56.5 events per 100 patient-years). The majority of cases were non-serious and mild to moderate in severity and did not lead to discontinuation of SKYRIZI. Serious infections were reported in 5 (0.4%) SKYRIZI 150 mg-treated patients and in 1 (0.3%) placebo-treated patient (see 7. Warnings and Precautions).

Over the entire psoriasis program including long-term exposure to SKYRIZI 150 mg, the rate of infections was 48% (759/1590, 79 events per 100 patient-years); the rate of serious infections was 1.4% (22/1590, 1.6 events per 100 patient-years).

Psoriatic Arthritis

In the first 24 weeks, infections occurred in 19.0% of the SKYRIZI 150 mg group compared with 19.3% of the placebo group. The most common infection adverse events in the SKYRIZI group (≥ 1% of subjects) were upper respiratory tract infection (4.1%), nasopharyngitis (3.5%), and gastroenteritis (1.0%). The majority of infections were non-serious and mild to moderate in severity and did not lead to discontinuation of SKYRIZI. Serious infections were reported in 1.0% of SKYRIZI 150 mg-treated patients and in 1.6% of placebo-treated patients.

Crohn’s Disease

The rate of infections in the pooled data from the 12-week induction studies was 19.2% (83.3 events per 100 subject-years) in subjects treated with SKYRIZI 600 mg intravenous compared to 24.4% (117.7 events per 100 subject-years in placebo). The rate of serious infections was 0.9% (3.4 events per 100 subject-years) in subjects treated with SKYRIZI 600 mg intravenous compared to 3.6% (16.7 events per 100 subject-years in placebo).

The rate of infections in the 52-week maintenance study was 34.1% (57.7 events per 100 subject-years) in subjects treated with SKYRIZI 360 mg subcutaneous after SKYRIZI induction compared to 40.2% (76.0 events per 100 subject-years) in subjects who received placebo after SKYRIZI induction. The rate of serious infections was 4.5% (6.0 events per 100 subject-years) in subjects treated with SKYRIZI 360 mg subcutaneous after SKYRIZI induction compared to 3.8% (5.0 events per 100 subject-years) in subjects who received placebo after SKYRIZI induction.

The majority of infections were non-serious and mild to moderate in severity and did not lead to discontinuation of SKYRIZI.

Ulcerative Colitis

The majority of infections were non-serious and mild to moderate in severity and did not lead to discontinuation of SKYRIZI.

The rate of infections in the pooled data from the 12-week induction study was 14.9% (77.5 events per 100 subject-years) in subjects treated with SKYRIZI 1200 mg intravenous compared to 16.7% (75.4 events per 100 subject-years) in placebo. The rate of serious infections was 0.7% (2.9 events per 100 subject-years) in subjects treated with SKYRIZI 1200 mg intravenous compared to 1.0% (5.1 events per 100 subject-years) in placebo.

The rate of infections in the 52-week maintenance study was 32.1% (67.4 events per 100 subject-years) in subjects treated with SKYRIZI 180 mg subcutaneous and 34.4% (56.5 events per 100 subject-years) in subjects treated with SKYRIZI 360 mg subcutaneous after SKYRIZI induction compared to 37.2% (64.6 events per 100 subject-years) in subjects who received placebo after SKYRIZI induction. The rate of serious infections was 1.0% (1.1 events per 100 subject-years) in subjects treated with SKYRIZI 180 mg subcutaneous and 0.5% (0.6 events per 100 subject-years) in subjects treated with SKYRIZI 360 mg subcutaneous after SKYRIZI induction compared to 2.0% (2.3 events per 100 subject-years) in subjects who received placebo after SKYRIZI induction.

8.2.1. Clinical Trial Adverse Reactions – Pediatrics

Adverse Reactions in Pediatric Plaque Psoriasis Trials

The safety of SKYRIZI was assessed in a four-part trial of pediatric subjects with moderate to severe plaque psoriasis. The study evaluated safety for up to 52 weeks in 137 pediatric subjects 6 to < 18 years of age. Overall, the safety profile observed in patients 6 to < 18 years of age with plaque psoriasis treated with SKYRIZI was generally consistent with the safety profile observed in adult patients with plaque psoriasis (see 7. Warnings and Precautions, 7.1.3. Pediatrics, 8.2. Clinical Trial Adverse Reactions, Adverse Reactions in Adult Plaque Psoriasis Trials.

The safety of SKYRIZI has not been established in pediatric patients < 6 years of age with moderate-to-severe plaque psoriasis.

Adverse Reactions in Pediatric Psoriatic Arthritis Trials

There are no clinical trial data available to Health Canada on the safety of SKYRIZI in pediatric patients with active psoriatic arthritis. The use of SKYRIZI in pediatric patients 6 to < 18 years of age with active psoriatic arthritis is supported by model-based extrapolation, which relies on efficacy, safety and pharmacokinetic evidence from clinical studies of SKYRIZI in adults with psoriatic arthritis, and pediatric patients with moderate-to-severe plaque psoriasis, based on similarity in disease and drug response in children (see 10.3. Pharmacokinetics, 14. Clinical Trials).

8.3. Less Common Clinical Trial Adverse Reactions

Adverse reactions that occurred at rates less than 1%:

Infections and Infestations: Folliculitis (in Plaque Psoriasis and Psoriatic Arthritis), tinea infections (onychomycosis, tinea cruris: in Psoriatic Arthritis)

Skin and Subcutaneous Tissue Disorders: Injection site reactions (injection site erythema, Injection site pruritus, Injection site swelling: in Psoriatic Arthritis)

8.5. Post-Market Adverse Reactions

The following adverse reactions have been identified during post-approval use of SKYRIZI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders: Eczema, rash, and urticaria.

Immune System Disorders: Anaphylactic reaction.

9. Drug Interactions

9.2. Drug Interactions Overview

SKYRIZI is not expected to undergo metabolism by hepatic enzymes or renal elimination. Drug interactions between SKYRIZI and substrates/inhibitors/inducers of drug metabolizing enzymes are not expected.

9.3. Drug-Behaviour Interactions

The interaction of SKYRIZI with individual behavioural risks has not been studied.

9.4. Drug-Drug Interactions

Live Vaccines

Live vaccines should not be given while a patient is undergoing therapy with SKYRIZI (see 7. Warnings and Precautions).

Immunosuppression Therapy

The safety and efficacy of SKYRIZI in combination with immunosuppressant drugs, including biologics, or with phototherapy, have not been evaluated.

Interactions with CYP450 Substrates

The formation of cytochrome P450 (CYP) enzymes can be altered by increased levels of certain cytokines (e.g., interleukin [IL]-β, IL-6, tumour necrosis factor, and interferon) during chronic inflammation. Drug interaction studies were conducted in patients with plaque psoriasis, Crohn’s disease or ulcerative colitis to assess the effect of repeated administration of risankizumab injection on the pharmacokinetics of cytochrome P450 (CYP) sensitive probe substrates. The exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), metoprolol (CYP2D6 substrate) and midazolam (CYP3A substrate) following administration of risankizumab injection were comparable to their exposures prior to risankizumab injection, indicating no interactions through these enzymes.

Population pharmacokinetic analyses indicated that risankizumab exposure was not clinically meaningfully impacted by concomitant medications (metformin, atorvastatin, lisinopril, amlodipine, ibuprofen, acetylsalicylate, levothyroxine and vitamin B complex) used by some patients with plaque psoriasis during the clinical studies. Similarly, no clinically meaningful impact on risankizumab exposure was observed with concomitant use of methotrexate in patients with psoriatic arthritis, with concomitant use of corticosteroids in patients with Crohn’s disease or with concomitant medications (amino salicylates, immunomodulators and ulcerative colitis-related antibiotics) used by some patients with ulcerative colitis, based on population pharmacokinetic analyses.

