Skyrizi

1.1 Plaque Psoriasis

SKYRIZI® is indicated for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.

1.2 Psoriatic Arthritis

SKYRIZI is indicated for the treatment of active psoriatic arthritis in adults.

1.3 Crohn’s Disease

SKYRIZI is indicated for the treatment of moderately to severely active Crohn's disease in adults.

1.4 Ulcerative Colitis

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

2.1 Procedures Prior to Treatment Initiation

• For the treatment of Crohn’s disease and ulcerative colitis, obtain liver enzymes and bilirubin levels prior to initiating treatment with SKYRIZI [see Warnings and Precautions ( 5.4)]
  
• Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with SKYRIZI [see Warnings and Precautions ( 5.3)]. 
  
• Complete all age-appropriate vaccinations as recommended by current immunization guidelines [see Warnings and Precautions ( 5.5)].

2.2 General Considerations for Administration

• Visually inspect SKYRIZI for particulate matter and discoloration prior to administration. The solution may contain a few translucent to white particles.
  ◦ SKYRIZI 150 mg/mL, 180 mg/1.2 mL, and 360 mg/2.4 mL: a colorless to yellow, and clear to slightly opalescent solution.
  ◦ SKYRIZI 90 mg/mL and 600 mg/10 mL: a colorless to slightly yellow, and clear to slightly opalescent solution.
  ◦ Do not use if the solution contains large particles or is cloudy or discolored.
  
• Discard after use. Do not reuse.

2.3 Recommended Dosage for Plaque Psoriasis 

The recommended dosage is 150 mg administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.

2.4 Recommended Dosage for Psoriatic Arthritis 

The recommended dosage is 150 mg administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.

SKYRIZI may be administered alone or in combination with non-biologic disease-modifying antirheumatic drugs (DMARDs).

2.5 Preparation and Administration Instructions (Plaque Psoriasis and Psoriatic Arthritis)

• Administer SKYRIZI 150 mg/mL prefilled pen or prefilled syringe subcutaneously. 

• Patients may self-inject SKYRIZI after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of SKYRIZI.

• Before injecting, remove the carton with SKYRIZI from the refrigerator and without removing the prefilled pen or prefilled syringe from the carton, allow SKYRIZI to reach room temperature out of direct sunlight (30 to 90 minutes for the prefilled pen and 15 to 30 minutes for the prefilled syringe).

• Do not inject into areas where the skin is tender, bruised, erythematous, indurated or affected by psoriasis. Administration of SKYRIZI in the upper, outer arm may only be performed by a healthcare professional or caregiver.

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

The SKYRIZI “Instructions for Use” contains more detailed instructions on the preparation and administration of SKYRIZI [see Instructions for Use]. Instruct the patient to read the Instructions for Use before administration.

2.6 Recommended Dosage for Crohn’s Disease

Adult Patients: Induction

The recommended induction dosage of SKYRIZI is 600 mg administered by intravenous infusion over a period of at least one hour at Week 0, Week 4, and Week 8.

Adult Patients: Maintenance

The recommended maintenance dosage of SKYRIZI is 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.

2.7 Recommended Dosage for Ulcerative Colitis

Adult Patients: Induction

The recommended induction dosage of SKYRIZI is 1,200 mg administered by intravenous infusion over a period of at least two hours at Week 0, Week 4, and Week 8.

Adult Patients: Maintenance

The recommended maintenance dosage of SKYRIZI is 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.

2.8 Preparation and Administration Instructions (Crohn’s Disease and Ulcerative Colitis)

Intravenous Induction Dosing Regimen:

1. SKYRIZI vial for intravenous administration is intended for administration by a healthcare provider using aseptic technique.

2. Prior to intravenous administration, determine the dose and number of SKYRIZI vials needed based on the patient’s indication (see table below). Withdraw 10 mL of SKYRIZI solution from a vial (600 mg/10 mL) and inject into an intravenous infusion bag or glass bottle containing 5% Dextrose Injection or 0.9% Sodium Chloride Injection (see Table 1 below) for a final concentration of approximately 1.2 mg/mL to 6 mg/mL. Discard any remaining solution in the vial.

3. Infuse the diluted solution intravenously over a period of at least one hour for the SKYRIZI 600 mg dose; at least two hours for the SKYRIZI 1,200 mg dose. If stored refrigerated, allow the diluted SKYRIZI solution in the infusion bag or glass bottle to warm to room temperature prior to the start of the intravenous infusion.

4. Do not administer SKYRIZI diluted solution concomitantly in the same intravenous line with other medicinal products.

Handling and Storage of the Vial and the Diluted Solution:

• Do not shake the vial or diluted solution in the infusion bag or glass bottle.

• Use the prepared infusion immediately. If not used immediately, store the diluted SKYRIZI solution refrigerated and protected from light for up to 20 hours between 36°F to 46°F (2°C to 8°C).

• Immediately after preparation or removal from refrigeration, the diluted SKYRIZI solution can be stored at room temperature at up to 77°F (25°C) (protected from sunlight) for 4 hours (cumulative time from start of dilution to start of infusion).

• Exposure to indoor light is acceptable during room temperature storage and administration.

• Do not freeze.

Subcutaneous Maintenance Dosing Regimen:

Using the single-dose 180 mg or 360 mg prefilled cartridge with On-Body Injector:

• SKYRIZI is intended for use under the guidance and supervision of a healthcare professional.