9.5. Drug-Food Interactions

Interactions with food have not been studied.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been studied.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been studied.

10. Clinical Pharmacology

10.1. Mechanism of Action

Risankizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds with high affinity to the p19 subunit of human interleukin 23 (IL-23) cytokine and inhibits IL-23 signalling in cell-based assays, including the release of the pro-inflammatory cytokine, IL-17. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Risankizumab was shown to not bind to human IL-12 in vitro.

10.2. Pharmacodynamics

No formal pharmacodynamic studies have been conducted with risankizumab.

10.3. Pharmacokinetics

The pharmacokinetics of risankizumab was similar between adult patients with plaque psoriasis and psoriatic arthritis and between subjects with Crohn’s disease and ulcerative colitis.

Risankizumab exhibited linear pharmacokinetics with dose-proportional increase in exposure across dose ranges of 18 to 360 mg and 0.25 to 1 mg/kg administered subcutaneously, and 200 to 1800 mg and 0.01 to 5 mg/kg administered intravenously.

Table 6 - Non-compartmental pharmacokinetic parameters following single dose administration of risankizumab in healthy adult subjects

Absorption

Following subcutaneous dosing of risankizumab, peak plasma concentrations were achieved between 3 to 14 days after dosing with an estimated absolute bioavailability of 74 to 89% based on population pharmacokinetic analyses.

Following a single 300 mg subcutaneous injection in healthy adult Caucasian subjects, risankizumab reached a mean (± SD) maximum plasma concentration (C_max) of 20.4 ± 8.02 mcg/mL by approximately 7 days post dose.

With the dosing regimen in adult patients with plaque psoriasis (150 mg at Week 0, Week 4, and every 12 weeks thereafter), population pharmacokinetic estimated mean (± SD) steady-state (C_max) and (C_trough) plasma concentrations are 11.9 ± 3.06 and 1.91 ± 1.17 mcg/mL, respectively. The pharmacokinetics of risankizumab were similar between patients with plaque psoriasis and psoriatic arthritis.

In adult subjects with Crohn’s disease treated with 600 mg intravenous induction dose at Weeks 0, 4, and 8 followed by 360 mg subcutaneousmaintenance dose at Week 12 and every 8 weeks thereafter, median C_max and C_trough concentrations are estimated to be 156 and 38.8 mcg/mL, respectively, during the induction period (Weeks 8-12) and steady state median C_max and C_trough concentrations are estimated to be 28.0 and 8.13 mcg/mL, respectively, during the maintenance period (Weeks 40 to 48) based on population pharmacokinetic modeling.

In adult subjects with ulcerative colitis treated with 1200 mg intravenous induction dose at Weeks 0, 4, and 8 followed by 180 mg or 360 mg subcutaneous maintenance dose at Week 12 and every 8 weeks thereafter, median C_max and C_trough concentrations are estimated to be 350 and 87.7 mcg/mL, respectively, during the induction period (Weeks 8-12) and steady state median C_max and C_trough concentrations are estimated to be 19.6 and 4.64 mcg/mL for 180 mg subcutaneous dose and 39.2 and 9.29 mcg/mL for 360 mg subcutaneous dose, respectively, during the maintenance period (Weeks 40-48).

Distribution

Based on population pharmacokinetic analyses, in a typical 90 kg adult patient with psoriasis, the steady-state volume of distribution (V_ss) was 11.2 L. In a typical 70 kg subject with Crohn’s disease, V_ss was 7.68 L.

Metabolism

The exact pathway through which risankizumab is metabolized has not been characterized. Therapeutic IgG monoclonal antibodies are typically degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgGs.

Elimination

Following a single 300 mg subcutaneous injection in healthy adult Caucasian subjects, risankizumab mean terminal elimination half-life (T_1/2 ) was approximately 29 days. Based on population pharmacokinetic analyses, the systemic clearance (CL) of risankizumab was 0.31 L/day and T_1/2 was 28 days for a typical 90 kg patient with psoriasis. For a typical 70 kg adult subject with Crohn’s disease, CL was 0.30 L/day and terminal elimination half-life was 21 days.

Special Populations and Conditions

• Pediatrics

  Plaque Psoriasis

  Based on population pharmacokinetic modelling, risankizumab exposures in subjects 6 to < 18 years of age with plaque psoriasis were broadly similar to those in adults. At the recommended dosing regimens evaluated in these subjects, population pharmacokinetic estimated median steady-state peak and trough plasma concentrations were 15.7 and 2.3 µg/mL, respectively, in subjects weighing ≥ 40 kg, and 11.1 and 1.6 µg/mL, respectively, in subjects weighing < 40 kg.

  The pharmacokinetics of risankizumab in pediatric subjects under 6 years of age has not been evaluated.

  Psoriatic Arthritis

  Risankizumab exposures in subjects 6 to < 18 years of age with psoriatic arthritis are predicted to be broadly similar to those observed in adult subjects with psoriatic arthritis based on population pharmacokinetic modelling and simulation.

  The pharmacokinetics of risankizumab in pediatric subjects under 6 years of age has not been evaluated.

  Crohn’s Disease

  Age was not found to have any significant impact on risankizumab exposure in subjects aged 16 years and older based on the population pharmacokinetic analyses.

  The pharmacokinetics of risankizumab in pediatric patients under 16 years of age has not been evaluated.

• Geriatrics

  Of the 2234 patients with plaque psoriasis exposed to SKYRIZI, a total of 243 were 65 years or older, and 24 patients were 75 years or older. Of the 1574 subjects with Crohn’s disease exposed to SKYRIZI, 72 were 65 years or older. Of the 1512 subjects with ulcerative colitis exposed to SKYRIZI, 103 were 65 years or older and 8 were 75 years or older. Based on population pharmacokinetic analyses in this limited patient population, there was no clinically meaningful difference in risankizumab exposure between patients 65 years of age or older and adult patients.

• Sex

  Based on the population pharmacokinetic analyses, the clearance of risankizumab was not significantly influenced by gender in adult patients with plaque psoriasis, psoriatic arthritis, Crohn’s disease or ulcerative colitis.

• Ethnic Origin

  No clinically meaningful differences in risankizumab exposure were found in 19 Chinese or 36 Japanese subjects compared with 12 Caucasian subjects in a clinical pharmacokinetic study in healthy subjects. Based on population pharmacokinetic analyses, race or ethnicity did not impact risankizumab clearance in patients with plaque psoriasis, psoriatic arthritis, Crohn’s disease or ulcerative colitis.

• Hepatic Insufficiency

  No specific studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of risankizumab. As an IgG1 monoclonal antibody, risankizumab is not expected to be metabolized by hepatic cytochrome P450 enzymes.

• Renal Insufficiency

  No specific studies have been conducted to determine the effect of renal impairment on the pharmacokinetics of risankizumab. As an IgG1 monoclonal antibody, risankizumab is not expected to be cleared via renal elimination.

• Obesity

  Risankizumab clearance and volume of distribution increase as body weight increases. Data from a limited number of patients with plaque psoriasis (N = 38) indicate that high body weight (>130 kg) may result in reduced efficacy.

10.4. Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity with SKYRIZI. 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.

Adult Plaque Psoriasis

For patients treated with SKYRIZI at the recommended clinical dose for up to 52 weeks in psoriasis clinical trials, treatment-emergent anti-drug antibodies were detected in 24% (263/1079) of evaluated patients. Of the patients who developed anti-drug antibodies, approximately 57% had antibodies that were classified as neutralizing which equates to 14% (150/1079) of all patients treated with SKYRIZI.

Antibodies to risankizumab including neutralizing antibodies were not generally associated with changes in clinical response or safety. Among the few patients (approximately 1%; 7/1000 at Week 16 and 6/598 at Week 52) with high antibody titers (> 128), clinical response appeared to be reduced.

Pediatric Plaque Psoriasis

In pediatric patients 6 to < 18 years of age, approximately 14.8% (13/88) of patients treated with SKYRIZI at the recommended dose developed anti-drug antibodies to risankizumab by Week 52. Of the patients who developed antibodies to risankizumab, approximately 15.4% (2/13) had antibodies that were classified as neutralizing, representing 2.3% (2/88) of all patients treated with SKYRIZI. Antibodies to risankizumab were not associated with changes in clinical response or safety based on these limited data.

Adult Psoriatic Arthritis

For patients treated with SKYRIZI at the recommended clinical dose for up to 28 weeks in psoriatic arthritis clinical trials, treatment-emergent anti-drug antibodies and neutralizing antibodies were detected in 12.1% (79/652) and 0% (0/652) of evaluated patients, respectively. There was no evidence of impact of anti-drug antibody development on efficacy in the clinical studies. A higher proportion of subjects with anti-drug antibodies experienced hypersensitivity reactions (6.3% [5/79]) and injection site reactions (2.5% [2/79]) compared to subjects without anti-drug antibodies (3.8% [22/574] with hypersensitivity reactions and 0.7% [4/574] with injection site reactions). None of these hypersensitivity and injection site reactions led to discontinuation of risankizumab.

Crohn’s Disease

A total of 13/607 (2.1%) of Crohn’s disease patients dosed at 600 mg intravenous every four weeks (Q4W), and 1/107 (0.9%) patients dosed at 360 mg subcutaneous (regardless of induction treatment) were positive for treatment-emergent anti-drug antibodies during the first 12 weeks of induction period and during the 52 weeks of maintenance period, respectively. Of these, neutralizing antibodies were detected in 2/607 (0.3%) patients dosed at 600 mg intravenous Q4W, and no patients dosed at 360 mg subcutaneous were positive for neutralizing antibodies.

Antibodies to risankizumab were not associated with changes in clinical response or safety for Crohn’s disease based on these limited data.

Ulcerative Colitis

For subjects treated with SKYRIZI at the recommended intravenous induction and maintenance doses (180 mg or 360 mg) for up to 64 weeks in ulcerative colitis clinical trials, treatment-emergent anti-drug antibodies and neutralizing antibodies were detected in 8.9% (8/90) and 6.7% (6/90) for the 180 mg subcutaneous dose, or 4.4% (4/91) and 2.2% (2/91) for the 360 mg subcutaneous dose, of evaluated subjects, respectively.

Antibodies to risankizumab were not associated with changes in clinical response or safety for ulcerative colitis based on these limited data.

1. 11. Storage, Stability, and Disposal

Temperature:

All SKYRIZI presentations should be stored in a refrigerator between 2 and 8°C (36 and 46 °F). Do not freeze.

Pre-filled Syringe, Pre-filled Pen, or Pre-filled Cartridge For Use with the On-Body Injector

SKYRIZI 55 mg/0.37 mL pre-filled syringe, 150 mg/mL pre-filled pen or pre-filled syringe, 180 mg/1.2 mL and 360 mg/2.4 mL pre-filled cartridge may be stored out of the refrigerator (up to a maximum of 25°C [77°F]) for up to 24 hours in the original carton to protect from light.

Vial

The solution in the vial and dilutions should not be shaken.

SKYRIZI 60 mg/mL vial for intravenous infusion, once reconstituted, can be stored at room temperature between 15 to 30°C (59 to 86°F) for administration within 8 hours or, refrigerated immediately for up to 20 hours between 2 and 8°C (36 and 46°F) for later administration. Storage time at room temperature begins once the diluted solution has been prepared. The infusion should be completed within 8 hours after dilution in the infusion bag.

Light:

Keep in the outer carton in order to protect from light.

The diluted solution for intravenous infusion should be protected from direct and indirect light and sunlight. Exposure to indoor light is acceptable during room temperature storage and administration.

Others:

Keep out of reach and sight of children.

12. Special Handling Instructions

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance(s): Risankizumab

Chemical name: Not applicable. Risankizumab is an immunoglobulin.

Molecular formula and molecular mass:

Based on the amino acid sequence, the molecular formula of the disulfide bonded risankizumab molecule without post-translational modifications is C₆₄₇₆H₉₉₉₂N₁₇₂₀O₂₀₁₆S₄₄.The predicted molecular weight of aglycosylated risankizumab is approximately 146 kDa.

Structure (for biologics)/Structural formula:

Risankizumab is a recombinant humanized IgG1 kappa immunoglobulin comprising two heavy chains, and two light chains. The heavy and light chains are covalently linked by a single disulfide bond and the heavy chains are linked to each other by two disulfide bonds. Each heavy chain contains a single N-linked glycosylation site.

Physicochemical properties:

Risankizumab is supplied as a sterile, preservative-free solution for subcutaneous administration.

The 150 mg/1 mL (150 mg/mL), 55 mg/0.37 mL (150 mg/mL), 180 mg/1.2 mL (150 mg/mL) and 360 mg/2.4 mL (150 mg/mL) solution is colourless to yellow and clear to slightly opalescent, with a pH of 5.7. The 90 mg/1 mL (90 mg/mL) solution is colourless to slightly yellow and clear to slightly opalescent, with a pH of 6.2.

Risankizumab is supplied as a concentrate for solution for intravenous infusion. The 600 mg/10 mL (60 mg/mL) a colourless to slightly yellow, and clear to slightly opalescent solution, with a pH of 5.7.

The solution may contain a few translucent to white product-related particles.

14. Clinical Trials

14.1. Clinical Trials by Indication

Adult Plaque Psoriasis

The efficacy and safety of SKYRIZI (risankizumab injection) was assessed in 2109 adult patients with moderate to severe plaque psoriasis in four multicenter, randomized, double-blind studies (ULTIMMA-1, ULTIMMA-2, IMMHANCE, and IMMVENT). Enrolled patients were 18 years of age and older with plaque psoriasis who had a body surface area (BSA) involvement of ≥ 10%, a static Physician Global Assessment (sPGA) score of ≥ 3 (moderate psoriasis) on a 5-point severity scale, a Psoriasis Area and Severity Index (PASI) score ≥ 12, and who were candidates for systemic therapy or phototherapy. Patients with guttate, erythrodermic, or pustular psoriasis were excluded from the studies.

ULTIMMA-1 and ULTIMMA-2 enrolled 997 patients (598 randomized to SKYRIZI 150 mg, 199 to ustekinumab 45 mg [≤ 100 kg body weight] or 90 mg [> 100 kg body weight] and 200 to placebo). Patients received treatment at Week 0, Week 4, and every 12 weeks thereafter.

IMMHANCE enrolled 507 patients (407 randomized to SKYRIZI 150 mg and 100 to placebo). Patients received treatment at Week 0, Week 4 and every 12 weeks thereafter. Patients who were originally on SKYRIZI and had a sPGA response of clear or almost clear (0/1) at Week 28 were re-randomized to continue SKYRIZI every 12 weeks or have treatment withdrawn.

IMMVENT enrolled 605 patients (301 randomized to SKYRIZI and 304 to adalimumab). Patients randomized to SKYRIZI received 150 mg of treatment at Week 0, Week 4 and every 12 weeks thereafter. Patients randomized to adalimumab received 80 mg at Week 0, 40 mg at Week 1 and 40 mg every other week through Week 15. Starting at Week 16, patients who were receiving adalimumab continued or switched treatment based on response:

• < PASI 50 were switched to SKYRIZI
• PASI 50 to < PASI 90 were re-randomized to either continue adalimumab or switch to SKYRIZI
• PASI 90 continued to receive adalimumab

In all four Phase 3 studies, randomization was stratified by weight (≤ 100 kg versus > 100 kg) and by prior exposure to tumour necrosis factor (TNF) antagonists (0 versus ≥ 1).