• Patients may self-inject SKYRIZI using the on-body injector with prefilled cartridge after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of SKYRIZI.

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

• Use the on-body injector to administer SKYRIZI 180 mg/1.2 mL or SKYRIZI 360 mg/2.4 mL prefilled cartridge subcutaneously on thigh or abdomen.

• Start the injection within 5 minutes after inserting the prefilled cartridge into the On-Body Injector.

• Do not inject into areas where the skin is tender, bruised, erythematous, indurated or affected by any lesions.

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

The SKYRIZI “Instructions for Use” contains more detailed instructions on the preparation and administration of SKYRIZI [see Instructions for Use]. Instruct the patient to read the Instructions for Use before administration.

Using the 90 mg/mL prefilled syringe:

• Administer each SKYRIZI 90 mg/mL prefilled syringe subcutaneously.

• Patients may self-inject SKYRIZI after training in subcutaneous injection technique. Provide proper training to patients and/or caregivers on the subcutaneous injection technique of SKYRIZI.

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

• Use the 90 mg/mL prefilled syringes to administer SKYRIZI 180 mg or SKYRIZI 360 mg subcutaneously as follows:

     ◦ When using SKYRIZI 90 mg/mL prefilled syringes, for a 180 mg maintenance dose, two 90 mg prefilled syringes are required. Inject one prefilled syringe after the other in different anatomic locations (such as thighs or abdomen).

     ◦ When using SKYRIZI 90 mg/mL prefilled syringes, for a 360 mg maintenance dose, four 90 mg prefilled syringes are required. Inject one prefilled 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. Administration of SKYRIZI in the upper, outer arm may only be performed by a healthcare professional or caregiver.

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

The SKYRIZI “Instructions for Use” contains more detailed instructions on the preparation and administration of SKYRIZI [see Instructions for Use]. Instruct the patient to read the Instructions for Use before administration.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors outcomes in women who become pregnant while treated with SKYRIZI. Patients should be encouraged to enroll by calling 1-877-302-2161 or visiting http://glowpregnancyregistry.com.

Risk Summary

Available pharmacovigilance and clinical trial data with risankizumab use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Although there are no data on risankizumab-rzaa, monoclonal antibodies can be actively transported across the placenta, and SKYRIZI may cause immunosuppression in the in utero-exposed infant. There are adverse pregnancy outcomes in women with inflammatory bowel disease (see Clinical Considerations). 

In an enhanced pre- and post-natal developmental toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of 5 or 50 mg/kg risankizumab-rzaa once weekly during the period of organogenesis up to parturition. Increased fetal/infant loss was noted in pregnant monkeys at the 50 mg/kg dose (see Data). The 50 mg/kg dose in pregnant monkeys resulted in approximately 5 times the exposure (AUC) in humans administered the maximum recommended induction dose (1,200 mg) and 32 times the exposure (AUC) to the maximum recommended maintenance dose (360 mg). No risankizumab-rzaa-related effects on functional or immunological development were observed in infant monkeys from birth through 6 months of age. The clinical significance of these findings for humans is unknown. 

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations 

Disease-associated maternal and embryo/fetal risk

Published data suggest that the risk of adverse pregnancy outcomes in women with inflammatory bowel disease is associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 g) infants, and small for gestational age at birth.

Fetal/Neonatal adverse reactions

Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses, and peaks during the third trimester. Because risankizumab may interfere with immune response to infections, risks and benefits should be considered prior to administering live vaccines to infants exposed to SKYRIZI in utero. There are insufficient data regarding infant serum levels of risankizumab at birth and the duration of persistence of risankizumab in infant serum after birth. Although a specific timeframe to delay live virus immunizations in infants exposed in utero is unknown, a minimum of 5 months after birth should be considered because of the half-life of the product.

Data

Animal Data

An enhanced pre- and post-natal developmental toxicity study was conducted in cynomolgus monkeys. Pregnant cynomolgus monkeys were administered weekly subcutaneous doses of risankizumab-rzaa of 5 or 50 mg/kg from gestation day 20 to parturition, and the cynomolgus monkeys (mother and infants) were monitored for 6 months after delivery. No maternal toxicity was noted in this study. There were no treatment-related effects on growth and development, malformations, developmental immunotoxicology, or neurobehavioral development. However, a dose-dependent increase in fetal/infant loss was noted in the risankizumab-rzaa-treated groups (32% and 43% in the 5 mg/kg and 50 mg/kg groups, respectively) compared with the vehicle control group (19%). The increased fetal/infant loss in the 50 mg/kg group was considered to be related to risankizumab-rzaa treatment. The no-observed adverse effect level (NOAEL) for maternal toxicity was identified as 50 mg/kg, and the NOAEL for developmental toxicity was identified as 5 mg/kg. The 5 mg/kg dose in pregnant monkeys resulted in approximately 0.6 times the exposure (AUC) in humans administered the maximum recommended induction dose (1,200 mg) and 5 times the exposure (AUC) in humans administered the maximum recommended maintenance dose (360 mg).   In the infants, mean serum concentrations increased in a dose-dependent manner and were approximately 17%-86% of the respective maternal concentrations. Following delivery, most adult female cynomolgus monkeys and all infants from the risankizumab-rzaa-treated groups had measurable serum concentrations of risankizumab-rzaa up to 91 days postpartum. Serum concentrations were below detectable levels at 180 days postpartum.

8.2 Lactation

Risk Summary

There are no data on the presence of risankizumab-rzaa in human milk, the effects on the breastfed infant, or the effects on milk production. Endogenous maternal IgG and monoclonal antibodies are transferred in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed infant to risankizumab-rzaa are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SKYRIZI and any potential adverse effects on the breastfed infant from SKYRIZI or from the underlying maternal condition.

8.4 Pediatric Use

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

8.5 Geriatric Use

Of the 6,862 subjects exposed to SKYRIZI, a total of 664 were 65 years or older (243 subjects with plaque psoriasis, 246 subjects with psoriatic arthritis, 72 subjects with Crohn’s disease and 103 subjects with ulcerative colitis), and 71 subjects were 75 years or older.

Clinical studies of SKYRIZI, within each indication, did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger adult subjects.

No clinically meaningful differences in the pharmacokinetics of risankizumab-rzaa were observed based on age[see Clinical Pharmacology ( 12.3)].

5.1 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, have been reported with use of SKYRIZI. If a serious hypersensitivity reaction occurs, discontinue SKYRIZI and initiate appropriate therapy immediately [see Adverse Reactions ( 6.1)]. 

5.2 Infections

SKYRIZI may increase the risk of infections [see Adverse Reactions ( 6.1)].

Treatment with SKYRIZI should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. 

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

5.3 Tuberculosis

Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with SKYRIZI. Across the Phase 3 psoriasis clinical studies, of the 72 subjects with latent TB who were concurrently treated with SKYRIZI and appropriate TB prophylaxis during the studies, none developed active TB during the mean follow-up of 61 weeks on SKYRIZI. Two subjects taking isoniazid for treatment of latent TB discontinued treatment due to liver injury. Of the 31 subjects from the PsO-3 study with latent TB who did not receive prophylaxis during the study, none developed active TB during the mean follow-up of 55 weeks on 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. Monitor patients for signs and symptoms of active TB during and after SKYRIZI treatment. Do not administer SKYRIZI to patients with active TB.

5.4 Hepatotoxicity in Treatment of Inflammatory Bowel Disease 

A serious adverse reaction of drug-induced liver injury in conjunction with a rash that required hospitalization was reported in a patient with Crohn’s disease (ALT 54x ULN, AST 30x ULN, and total bilirubin 2.2x ULN) following two 600 mg intravenous doses of SKYRIZI. The liver test abnormalities resolved following administration of steroids. SKYRIZI was subsequently discontinued.

For the treatment of Crohn’s disease and ulcerative colitis, evaluate liver enzymes and bilirubin at baseline, and during induction at least up to 12 weeks of treatment. Monitor thereafter according to routine patient management.

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

5.5 Administration of Vaccines

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

6.1 Clinical Trials Experience

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

Plaque Psoriasis

A total of 2234 subjects were treated with SKYRIZI in clinical development trials in plaque psoriasis. Of these, 1208 subjects with psoriasis were exposed to SKYRIZI for at least one year.

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

Table 2 summarizes the adverse drug 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 trials.

Adverse drug reactions that occurred in < 1% but > 0.1% of subjects in the SKYRIZI group and at a higher rate than in the placebo group through Week 16 were folliculitis and urticaria.

Specific Adverse Drug Reactions

Infections

In the first 16 weeks, infections occurred in 22.1% of the SKYRIZI group (90.8 events per 100 subject-years) compared with 14.7% of the placebo group (56.5 events per 100 subject-years) and did not lead to discontinuation of SKYRIZI. The rates of serious infections for the SKYRIZI group and the placebo group were ≤0.4%. Serious infections in the SKYRIZI group included cellulitis, osteomyelitis, sepsis, and herpes zoster. In Studies PsO-1 and PsO-2, through Week 52, the rate of infections (73.9 events per 100 subject-years) was similar to the rate observed during the first 16 weeks of treatment.

Safety Through Week 52

Through Week 52, no new adverse reactions were identified, and the rates of the adverse reactions were similar to those observed during the first 16 weeks of treatment. During this period, serious infections that led to study discontinuation included pneumonia.

Psoriatic Arthritis

The overall safety profile observed in subjects with psoriatic arthritis treated with SKYRIZI is generally consistent with the safety profile in subjects with plaque psoriasis. Additionally, in the Phase 3 placebo-controlled trials the incidence of hepatic events was higher in the SKYRIZI group (5.4%, 16.7 events per 100 patient years) compared to the placebo group (3.9%, 12.6 events per 100 patient years). Of these, the most common events that were reported more frequently in both the placebo group and the SKYRIZI group were ALT increased (placebo: n=12 (1.7%); SKYRIZI: n=16 (2.3%)), AST increased (placebo: n=9 (1.3%); SKYRIZI: n=13 (1.8%)), and GGT increased (placebo: n=5 (0.7%); SKYRIZI: n=8 (1.1%)). There were no serious hepatic events reported. The incidence of hypersensitivity reactions was higher in the SKYRIZI group (n=16, 2.3%) compared to the placebo group (n=9, 1.3%). In the Phase 3 placebo-controlled trials, hypersensitivity reactions reported at a higher rate in the SKYRIZI group included rash (placebo: n=4 (0.6%); SKYRIZI: n=5 (0.7%), allergic rhinitis (placebo: n=1 (0.1%); SKYRIZI: n=2 (0.3%), and facial swelling (placebo: n=0 (0.0%); SKYRIZI n=1 (0.1%). One case of anaphylaxis was reported in a subject who received SKYRIZI in the Phase 2 clinical trial.