In ULTIMMA-1 and ULTIMMA-2, the co-primary endpoints were the proportions of patients who achieved PASI 90 and sPGA of 0/1 at Week 16, comparing SKYRIZI to placebo. In IMMHANCE, the co-primary endpoints at Week 16 were the proportions of patients who achieved PASI 90 and sPGA of 0/1, comparing SKYRIZI to placebo. In IMMVENT, the co-primary endpoints at Week 16 were the proportions of patients who achieved PASI 90 and sPGA of 0/1, comparing SKYRIZI to adalimumab.

Other endpoints included the proportion of patients who achieved PASI 75, PASI 100, and sPGA of clear (0). Patient-reported outcomes were assessed based on the Dermatology Life Quality Index (DLQI) and Psoriasis Symptom Scale (PSS).

Patient demographics (Table 7) and baseline disease characteristics were generally balanced across treatment groups and studies. The majority of patients who were randomized to SKYRIZI were male (69.5%) and white (78.1%). Overall, patients had a median baseline PASI score of 17.8 and a median BSA of 20.0%. Baseline sPGA score was severe in 19.3% of patients. A total of 9.8% of study patients had a history of diagnosed psoriatic arthritis.

Across all studies, 38.1% of patients had received prior phototherapy, 48.3% had received prior non-biologic systemic therapy, and 42.1% had received prior biologic therapy for the treatment of psoriasis. Of the patients who had received prior biologic therapy, 23.7% had received at least one anti-tumour necrosis factor (TNF) alpha agent.

Table 7 – Summary of Patient Demographics for Clinical Trials in Plaque Psoriasis

The results of the ULTIMMA-1 and ULTIMMA-2 studies are presented in Table 8 and Table 9.

In ULTIMMA-1 and ULTIMMA-2, SKYRIZI demonstrated superiority to placebo for the co-primary endpoints of PASI 90 and sPGA of 0/1 (clear or almost clear) at Week 16 (Table 8).

Table 8 – Co-Primary Endpoint Results at Week 16 (NRI^a) in Adults with Plaque Psoriasis in ULTIMMA-1 and ULTIMMA-2

Table 9 – Secondary Endpoint Results (NRI^a) in Adults with Plaque Psoriasis in ULTIMMA-1 and ULTIMMA-2

The results of the IMMHANCE study are presented in Table 10 and Table 11.

Table 10 – Efficacy Results at Week 16 (NRI^a) in Adults with Plaque Psoriasis in IMMHANCE

Table 11 – Results at Week 52 and 104 (NRI^a) in Adults with Plaque Psoriasis who were considered responders (achieved sPGA 0/1 at Week 28) and were re-randomized in IMMHANCE

The results of the IMMVENT study are presented in Table 12 and Figure 1.

Table 12 - Efficacy Results at Week 16 (NRI^a) in Adults with Plaque Psoriasis in IMMVENT

Among the patients who had PASI 50 to < PASI 90 with adalimumab at Week 16 and were re-randomized, 66.0% (35/53) and 39.6% (21/53) of patients re-randomized to SKYRIZI achieved PASI 90 and PASI 100, respectively, compared with 21.4% (12/56) and 7.1% (4/56) who continued to receive adalimumab at Week 44.

Figure 1. Proportion of Patients Achieving of PASI 90 After Re-randomization in IMMVENT

ADA/ADA: Patients randomized to adalimumab and continued adalimumab

ADA/RZB: Patients randomized to adalimumab and switched to SKYRIZI

p < 0.05 at Week 4 and p < 0.001 at each time point beginning at Week 8

RZB = risankizumab; ADA = adalimumab

Maintenance and Durability of Response

IMMHANCE patients originally on SKYRIZI who were considered responders (achieved sPGA of 0/1 at Week 28) were re-randomized to continue SKYRIZI every 12 weeks through Week 88 (n = 111) or were withdrawn from therapy (n = 225). Among patients who were considered responders and relapsed (sPGA ≥ 3) following withdrawal from SKYRIZI, 83.7% (128/153) regained sPGA of 0/1 response after 16 weeks of re-treatment.

Loss of sPGA of 0/1 was observed as early as 12 weeks after a missed dose. Of those subjects who were re-randomized to withdraw from treatment, 80.9% (182/225) relapsed and the median time to relapse was 42 weeks. No characteristics were identified to predict the time to loss of response or likelihood of regaining response at the individual patient level.

Quality of Life/Patient-Reported Outcomes

In ULTIMMA-1 and ULTIMMA-2, the percentage of patients with Dermatology Life Quality Index (DLQI) of 0/1 (no impact on health-related quality of life) at Week 16 were 65.8 and 66.7%, respectively, in the SKYRIZI groups, 7.8 and 4.1%, respectively, in the placebo groups, and 43.0 and 46.5%, respectively, in the ustekinumab groups.

In ULTIMMA-1 and ULTIMMA-2, psoriasis symptoms of itch, pain, redness, and burning were assessed with the Psoriasis Symptom Scale (PSS). In ULTIMMA-1 and ULTIMMA-2, 29.3 and 31.3% of patients, respectively, in the SKYRIZI groups, and 2.0 and 0% of patients, respectively, in the placebo groups, reported a PSS total score of 0 at Week 16.

Plaque Psoriasis Involving the Scalp or Genital Area

The efficacy and safety of SKYRIZI was assessed in a multicenter, randomized, double-blind, placebo-controlled study (UNLIMMITED) that enrolled subjects 18 years of age and older with moderate to severe scalp psoriasis (UNLIMMITED-S), defined as Psoriasis Scalp Severity Index (PSSI) ≥12, scalp Investigator Global Assessment (scalp IGA) ≥3 (“moderate”), and ≥30% of the scalp affected, or moderate to severe genital psoriasis (UNLIMMITED-G), defined as static Physician’s Global Assessment of Genitalia (sPGA-G) ≥3 (“moderate”) at baseline. All subjects had BSA ≥1% and overall sPGA ≥3 (“moderate”) at baseline.

In UNLIMMITED, subjects were randomized to receive either SKYRIZI 150 mg or placebo subcutaneously at Weeks 0 and 4. Starting at Week 16, all subjects received SKYRIZI 150 mg every 12 weeks until the last dose at Week 40.

Plaque Psoriasis Involving the Scalp

UNLIMMITED-S enrolled 105 subjects with moderate to severe plaque psoriasis of the scalp. The median age of enrolled subjects at baseline was 44 years (range 20 to 83 years). Fifty-six percent (56%) of the subjects were male, 83% were White, 8% were Black or African American, and 5% were Asian. Thirty-six percent (36%) identified as Hispanic or Latino. At baseline, 74% of the subjects had moderate plaque psoriasis of the scalp (scalp IGA of 3) and 26% had severe plaque psoriasis of the scalp (scalp IGA of 4). Median baseline PSSI was 32. Baseline BSA involvement was ≥10% for 62% of the subjects and <10% for 38% of the subjects. Baseline overall sPGA score was 4 (“severe”) in 24% of the subjects.

At baseline, 54% of subjects were naïve to both non-biologic systemic and biologic therapy, 0% of subjects had received prior phototherapy, 15% had received prior non-biologic systemic therapy, and 37% had received prior biologic therapy.