Crohn’s Disease

SKYRIZI was studied up to 12 weeks in subjects with moderately to severely active Crohn’s disease in two randomized, double-blind, placebo-controlled induction studies (CD-1, CD-2) and a randomized, double-blind, placebo-controlled, dose-finding study (CD-4; NCT02031276). Long-term safety up to 52 weeks was evaluated in subjects who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (CD-3) [see Clinical Studies ( 14.3)].

In the two induction studies (CD-1, CD-2) and the dose finding study (CD-4), 620 subjects received the SKYRIZI intravenous induction regimen at Weeks 0, 4 and 8. In the maintenance study (CD-3), 297 subjects who achieved clinical response, defined as a reduction in CDAI of at least 100 points from baseline after 12 weeks of induction treatment with intravenous SKYRIZI in studies CD-1 and CD-2, received a maintenance regimen of SKYRIZI either 180 mg or 360 mg subcutaneously at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks.

Adverse reactions reported in > 3% of subjects in induction studies and at a higher rate than placebo are shown in Table 3.

Adverse reactions reported in >3% of subjects in the maintenance study and at a higher rate than placebo are shown in Table 4.

Specific Adverse Drug Reactions

Infections

In the maintenance study (CD-3) through Week 52, the rate of infections was 32.3% (50.2 events per 100 subject-years) in subjects who received SKYRIZI 180 mg and 36.6% (60.8 events per 100 subject-years) in subjects who received SKYRIZI 360 mg compared to 36.4% (60.3 events per 100 subject-years) in subjects who received placebo after SKYRIZI induction. The rate of serious infections was 2.6% (2.7 events per 100 subject-years) in subjects who received SKYRIZI 180 mg and 5.6% (7.4 events per 100 subject-years) in subjects who received SKYRIZI 360 mg compared to 2.1% (2.4 events per 100 subject-years) in subjects who received placebo after SKYRIZI induction.

Lipid Elevations

Elevations in lipid parameters (total cholesterol and low-density lipoprotein cholesterol [LDL-C]) were first assessed at 4 weeks following initiation of SKYRIZI in the induction trials (CD-1, CD-2). Increases from baseline and increases relative to placebo were observed at Week 4 and remained stable to Week 12. Following SKYRIZI induction, mean total cholesterol increased by 9.4 mg/dL from baseline to a mean absolute value of 175.1 mg/dL at Week 12. Similarly, mean LDL-C increased by 6.6 mg/dL from baseline to a mean absolute value of 92.6 mg/dL at Week 12. Mean LDL-C increased by 3.1 mg/dL from baseline to a mean absolute value of 99.0 mg/dL at Week 52 with SKYRIZI 180 mg maintenance treatment and by 2.3 mg/dL from baseline to a mean absolute value of 102.2 mg/dL at Week 52 with SKYRIZI 360 mg maintenance treatment (CD-3).

Ulcerative Colitis 

SKYRIZI was studied up to 12 weeks in subjects with moderately to severely active ulcerative colitis in a randomized, double-blind, placebo-controlled induction study (UC-1) and a randomized, double-blind, placebo-controlled, dose-finding study (UC-3). Long-term safety up to 52 weeks was evaluated in subjects who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (UC-2) [see Clinical Studies ( 14.4)]. 

In the induction studies (UC-1 and UC-3), 712 subjects received the SKYRIZI 1,200 mg intravenous induction regimen at Weeks 0, 4 and 8. In the maintenance study (UC-2), 347 subjects who achieved clinical response, defined as a decrease in mMS of ≥2 points and ≥30% from baseline and a decrease in RBS ≥1 from baseline or an absolute RBS ≤1, received a maintenance regimen of SKYRIZI either 180 mg or 360 mg subcutaneously at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks.

The adverse reaction reported in ≥3% subjects treated with SKYRIZI in the ulcerative colitis induction studies (UC-1 and UC-3) and at a higher rate than placebo was arthralgia (3% SKYRIZI vs 1% placebo).

Adverse reactions reported in ≥3% of subjects treated with SKYRIZI in the maintenance study (UC-2) and at a higher rate than placebo are shown in Table 5.

Specific Adverse Drug Reactions

The rates of infections, serious infections, and lipid elevations in subjects with UC who received SKYRIZI compared to subjects who received placebo in the induction studies (UC-1 and UC-3) and maintenance study (UC-2) were similar to the rates in subjects with CD who received SKYRIZI compared to subjects who received placebo in the induction studies (CD-1, CD-2, and CD-4) and maintenance study (CD-3).

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other products, including other risankizumab products, may be misleading.

Plaque Psoriasis

By Week 52, approximately 24% (263/1079) of subjects treated with SKYRIZI at the recommended dose developed antibodies to risankizumab-rzaa. Of the subjects who developed antibodies to risankizumab-rzaa, approximately 57% (14% of all subjects treated with SKYRIZI) had antibodies that were classified as neutralizing. Higher antibody titers in approximately 1% of subjects treated with SKYRIZI were associated with lower risankizumab-rzaa concentrations and reduced clinical response.

Psoriatic Arthritis

By Week 28, approximately 12.1% (79/652) of subjects treated with SKYRIZI at the recommended dose developed antibodies to risankizumab-rzaa. None of the subjects who developed antibodies to risankizumab-rzaa had antibodies that were classified as neutralizing. Antibodies to risankizumab-rzaa were not associated with changes in clinical response for psoriatic arthritis. 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-rzaa.

Crohn’s Disease

By Week 64, antibodies to risankizumab-rzaa developed in approximately 3.4% (2/58) of subjects treated with SKYRIZI induction followed by 360 mg maintenance regimen. No subjects (0/57) treated with SKYRIZI induction followed by 180 mg maintenance regimen developed antibodies to risankizumab-rzaa. None of the subjects who developed antibodies to risankizumab-rzaa had antibodies that were classified as neutralizing.

Ulcerative Colitis

By Week 64, antibodies to risankizumab-rzaa developed in approximately 8.9% (8/90) or 4.4% (4/91) of subjects treated with SKYRIZI induction followed by the 180 mg or 360 mg maintenance regimen, respectively. Of the subjects who developed antibodies to risankizumab-rzaa, 75% (6.7% of all subjects treated with SKYRIZI induction followed by the 180 mg maintenance regimen) or 50% (2.2% of all subjects treated with SKYRIZI induction followed by the 360 mg maintenance regimen), respectively, had antibodies that were classified as neutralizing.

6.3 Postmarketing Experience

The following adverse reactions have been reported during post-approval 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 SKYRIZI exposure:

• Skin and subcutaneous tissue disorders: eczema and rash

12.1 Mechanism of Action

Risankizumab-rzaa is a humanized IgG1 monoclonal antibody that selectively binds to the p19 subunit of human IL-23 cytokine and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses.

Risankizumab-rzaa inhibits the release of pro-inflammatory cytokines and chemokines.

12.2 Pharmacodynamics

No formal pharmacodynamics studies have been conducted with risankizumab-rzaa.

12.3 Pharmacokinetics

Risankizumab-rzaa plasma concentrations, after single dose administration increased dose proportionally from 18 mg to 360 mg when administered subcutaneously (0.12 to 2.4 times the lowest recommended dose and 0.05 to 1 times the highest recommended dose) and from 200 mg to 1,800 mg when administered as an up to 3-hour intravenous infusion (0.2 to 3 times the recommended dose) in healthy subjects.  

In subjects with plaque psoriasis treated with 150 mg subcutaneously at Weeks 0, 4, and every 12 weeks thereafter, steady-state peak concentration (Cmax) and trough concentration (Ctrough) are estimated to be 12 mcg/mL and 2 mcg/mL, respectively. 

With the same subcutaneous dosing regimen, the pharmacokinetics of risankizumab-rzaa in subjects with psoriatic arthritis were similar to that in subjects with plaque psoriasis.

In subjects with Crohn’s disease treated with 600 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, the median Cmax and Ctrough are estimated to be 156 mcg/mL and 38.8 mcg/mL, respectively, during Weeks 8-12; and the steady state median Cmax and Ctrough are estimated to be 14.0 mcg/mL and 4.1 mcg/mL, respectively for 180 mg or 28.0 mcg/mL and 8.1 mcg/mL, respectively, for 360 mg, during Weeks 40-48.

In subjects with ulcerative colitis treated with 1,200 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, the median Cmax and Ctrough are estimated to be 350 and 87.7 mcg/mL, respectively, during the induction period (Weeks 8-12); and the steady state median Cmax and Ctrough are estimated to be 19.6 and 4.64 µg/mL, respectively, for 180 mg or 39.2 mcg/mL and 9.29 mcg/mL, respectively, for 360 mg, during the maintenance period (Weeks 40-48).

Based on population pharmacokinetic analyses, the pharmacokinetics of risankizumab-rzaa in subjects with ulcerative colitis was generally similar to that in subjects with Crohn’s disease.

Absorption

The absolute bioavailability of risankizumab-rzaa was estimated to be 74 to 89% following subcutaneous injection. In healthy subjects, following administration of a single subcutaneous dose, Cmax was reached by 3 to 14 days.  

Distribution

The estimated steady-state volume of distribution (inter-subject CV%) was 11.2 L (34%) in subjects with plaque psoriasis, and 7.68 L (64%) in subjects with Crohn’s disease.

Elimination

The estimated systemic clearance (inter-subject CV%) was 0.31 L/day (24%) and 0.30 L/day (34%) and terminal elimination half-life was approximately 28 days and 21 days in subjects with plaque psoriasis and Crohn’s disease, respectively.

Metabolism

The metabolic pathway of risankizumab-rzaa has not been characterized. As a humanized IgG1 monoclonal antibody, risankizumab-rzaa is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.

Specific Populations

Risankizumab-rzaa exposures (Ctrough) in geriatric patients (≥65 years) are comparable to those in younger adult patients within each indication. No studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of risankizumab-rzaa. 

Body Weight

Risankizumab-rzaa clearance and volume of distribution increase and plasma concentrations decrease as body weight increases; however, no dose adjustment is recommended based on body weight.