The primary endpoint was the achievement of investigator’s global assessment of the scalp (scalp IGA) score of clear or almost clear (0 or 1) at Week 16. Scalp IGA is a 5-point scale from 0 (clear), 1 (almost clear), 2 (mild disease), 3 (moderate disease) to 4 (severe disease) incorporating an assessment of the severity of the 3 primary signs of plaque psoriasis: erythema, scaling, and plaque elevation across all areas of involvement, including cleared lesions. Key secondary endpoints included achievement of Psoriasis Scalp Severity index (PSSI) 90 (improvement of ≥ 90% from baseline) and achievement of PSSI 100 (improvement of ≥ 100% from baseline), both at Week 16. PSSI is a composite score ranging from 0 to 72 that consists of an assessment of erythema, induration, and desquamation on a scale from 0 (none), 1 (slight), 2 (moderate), 3 (severe), to 4 (very severe) and the percentage of scalp involved on a scale from 1 (<10%), 2 (10-29%), 3 (30-49%), 4 (50-69%), 5 (70-89%), to 6 (90-100%).

Results of the primary endpoint and two key secondary endpoints in UNLIMMITED-S are presented in Table 13.

Table 13 - Efficacy Results at Week 16 in Adults with Scalp Psoriasis in UNLIMMITED-S

Plaque Psoriasis Involving the Genital Area

UNLIMMITED-G enrolled 109 subjects with moderate to severe plaque psoriasis of the genital area. The median age of enrolled subjects at baseline was 45 years (range 19 to 77 years) and 15% of the subjects were 65 years of age and older. Sixty-five percent (65%) of the subjects were male, 90% were White, 4% were Asian, and 2% were Black or African American. Twenty-nine percent (29%) identified as Hispanic or Latino. At baseline, BSA involvement was ≥10% for 63% of the subjects and <10% for 37% of the subjects. Baseline overall sPGA score was 4 (“severe”) in 19% of the subjects.

At baseline, 61% of subjects were naïve to both non-biologic systemic and biologic therapy, 3% of subjects had received prior phototherapy, 17% had received prior non-biologic systemic therapy, and 26% had received prior biologic therapy.

The primary endpoint was achievement of static Physician Global Assessment of genitalia (sPGA-G) score of clear or minimal (0 or 1) at Week 16. The sPGA-G is a 6-point score from 0 (clear), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe), to 5 (very severe), based on the physician’s assessment of the average thickness, erythema, and scaling of all psoriatic lesions. The assessment is considered ‘static’ which refers to the patient’s disease state at the time of the assessments, without comparison to any of the patient’s previous disease states.

Results of the primary endpoint in UNLIMMITED-G are presented in Table 14.

Table 14 - Efficacy Results at Week 16 in Adults with Genital Psoriasis in UNLIMMITED-G

At Week 16, the proportion of subjects who reported a sPGA-G score of clear (0) was 51% (28/55) for subjects receiving SKYRIZI and 6% (3/54) for subjects receiving placebo.

For the subset of the overall subject population with a baseline Genital Psoriasis Symptoms Scale (GPSS) Itch numeric rating scale (NRS) score of ≥4 (GPSS Itch NRS is an 11-point scale)(N=86, 79%), the proportion of subjects that reported a ≥4-point reduction in GPSS Itch NRS score at Week 16, was 49% (20/41) for subjects receiving SKYRIZI and 7% (3/45) for subjects receiving placebo.

Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ) Item 2 measures patient-perceived impact on sexual health due to genital area psoriasis on sexual activity frequency (intercourse or other activities) in the past week (uses a scale from 0 to 4 with higher scores indicating greater limitations). For the subset of the overall subject population who reported a GenPs-SFQ Item 2 score ≥2 at baseline (N=63, 58%), the proportion of subjects that reported a score of 0 or 1 at Week 16, was 71% (22/31) for subjects receiving SKYRIZI and 22% (7/32) for subjects receiving placebo.

At Week 16, the proportion of subjects that reported a DLQI score of 0 or 1 (no impact on health-related quality of life) was 60% (33/55) for subjects receiving SKYRIZI and 4% (2/54) for subjects receiving placebo.

Pediatric Plaque Psoriasis (6 to < 18 years of age)

The efficacy, safety, and pharmacokinetics of SKYRIZI were assessed in a total of 137 pediatric patients 6 to < 18 years of age with moderate-to-severe plaque psoriasis who were candidates for phototherapy or systemic therapy in the Phase 3, four-part study (OptIMMize-1). A total of 12, 82, 13, and 30 subjects were enrolled in Parts 1, 2, 3, and 4, respectively. Parts 1 and 3 were included to support dose selection. Patients who completed this study had the opportunity to enroll in the open-label extension study, OptIMMize-2.

OptIMMize-1

The OptIMMize-1 study included a randomized, efficacy assessor-blinded, active treatment-controlled cohort of 82 pediatric patients 12 to < 18 years of age (Part 2). Part 2 included a 16-week initial treatment period (Period A), followed by an up to 36-week re-randomized treatment or withdrawal period through Week 52 (Period B) for risankizumab responders. This study also included a single-arm, open-label cohort of 30 pediatric patients 6 to < 12 years of age (Part 4). Enrolled patients had moderate to severe plaque psoriasis defined as BSA involvement of ≥ 10% with sPGA score of ≥ 3 or a PASI score ≥ 12.

In Part 2, patients were randomized 2:1 to receive SKYRIZI (N = 54) or ustekinumab (N = 28). Patients had a median baseline PASI score of 15.7 and a median BSA of 18.0%. A total of 3.7% received prior biologic therapy (see Table 19). The duration of treatment was up to 68 weeks.

In Part 4, patients had a median baseline PASI score of 14.7, and a median BSA of 14.5%. A total of 3.3% received prior biologic therapy (see Table 19). The duration of treatment was 52 weeks.

In Part 2 and Part 4, subjects weighing ≥ 40 kg received SKYRIZI 150 mg and subjects weighing < 40 kg received SKYRIZI 55 mg at Week 0, Week 4, and every 12 weeks thereafter. The co-primary endpoints were sPGA of 0/1 (clear or almost clear) and PASI 75 at Week 16.

Table 15 - Summary of Patient Demographics for Clinical Trials in Pediatric Plaque Psoriasis

The co-primary efficacy endpoints were the proportion of patients who achieved a PASI 75 response and an sPGA score of 0 (cleared) or 1 (minimal) at Week 16. Secondary endpoints included PASI 90, 100, and sPGA score of cleared (0) at Week 16. The Week 16 efficacy results from OptIMMize-1 are summarized in Table 16.

Table 16 - Efficacy Results in OptIMMize-1 at Week 16

In Part 2 Period B, patients originally on SKYRIZI who achieved sPGA of 0 or 1 at Week 16 were re-randomized to continue SKYRIZI every 12 weeks through Week 52 (N = 22) or were withdrawn from therapy (N = 21). 95.5% of the patients at Week 52 maintained sPGA of 0 or 1 compared with 42.9% for those withdrawn from SKYRIZI.

Adult Psoriatic Arthritis

The safety and efficacy of SKYRIZI were assessed in 1,407 patients in 2 randomized, double-blind, placebo-controlled studies (964 in KEEPSAKE1 and 443 in KEEPSAKE2) in patients 18 years and older with active PsA (Table 17).

Patients in these studies had a diagnosis of PsA for at least 6 months based on the Classification Criteria for Psoriatic Arthritis (CASPAR), a median duration of PsA of 4.9 years at baseline, ≥ 5 tender joints and ≥ 5 swollen joints, and active plaque psoriasis or nail psoriasis at baseline. 55.9% of patients had ≥3% BSA with active plaque psoriasis. 63.4 and 27.9% of patients had enthesitis and dactylitis, respectively. In KEEPSAKE1 where nail psoriasis was further assessed, 67.3% had nail psoriasis.

In KEEPSAKE1, all patients had a previous inadequate response or intolerance to non-biologic DMARD therapy and were biologic naïve. In KEEPSAKE2, 53.5% of patients had a previous inadequate response or intolerance to non-biologic DMARD therapy and 46.5% of patients had a previous inadequate response or intolerance to biologic therapy.

In both studies, 59.6% of patients received concomitant methotrexate (MTX), 11.6% received concomitant non-biologic DMARDs other than MTX, and 28.9% received SKYRIZI monotherapy.

In both studies, patients were randomized to receive SKYRIZI 150 mg or placebo at Weeks 0, 4, and 16. Starting from Week 28, all patients received SKYRIZI every 12 weeks.

The primary endpoint was the proportion of patients who achieved an American College of Rheumatology (ACR) 20 response at Week 24.

Table 17 – Summary of Patient Demographics for Clinical Trials in Psoriatic Arthritis

In both Psoriatic Arthritis studies (KEEPSAKE 1 and KEEPSAKE 2), treatment with SKYRIZI resulted in clinically meaningful improvements in measures of disease activity compared with placebo at Week 24.

Time to onset of efficacy was rapid across measures with greater responses versus placebo seen as early as Week 4 in 25.7 and 19.6% of patients for ACR20 for KEEPSAKE1 and KEEPSAKE2, respectively.

In both studies, similar responses were seen regardless of concomitant non-biologic DMARD use, number of prior non biologic DMARDs, age, gender, race, and BMI. In KEEPSAKE2, responses were seen regardless of prior biologic therapy.

Table 18 – Efficacy Results in Studies KEEPSAKE1 and KEEPSAKE2

An exploratory analysis of uncontrolled open-label data in subjects who received SKYRIZI for 52 weeks showed a maintenance of response for ACR20 at Week 52, with 89.1% (238/267) and 74.8% (83/111) for those subjects who were responders at Week 24 in KEEPSAKE1 and KEEPSAKE2, respectively.

Dactylitis and Enthesitis

In an analysis of pooled data from studies KEEPSAKE1 and KEEPSAKE2 at Week 24, 48.4 vs 34.8% of patients treated with SKYRIZI vs placebo had resolution of enthesitis (LEI = 0) at Week 24, and 68.1 vs 51.0% of patients treated with SKYRIZI vs placebo had resolution of dactylitis (LDI = 0) at Week 24.

In both studies, improvements were shown in all components of the ACR scores at Week 24 including subject’s assessment of pain (see Table 19).

Table 19 – Mean Change from Baseline in ACR Components

Skin Psoriasis

Among the subset of patients with BSA ≥ 3% at Baseline, a greater percentage of patients in the risankizumab vs. placebo arms of studies KEEPSAKE1 and KEEPSAKE2 achieved PASI 100 response at Week 24. Subjects in the risankizumab arms of both studies also demonstrated greater improvements in BSA-PsO at Week 24.

Nail Psoriasis

Treatment with SKYRIZI resulted in improvement in nail psoriasis as measured by modified Nail Psoriasis Severity Index (mNAPSI) and the 5-point Physician’s Global Assessment of Fingernail Psoriasis (PGA-F) in patients with nail psoriasis (67.3%) at baseline in KEEPSAKE1 at Week 24 (see Table 20).

Table 20 – Nail Psoriasis Efficacy Results in KEEPSAKE1

Radiographic Response

In Study KEEPSAKE1, inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified Total Sharp Score (mTSS) at Week 24, compared with baseline. The mTSS score was modified for psoriatic arthritis by addition of hand distal interphalangeal (DIP) joints. SKYRIZI numerically reduced the mean progression of structural damage at Week 24 compared with placebo (mean change from baseline in mTSS score was 0.23 in the SKYRIZI group compared with 0.32 in the placebo group). The proportion of patients with no radiographic progression (defined as a change from baseline in mTSS ≤ 0) was higher with SKYRIZI (92.4%) compared with placebo (87.7%) at Week 24.

Physical Function and Health Related Quality of Life

In KEEPSAKE1 and KEEPSAKE2, physical function and disability were assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI), 36-Item Short Form Health Survey (SF-36) V2. Fatigue was assessed using Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue).

In KEEPSAKE 1, patients treated with SKYRIZI showed improvement from baseline in physical function as assessed by HAQ-DI at Week 24 (-0.31) compared with placebo (-0.11) (p-value ≤0.001). In KEEPSAKE 2, patients treated with SKYRIZI showed improvement from baseline in HAQ-DI at Week 24 (-0.22) compared with placebo (-0.05) (p-value ≤0.001). In both studies, a greater proportion of patients achieved a clinically meaningful reduction of at least 0.35 in HAQ-DI score from baseline in the SKYRIZI group compared with placebo at Week 24.

In both studies at Week 24, patients treated with SKYRIZI also demonstrated improvements in the SF-36 V2 physical component summary scores and in FACIT-Fatigue scores compared with patients who received placebo.

At baseline, psoriatic spondylitis was reported in 19.6 and 19.6% of patients in KEEPSAKE1 and KEEPSAKE2, respectively. Patients with psoriatic spondylitis who were treated with SKYRIZI showed improvements from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity (ASDAS) scores compared with placebo at Week 24.

Pediatric Psoriatic Arthritis (6 to < 18 years of age)

There are no clinical trial data available to Health Canada on the efficacy and safety of SKYRIZI in pediatric patients with active psoriatic arthritis. The use of SKYRIZI in pediatric patients 6 to < 18 years of age with active psoriatic arthritis is supported by model-based extrapolation, which relies on efficacy, safety and pharmacokinetic evidence from clinical studies of SKYRIZI in adults with psoriatic arthritis and plaque psoriasis, and pediatric patients with moderate-to-severe plaque psoriasis, based on similarity in disease and drug response in children (see 10.3. Pharmacokinetics, 14.1. Clinical Trials, 8.2.1. Clinical Trial Adverse Reactions).

Crohn’s Disease

The efficacy and safety of risankizumab was assessed in 1419 subjects with moderately to severely active Crohn’s disease in three multicentre, randomised, double-blind, placebo-controlled clinical studies. Enrolled subjects were 16 years of age or older with a Crohn’s Disease Activity Index (CDAI) of 220 to 450, an average daily stool frequency (SF) ≥ 4 and/or average daily abdominal pain score (APS) ≥ 2, and a Simple Endoscopic Score for CD (SES-CD) of ≥ 6, or ≥ 4 for isolated ileal disease, excluding the narrowing component and confirmed by a central reviewer.

ADVANCE and MOTIVATE were 12-week induction studies that evaluated the ability of risankizumab administered by intravenous (IV) injection to achieve CD-related clinical, endoscopic, and quality of life changes. FORTIFY was a 52-week maintenance study that similarly evaluated risankizumab administered by subcutaneous (SC) injection in subjects who achieved clinical response (≥ 30% decrease in SF and/or ≥ 30% decrease in APS and both not worse than baseline) after 12 weeks of risankizumab intravenous treatment in the induction studies.

Table 21 - Summary of Subject Demographics for Clinical Trials in Crohn’s Disease

ADVANCE and MOTIVATE

In studies ADVANCE and MOTIVATE, subjects were randomized to receive either SKYRIZI 600 mg IV, SKYRIZI 1200 mg IV, or placebo at Week 0, Week 4, and Week 8. The SKYRIZI 1200 mg dose did not demonstrate additional treatment benefit relative to the 600 mg dose and is not a recommended induction regimen.

In ADVANCE, 58% (491/850) of subjects had failed or were intolerant to prior treatment with one or more biologic therapies (prior biologic failure), and 42% (359/850) of subjects had failed or were intolerant to treatment with conventional therapy but not to biologic therapy (without prior biologic failure). In ADVANCE, among the subjects without prior biologic failure, 87% (314/359) were naïve to biologic treatment; the remaining 13% had received biologic therapy but neither failed nor demonstrated intolerance. All subjects in MOTIVATE had prior biologic failure. At baseline, 32 and 23% of subjects were taking concomitant corticosteroids and/or immunomodulators, respectively.