Drug Interaction Studies

Cytochrome P450 Substrates

No clinically significant changes in exposure of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), metoprolol (CYP2D6 substrate), or midazolam (CYP3A substrate) were observed when used concomitantly with risankizumab-rzaa in subjects with plaque psoriasis (risankizumab-rzaa 150 mg administered subcutaneously at Weeks 0, 4, 8, and 12) and subjects with Crohn’s disease or ulcerative colitis (risankizumab-rzaa 1,800 mg administered intravenously at Weeks 0, 4, and 8, i.e., 3 times and 1.5 times the recommended dose for Crohn’s disease and ulcerative colitis, respectively).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity and mutagenicity studies have not been conducted with SKYRIZI.

No effects on male fertility parameters were observed in sexually mature male cynomolgus monkeys dosed weekly for 26 weeks with 50 mg/kg risankizumab-rzaa at 4 times the exposure (AUC) in humans administered the maximum recommended induction dose (1,200 mg) and 39 times the exposure in humans administered the maximum recommended maintenance dose (360 mg).

14.1 Plaque Psoriasis

Four multicenter, randomized, double-blind studies [PsO-1 (NCT02684370), PsO-2 (NCT02684357), PsO-3 (NCT02672852), and PsO-4 (NCT02694523)] enrolled 2,109 subjects 18 years of age and older with moderate to severe plaque psoriasis who had a body surface area (BSA) involvement of ≥10%, a static Physician’s Global Assessment (sPGA) score of ≥3 (“moderate”) in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 4, and a Psoriasis Area and Severity Index (PASI) score ≥12.

Overall, subjects had a median baseline PASI score of 17.8 and a median BSA of 20%. Baseline sPGA score was 4 (“severe”) in 19% of subjects. A total of 10% of study subjects had a history of diagnosed psoriatic arthritis.

Across all studies, 38% of subjects had received prior phototherapy, 48% had received prior non-biologic systemic therapy, and 42% had received prior biologic therapy for the treatment of psoriasis.

Studies PsO-1 and PsO-2

In studies PsO-1 and PsO-2, 997 subjects were enrolled (including 598 subjects randomized to the SKYRIZI 150 mg group, 200 subjects randomized to the placebo group, and 199 to the biologic active control group). Subjects received treatment at Weeks 0, 4, and every 12 weeks thereafter.

Both studies assessed the responses at Week 16 compared with placebo for the two co-primary endpoints:

• the proportion of subjects who achieved an sPGA score of 0 (“clear”) or 1 (“almost clear”)
  
• the proportion of subjects who achieved at least a 90% reduction from baseline PASI (PASI 90)

Secondary endpoints included the proportion of subjects who achieved PASI 100, sPGA 0, and Psoriasis Symptom Scale (PSS) 0 at Week 16.

The results are presented in Table 6.

Examination of age, gender, race, body weight, baseline PASI score and previous treatment with systemic or biologic agents did not identify differences in response to SKYRIZI among these subgroups at Week 16.

In PsO-1 and PsO-2 at Week 52, subjects receiving SKYRIZI achieved sPGA 0 (58% and 60%, respectively), PASI 90 (82% and 81%, respectively), and PASI 100 (56% and 60%, respectively).

Patient Reported Outcomes

Improvements in signs and symptoms related to pain, redness, itching and burning at Week 16 compared to placebo were observed in both studies as assessed by the PSS. In PsO-1 and PsO-2, about 30% of the subjects who received SKYRIZI achieved PSS 0 (“none”) at Week 16 compared to 1% of the subjects who received placebo.

Study PsO-3

Study PsO-3 enrolled 507 subjects (407 randomized to SKYRIZI 150 mg and 100 to placebo). Subjects received treatment at Weeks 0, 4, and every 12 weeks thereafter.

At Week 16, SKYRIZI was superior to placebo on the co-primary endpoints of sPGA 0 or 1 (84% SKYRIZI and 7% placebo) and PASI 90 (73% SKYRIZI and 2% placebo). The respective response rates for SKYRIZI and placebo at Week 16 were: sPGA 0 (46% SKYRIZI and 1% placebo); PASI 100 (47% SKYRIZI and 1% placebo); and PASI 75 (89% SKYRIZI and 8% placebo).

Maintenance and Durability of Response

In PsO-1 and PsO-2, among the subjects who received SKYRIZI and had PASI 100 at Week 16, 80% (206/258) of the subjects who continued on SKYRIZI had PASI 100 at Week 52. For PASI 90 responders at Week 16, 88% (398/450) of the subjects had PASI 90 at Week 52.

In PsO-3, subjects who were originally on SKYRIZI and had sPGA 0 or 1 at Week 28 were re-randomized to continue SKYRIZI every 12 weeks or withdrawal of therapy. At Week 52, 87% (97/111) of the subjects re-randomized to continue treatment with SKYRIZI had sPGA 0 or 1 compared to 61% (138/225) who were re-randomized to withdrawal of SKYRIZI.

14.2 Psoriatic Arthritis

The safety and efficacy of SKYRIZI were assessed in 1407 subjects in 2 randomized, double-blind, placebo-controlled studies (964 in PsA-1 [NCT03675308] and 443 in PsA-2 [NCT03671148]) in subjects 18 years and older with active psoriatic arthritis (PsA).