The co-primary endpoints were SF/APS clinical remission and endoscopic response, both assessed at Week 12. SF/APS clinical remission was defined as SF ≤ 2.8 and APS ≤ 1, neither worse than baseline. Endoscopic response was defined as greater than 50% decrease in SES-CD from baseline, or a decrease of at least 2 points for subjects with a baseline score of 4 and isolated ileal disease. In both studies, a greater proportion of subjects receiving SKYRIZI achieved clinical remission and endoscopic response at Week 12 compared to placebo. Key secondary endpoints measured at Week 12 included the proportion of subjects with CDAI clinical remission, endoscopic remission, and CDAI clinical response, which consistently favoured SKYRIZI compared to placebo (Table 22).

Table 22 - Results of Key Efficacy Endpoints at Week 12 in Subjects with Crohn’s Disease in Studies ADVANCE and MOTIVATE

Clinical response and clinical remission were observed at Week 4 in greater proportions of subjects receiving SKYRIZI than placebo.

In ADVANCE and MOTIVATE, a greater proportion of subjects receiving SKYRIZI (21 and 14%, respectively) compared to placebo (8 and 4%, respectively) demonstrated an absence of ulceration at Week 12 (SES-CD ulcerated surface subscore of 0 in subjects with a subscore ≥ 1 at Baseline).

In ADVANCE, in subjects receiving SKYRIZI who had prior biologic failure (N = 195), 41% demonstrated SF/APS clinical remission and 33% demonstrated endoscopic response at Week 12, compared with 23 and 11%, respectively, receiving placebo (N = 97). In subjects receiving SKYRIZI who had prior conventional therapy failure, but without prior biologic failure (N = 141), 48% demonstrated SF/APS clinical remission and 50% demonstrated endoscopic response at Week 12, compared with 21 and 13%, respectively, receiving placebo (N = 78).

In ADVANCE and MOTIVATE, least squared mean change from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) score at Week 12 was 44.3 and 39.6 in subjects receiving SKYRIZI, and 23.6 and 27.2 in subjects receiving placebo; least squared mean change from baseline in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) score at Week 12 was 11.2 and 10.5 in subjects receiving SKYRIZI, and 6.0 and 7.7 in subjects receiving placebo.

FORTIFY

FORTIFY evaluated 462 subjects who achieved SF/APS clinical response after 12 weeks of SKYRIZI intravenous treatment in the induction studies ADVANCE and MOTIVATE. SF/APS clinical response was defined as ≥ 30% decrease in average daily SF and/or ≥ 30% decrease in average daily APS and both not worse than baseline of the induction regimen study. Subjects were randomized to receive a maintenance regimen of SKYRIZI 360 mg subcutaneous, SKYRIZI 180 mg subcutaneous, or placebo subcutaneous every 8 weeks for up to 52 weeks. The SKYRIZI 180 mg subcutaneous dose did not demonstrate consistent treatment benefit relative to placebo and is not a recommended maintenance regimen.

The co-primary endpoints were SF/APS clinical remission and endoscopic response, both assessed at Week 52. Co-primary endpoints were also measured in subjects with and without prior biologic failure.

A greater proportion of subjects receiving SKYRIZI achieved clinical remission and endoscopic response at Week 52 compared to placebo. Key secondary endpoints measured at Week 52 included the proportion of subjects with CDAI clinical remission, endoscopic remission, ulcer-free endoscopy (mucosal healing), and CDAI clinical response (Table 23).

Table 23 - Results of Key Efficacy Endpoints at Week 52 in Subjects with Crohn’s Disease in Study FORTIFY

In FORTIFY, in subjects receiving SKYRIZI who had prior biologic failure (N = 102), 48% demonstrated SF/APS clinical remission and 44% demonstrated endoscopic response at Week 52, compared with 34 and 20%, respectively, receiving placebo (N = 123). In subjects receiving SKYRIZI who had prior conventional therapy failure, but without prior biologic failure (N = 39), 62% demonstrated SF/APS clinical remission and 54% demonstrated endoscopic response at Week 52, compared with 56 and 27%, respectively, receiving placebo (N = 41).

Maintenance of clinical remission (clinical remission at Week 52 among subjects with clinical remission at Week 0 of FORTIFY) was observed in 69% of subjects treated with SKYRIZI 360 mg subcutaneous (N = 72) and 51% of subjects treated with placebo (N = 91).

Ulcerative Colitis

The efficacy and safety of SKYRIZI was assessed in subjects with moderately to severely active ulcerative colitis in two multicenter, randomized, double-blind, placebo-controlled clinical studies (INSPIRE and COMMAND). Enrolled subjects were ≥ 18 and ≤ 80 years of age with Adapted Mayo Score (aMS) of 5 to 9 with an endoscopic subscore (ES) of 2 or 3. The aMS is based on the Mayo scoring system excluding Physician’s Global Assessment and ranges from 0 to 9. It consists of three sub-scores, each ranging from 0 (normal) to 3 (most severe): stool frequency subscore (SFS), rectal bleeding subscore (RBS), and a centrally-reviewed endoscopy subscore (ES). An ES of 2 was defined by marked erythema, lack of vascular pattern, friability, and erosions; an ES of 3 was defined by spontaneous bleeding and ulceration.

INSPIRE was an induction phase study that evaluated the ability of SKYRIZI administered by intravenous (IV) injection to achieve clinical remission. COMMAND was a subsequent 52-week withdrawal maintenance phase study (64 weeks of continuous treatment) that evaluated the ability of SKYRIZI administered by subcutaneous injection to achieve clinical remission in subjects who achieved clinical response after 12 weeks of SKYRIZI treatment in the induction study.

Subjects with inadequate response, or intolerance to oral aminosalicylates, corticosteroids, immunomodulators, biologics, and/or Janus Kinase inhibitors (JAKi) were enrolled.

Table 24 - Summary of Subject Demographics for Clinical Trials in Ulcerative Colitis

INSPIRE (Induction phase study)

In study INSPIRE, 975 subjects were randomized and received either SKYRIZI 1200 mg or placebo by intravenous induction at Week 0, Week 4, and Week 8. Randomization was stratified by number of prior failed biologics (0, 1 vs > 1), baseline steroid use (yes vs no), and baseline Adapted Mayo score (≤ 7 vs > 7).

In INSPIRE, 52% (503/975) of subjects had failed (inadequate response or intolerance) one or more advanced therapies. Of these 503 subjects, 488 (97%) failed biologics and 90 (18%) failed JAK inhibitors.

Enrolled subjects were permitted to use a stable dose of oral corticosteroids (up to 20 mg/day prednisone or equivalent), immunomodulators, and aminosalicylates. At baseline in INSPIRE, 36% of subjects received corticosteroids, 17% of subjects received immunomodulators and 73% of subjects received aminosalicylates. Patient disease activity was moderate (aMS ≤7) in 58% of subjects and severe (aMS >7) in 42% of subjects.

The primary efficacy endpoint was the proportion of subjects in clinical remission at Week 12. Clinical remission was defined per aMS [defined as stool frequency subscore (SFS) ≤ 1, and not greater than baseline, RBS = 0, and ES ≤ 1 without evidence of friability]. Key secondary endpoints included the proportion of subjects in clinical response, endoscopic improvement, and histologic-endoscopic mucosal improvement. Results of the primary endpoint and key secondary endpoints are summarized in Table 25.

Table 25 - Results of Key Efficacy Endpoints at Week 12 in Subjects with Ulcerative Colitis in INSPIRE Study

Clinical disease activity and symptoms

The partial adapted Mayo score (paMS) is composed of SFS and RBS. Clinical response per paMS is defined as a decrease of ≥ 1 point and ≥ 30% from Baseline and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1. Clinical response per paMS was observed at Week 4 in 52% of subjects treated with SKYRIZI and 31% of patients treated with placebo.