Subjects 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 psoriatic nail disease at baseline. Regarding baseline clinical presentation, 55.9% of subjects had ≥3% BSA with active plaque psoriasis; 63.4% and 27.9% of subjects had enthesitis and dactylitis, respectively. In PsA-1 where psoriatic nail disease was further assessed, 67.3% had psoriatic nail disease.

In PsA-1, all subjects had a previous inadequate response or intolerance to non-biologic DMARD therapy and were biologic naïve. In PsA-2, 53.5% of subjects had a previous inadequate response or intolerance to non-biologic DMARD therapy, and 46.5% of subjects had a previous inadequate response or intolerance to biologic therapy.

In both studies, subjects were randomized to receive SKYRIZI 150 mg or placebo at Weeks 0, 4, and 16. Starting from Week 28, all subjects received SKYRIZI every 12 weeks. Both studies included a long-term extension for up to an additional 204 weeks. Regarding use of concomitant medications, 59.6% of subjects were receiving concomitant methotrexate (MTX), 11.6% were receiving concomitant non-biologic DMARDs other than MTX, and 28.9% were receiving SKYRIZI monotherapy.

For both studies, the primary endpoint was the proportion of subjects who achieved an American College of Rheumatology (ACR) 20 response at Week 24.

Clinical Response

In both studies, treatment with SKYRIZI resulted in significant improvement in measures of disease activity compared with placebo at Week 24. See Tables 7 and 8 for key efficacy results.

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 PsA-2, responses were seen regardless of prior biologic therapy.

The percent of subjects achieving ACR20 responses in study PsA-1 through Week 24 is shown in Figure 1.

Figure 1. Percent of Subjects Achieving ACR20 Responses in Study PsA-1 through Week 24

The results of the components of the ACR response criteria for both studies are shown in Table 9.

Treatment with SKYRIZI resulted in improvement in dactylitis and enthesitis in subjects with pre-existing dactylitis or enthesitis.

In patients with coexistent plaque psoriasis receiving SKYRIZI, the skin lesions of psoriasis improved with treatment, relative to placebo, as measured by the Psoriasis Area Severity Index (PASI 90) at Week 24.

Physical Function

In both studies, patients treated with SKYRIZI showed statistically significant improvement from baseline in physical function compared with placebo as assessed by HAQ-DI at Week 24 . The mean difference (95% CI) from placebo in HAQ-DI change from baseline at Week 24 was -0.20 (-0.26, -0.14) in study PsA-1 and -0.16 (-0.26, -0.07) in study PsA-2.

In both studies, a greater proportion of subjects achieved a reduction of at least 0.35 in HAQ-DI score from baseline in the SKYRIZI group compared with placebo at Week 24.

Other Health Related Outcomes

In both studies, general health status was assessed by the 36-Item Short Form Health Survey (SF-36 V2). Fatigue was assessed by Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue).

In both studies at Week 24, subjects treated with SKYRIZI showed improvements in the SF-36 physical component summary scores compared with subjects who received placebo. There were also numerical improvements in subjects treated with SKYRIZI in physical functioning, role physical, bodily pain, general health, vitality, social functioning, mental health, role emotional domain scores and mental component summary scores in both studies at week 24 compared to placebo. In both studies at Week 24, subjects treated with SKYRIZI showed improvements in FACIT-Fatigue scores compared with subjects who received placebo.

14.3 Crohn’s Disease

Induction Trials (Studies CD-1 and CD-2)

In two 12-week induction studies (CD-1; NCT03105128 and CD-2; NCT03104413), subjects with moderately to severely active Crohn’s disease were randomized to receive SKYRIZI 600 mg, SKYRIZI 1,200 mg, or placebo as an intravenous infusion at Week 0, Week 4, and Week 8. Moderately to severely active CD was defined as a Crohn’s Disease Activity Index (CDAI) of 220 to 450 and Simple Endoscopic Score for Crohn’s disease (SES-CD) ≥6 (or ≥4 for isolated ileal disease). Subjects with inadequate response, loss of response, or intolerance to oral aminosalicylates, corticosteroids, immunosuppressants, and/or biologic therapy were enrolled.  

At baseline, the median CDAI was 307 (range: 76 – 634) and 307 (range: 72 – 651), and the median SES-CD was 12 (range: 4 – 45) and 13 (range 4 – 40), in CD-1 and CD-2, respectively. In CD-1, 58% (491/850) of subjects had failed or were intolerant to treatment with one or more biologic therapies (prior biologic failure). All subjects in CD-2 had prior biologic failure. At baseline, 30% and 34% of patients were receiving corticosteroids, 24% and 23% of patients were receiving immunomodulators (azathioprine, 6-mercaptopurine, methotrexate), and 31% and 19% of patients were receiving aminosalicylates in CD-1 and CD-2, respectively. In CD-1 and CD-2 combined, the median age was 36 years (ranging from 16 to 80 years), 81% (1145/1419) of subjects were white, and 53% (753/1419) were male.

In CD-1 and CD-2, the co-primary endpoints were clinical remission and endoscopic response at Week 12. Secondary endpoints included clinical response and endoscopic remission (see Table 10 and Table 11). The SKYRIZI 1,200 mg dosage did not demonstrate additional treatment benefit over the 600 mg dosage and is not a recommended regimen [see Dosage and Administration ( 2.6)].

Onset of clinical response and clinical remission based on CDAI occurred as early as Week 4 in a greater proportion of subjects treated with the SKYRIZI 600 mg induction regimen compared to placebo.

Reductions in stool frequency and abdominal pain were observed in a greater proportion of subjects treated with the SKYRIZI 600 mg induction regimen compared to placebo at Week 12.

Study CD-3

The maintenance study CD-3 evaluated 382 subjects who achieved clinical response defined as a reduction in CDAI of at least 100 points from baseline after 12 weeks of induction treatment with intravenous SKYRIZI in studies CD-1 and CD-2. Subjects were randomized to receive a maintenance regimen of SKYRIZI 180 mg or SKYRIZI 360 mg or placebo at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks.

The co-primary endpoints in CD-3 were clinical remission and endoscopic response at Week 52 (see Table 12).

Endoscopic remission was observed at Week 52 in 33% (44/135) of subjects treated with the SKYRIZI 180 mg maintenance regimen and 41% (48/117) of subjects treated with the SKYRIZI 360 mg maintenance regimen, compared to 13% (17/130) of subjects treated with placebo. This endpoint was not statistically significant under the prespecified multiple testing procedure.

14.4 Ulcerative Colitis

Induction Trial (Study UC-1)

In the 12-week induction study (UC-1; NCT03398148), 966 subjects with moderately to severely active ulcerative colitis were randomized and received SKYRIZI 1,200 mg or placebo as an intravenous infusion at Week 0, Week 4, and Week 8. Disease activity was assessed by the modified Mayo score (mMS), a 3-component Mayo score (0-9) which consists of the following subscores (0 to 3 for each subscore): stool frequency (SFS), rectal bleeding (RBS), and findings on centrally read endoscopy score (ES). An ES of 2 was defined by marked erythema, lack of vascular pattern, any friability, and/or erosions; an ES of 3 was defined by spontaneous bleeding and ulceration. Enrolled subjects had a mMS between 5 and 9, with an ES of 2 or 3. Subjects with inadequate response, or intolerance to oral aminosalicylates, corticosteroids, immunomodulators, biologics, Janus Kinase inhibitors (JAKi), and/or sphingosine-1-phosphate receptor modulators (S1PRM) were enrolled.  

At baseline in UC-1, the median mMS was 7; 37% had severely active disease (mMS >7); 69% had an ES of 3. In UC-1, 52% (499/966) of subjects had failed (inadequate response or intolerance) treatment with one or more biologics, JAKi or S1PRM. Of these 499 subjects, 484 (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, 36% of subjects were receiving corticosteroids, 16% of subjects were receiving immunomodulators (including azathioprine, 6-mercaptopurine, methotrexate), and 73% of subjects were receiving aminosalicylates in UC-1.

In UC-1, the primary endpoint was clinical remission defined using the mMS at Week 12 (see Table 13). Key secondary endpoints included clinical response, endoscopic improvement, and histologic endoscopic mucosal improvement (see Table 13).

UC-1 was not designed to evaluate the relationship of histologic endoscopic mucosal improvement at week 12 to disease progression and long-term outcomes.

Rectal Bleeding and Stool Frequency Subscores

Decreases in rectal bleeding and stool frequency subscores in subjects treated with SKYRIZI compared to placebo were observed as early as 4 weeks.

Endoscopic Assessment

Endoscopic remission was defined as ES of 0. At Week 12, a greater proportion of subjects treated with SKYRIZI compared to placebo achieved endoscopic remission (11% vs 3%).

Bowel Urgency

A greater proportion of subjects treated with the SKYRIZI 1,200 mg induction regimen compared to placebo had no bowel urgency (44% vs 27%) at Week 12.

Fatigue

In UC-1, subjects treated with SKYRIZI experienced a clinically meaningful improvement in fatigue, assessed by change from baseline in FACIT-F score, at Week 12, compared to placebo-treated subjects. The effect of SKYRIZI to improve fatigue after 12 weeks of induction has not been established.

Other UC Symptoms

The proportion of subjects who had no nocturnal bowel movements was greater in subjects treated with SKYRIZI compared to placebo at Week 12 (67% vs 43%).

Maintenance Study UC-2

The maintenance study (UC-2; NCT03398135) evaluated 547 subjects who received one of three SKYRIZI induction regimens, including the 1,200 mg regimen, for 12 weeks in Studies UC-1 or UC-3 and demonstrated clinical response per mMS after 12 weeks. Subjects were randomized to receive a maintenance regimen of subcutaneous (SC) SKYRIZI 180 mg or SKYRIZI 360 mg or placebo at Week 12 and every 8 weeks thereafter for up to an additional 52 weeks.

In UC-2, 75% (411/547) of subjects had failed (inadequate response or intolerance) treatment with one or more biologics, JAKi, or S1PRM. Of these 411 subjects, 407 (99%) failed biologics and 78 (19%) failed JAK inhibitors. 

The primary endpoint in UC-2 was clinical remission using mMS at Week 52 (see Table 14). Key secondary endpoints included corticosteroid-free clinical remission, endoscopic improvement, and histologic endoscopic mucosal improvement (see Table 14).

Endoscopic Assessment 

Endoscopic remission was defined as ES of 0. In UC-2, a greater proportion of subjects treated with SKYRIZI 180 mg and SKYRIZI 360 mg compared to placebo achieved endoscopic remission at Week 52 (23% and 24% vs 15%).