Endoscopic and histologic assessment

Endoscopic remission (normalization of the endoscopic appearance of the mucosa) was defined as ES of 0. At Week 12, endoscopic remission was achieved in 11% of subjects treated with SKYRIZI and 3% of subjects treated with placebo.

1. Bowel Urgency
2. No bowel urgency was reported by 44% of subjects treated with SKYRIZI and 28% of subjects treated with placebo at Week 12.

COMMAND (maintenance phase study)

The maintenance study COMMAND evaluated 548 subjects who received one of three SKYRIZI intravenous induction regimens, including the 1,200 mg regimen in Study INSPIRE, and demonstrated clinical response per aMS after 12 weeks. Subjects were randomized to receive a maintenance regimen of SKYRIZI 180 mg subcutaneous or 360 mg subcutaneous every 8 weeks, or to withdraw from SKYRIZI induction and receive placebo subcutaneous every 8 weeks for up to 52 weeks. Randomization was stratified by prior failed biologics at induction baseline (yes vs. no), last IV risankizumab induction dose, and clinical remission per Adapted Mayo score (per local read) at the last visit of induction.

In COMMAND, 75% (411/548) of subjects had failed (inadequate response or intolerance) one or more advanced therapies prior to induction baseline. Of these 411 subjects, 407 (99%) failed biologics and 78 (19%) failed JAK inhibitors.

The primary efficacy endpoint was the proportion of subjects in clinical remission at Week 52. Clinical remission was defined per aMS [defined as stool frequency subscore (SFS) ≤ 1, and not greater than baseline, RBS = 0, and ES ≤ 1 without evidence of friability]. Key secondary endpoints included the proportion of subjects in corticosteroid-free clinical remission, endoscopic improvement, and histologic endoscopic mucosal improvement at Week 52. Results of the primary endpoint and key secondary endpoints are summarized in Table 26.

Table 26 - Results of Key Efficacy Endpoints at Week 52 (64 Weeks from Initiation of SKYRIZI induction dose) in Subjects with Ulcerative Colitis in COMMAND Study

* Subjects with advanced therapy failure: defined as subjects with documented intolerance or inadequate response to one or more biologic therapies or JAK inhibitors; Subjects without advanced therapy failure: defined as subjects with documented intolerance or inadequate response to oral aminosalicylates, corticosteroids, or immunomodulators and may also include subjects who received therapy with a biologic therapy, or JAK inhibitor in the past but stopped therapy based on reasons other than inadequate response or intolerance.

1. 1. The placebo group consisted of subjects who achieved clinical response to 12 weeks of SKYRIZI induction therapy and were randomized to receive placebo in the maintenance study (COMMAND).
2. 2. Clinical remission per aMS: SFS ≤ 1, and not greater than baseline, RBS = 0, and ES ≤ 1 without evidence of friability
3. 3. Based on the Cochran-Mantel-Haenszel (CMH) method, adjusted by stratification factors: induction Baseline Advanced Therapy-IR status (yes vs no), clinical remission status per Adapted Mayo score at Week 0 and last IV risankizumab induction dose (600 mg vs 1200 mg vs 1800 mg)
4. 4. Statistically significant under multiplicity control for SKYRIZI vs placebo comparison
5. 5. Clinical remission per aMS at Week 52 and corticosteroid-free for ≥ 90 days
6. 6. ES of ≤ 1 without the evidence of friability
7. 7. ES ≤ 1 without the evidence of friability and Geboes score ≤ 3.1 (indicating neutrophil infiltration in < 5% of crypts, no crypt destruction and no erosions, ulcerations or granulation tissue)

Maintenance of clinical remission (clinical remission per aMS at Week 52 among subjects who achieved clinical remission at the end of SKYRIZI induction treatment) was observed in 70% of subjects treated with SKYRIZI 180 mg SC (N=44), 50% of subjects treated with SKYRIZI 360 mg SC (N=40), and 40% of subjects treated with placebo (N=53) in the COMMAND study.

1. Endoscopic assessment
2. Endoscopic remission (normalization of the endoscopic appearance of the mucosa) was defined as ES of 0. At Week 52, endoscopic remission was achieved in 23% of subjects treated with SKYRIZI 180 mg, 24% of subjects treated with SKYRIZI 360 mg, and 15% of subjects treated with placebo.

15. Microbiology

Not applicable.

16. Non-Clinical Toxicology

General Toxicology:

In a 26-week repeat-dose toxicity study in cynomolgus monkeys, risankizumab was well-tolerated at weekly doses up to 50 mg/kg. There were no risankizumab-related adverse effects observed, including on cardiovascular, respiratory, and nervous system functions. At the no-observed-adverse-effect level (NOAEL) of 50 mg/kg once weekly, the systemic exposure (AUC) was approximately 3-times higher than the clinical exposure in adult patients given the maximum recommended induction dose of 1200 mg intravenous every 4 weeks and 23-times higher than the clinical exposure in adult patients given the maximum recommended maintenance dose of 360 mg subcutaneous, every 8 weeks, based on AUC.

Carcinogenicity:

Carcinogenicity studies have not been conducted with risankizumab.

Genotoxicity:

Genotoxicity studies have not been conducted with risankizumab.

Reproductive and Developmental Toxicology:

In an enhanced pre- and post-natal development toxicity study, pregnant cynomolgus monkeys (21, 22, and 21 in the 0, 5 and 50 mg/kg groups, respectively) were administered weekly subcutaneous doses of risankizumab from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of 1 of 18 control monkeys, 2 of 17 low-dose monkeys, and 3 of 15 high-dose monkeys. These neonatal deaths were attributed to maternal neglect, trauma, and/or early or late delivery, although, a drug-related effect could not be ruled out. An increase in the fetal loss rate (spontaneous abortions, including stillbirths) was also observed at both dose levels. While the incidence rate for fetal loss in each dose group was within the historical control range for the testing facility, a drug-related effect could not be ruled out. The clinical significance of these findings is unknown. No risankizumab-related adverse effects, including any effects on neurobehavioural or immunological development, were observed in surviving infants from birth through 6 months of age. The systemic exposures at 5 and 50 mg/kg were 0.6- and 5-times the clinical exposure in adult patients given the maximum recommended induction dose of 1200 mg intravenous every 4 weeks, respectively, and 4- and 32-times the clinical exposure in adult patients given the maximum recommended maintenance dose of 360 mg subcutaneous every 8 weeks, respectively, based on AUC.

In the infants, mean serum concentrations increased in a dose-dependent manner and were approximately 20 to 90% of the respective maternal concentrations. Following delivery, most maternal animals and all infants from the risankizumab-administered groups had measurable serum concentrations of risankizumab up to 91 days postpartum. Serum concentrations were below detectable levels at 180 days postpartum in all infants and in all but one maternal animal.

No dedicated fertility studies have been conducted in animals however, in the 26-week repeat-dose toxicity study, histopathology of reproductive organs from female cynomolgus monkeys did not show any relevant adverse finding at a dose of 50 mg/kg. In addition, in a separate 26-week repeat dose study conducted in sexually mature male cynomolgus monkeys, no adverse effects on male fertility-related parameters were observed at a dose of 50 mg/kg. Specifically, there were no risankizumab-related adverse effects on testicular volume, semen analysis (total sperm count, sperm concentration, sperm motility, and sperm morphology), serum testosterone concentration, reproductive organ weights, or histopathological findings in reproductive organs. The margins of exposure at the 50 mg/kg dose level were 3-times higher than the clinical exposure in adult patients given the maximum recommended induction dose of 1200 mg intravenous every 4 weeks, and 23-times higher than the clinical exposure in adult patients given the maximum recommended maintenance dose of 360 mg subcutaneous every 8 weeks, based on AUC.

Juvenile Toxicity:

Juvenile toxicity studies have not been conducted with risankizumab.