Get your patient on Skyrizi (Risankizumab-Rzaa)

SKYRIZI ^® is indicated for the treatment of moderate-to-severe plaque psoriasis in adults and pediatric patients 6 years of age and older who are candidates for systemic therapy or phototherapy.

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

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

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

• 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 )]

• Visually inspect SKYRIZI for particulate matter and discoloration prior to administration. The solution may contain a few translucent to white particles.

○ SKYRIZI 55 mg/0.37 mL prefilled syringe, 150 mg/mL prefilled pen or prefilled syringe, 180 mg/1.2 mL prefilled syringe or prefilled cartridge, and 360 mg/2.4 mL prefilled cartridge: a colorless to yellow, and clear to slightly opalescent solution.

○ SKYRIZI 90 mg/mL prefilled syringe and 600 mg/10 mL vial: 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.

Adults

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

Pediatric Patients 6 Years of Age and Older

The recommended dosage for pediatric patients 6 years of age and older is based on body weight (see Table 1 ) and administered by subcutaneous injection at Week 0, Week 4, and every 12 weeks thereafter.

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).

• Administer SKYRIZI 55 mg/0.37 mL prefilled syringe, 150 mg/mL prefilled pen or prefilled syringe subcutaneously.

• Provide proper training to patients and/or caregivers on the subcutaneous injection technique of SKYRIZI. After proper training:

Adults

• Adults may self-inject SKYRIZI.

Pediatric Patients 6 Years of Age and Older

• For pediatric patients 10 years of age and older, it is recommended that SKYRIZI be administered by or under the supervision of an adult.
  
• For pediatric patients 6 to less than 10 years of age, SKYRIZI should be administered by an adult.

• 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.

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.

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.

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 2 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 up to 8 hours. 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.

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 or 180 mg/1.2 mL prefilled syringe:

• Administer each SKYRIZI 90 mg/mL or 180 mg/1.2 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 or 180 mg/1.2 mL prefilled syringe(s) to administer SKYRIZI 180 mg or SKYRIZI 360 mg subcutaneously as follows:

○ 180 mg maintenance dose:

▪ SKYRIZI 90 mg/mL prefilled syringes: Two 90 mg prefilled syringes are required. Inject one prefilled syringe after the other in different anatomic locations (such as thighs or abdomen).

▪ SKYRIZI 180 mg/1.2 mL prefilled syringe: One 180 mg prefilled syringe is required.

○ 360 mg maintenance dose:

▪ SKYRIZI 90 mg/mL prefilled syringes: Four 90 mg prefilled syringes are required. Inject one prefilled syringe after the other in different anatomic locations (such as thighs or abdomen).

▪ SKYRIZI 180 mg/1.2 mL prefilled syringes: Two 180 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.

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.  Therefore, SKYRIZI may be present in infants exposed in utero . The potential clinical impact of risankizumab exposure in infants exposed in utero should be considered.

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.

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.

Moderate-to-Severe Plaque Psoriasis

The safety and effectiveness 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.

Use of SKYRIZI for this indication is supported by evidence from a four-part trial in a total of 137 pediatric subjects 6 years of age and older with moderate-to-severe plaque psoriasis. In addition to two lead-in pharmacokinetic cohorts, the trial also included a randomized, efficacy assessor-blinded, active treatment-controlled cohort that enrolled 82 pediatric subjects 12 years of age and older and a single-arm, open-label cohort that enrolled 30 pediatric subjects 6 to less than 12 years of age [see Adverse Reactions (6.1 ), Clinical Pharmacology (12.3 ), and Clinical Studies (14.1 )] .

The safety and effectiveness of SKYRIZI have not been established in pediatric patients younger than 6 years of age with moderate-to-severe plaque psoriasis.

Psoriatic Arthritis, Crohn’s Disease, and Ulcerative Colitis

The safety and effectiveness of SKYRIZI have not been established in pediatric patients with psoriatic arthritis, Crohn’s disease or ulcerative colitis.

Of the 6,862 subjects exposed to SKYRIZI, a total of 664 were 65 years and 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 and 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 )] .

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 )].

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.

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.

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.

Avoid use of live vaccines in patients treated with SKYRIZI. Drugs 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.

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.

Adverse Reactions in Adults with Plaque Psoriasis

A total of 2234 adults were treated with SKYRIZI in clinical development trials in plaque psoriasis. Of these, 1208 subjects with plaque 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 3 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 trials.

Adverse 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 Reactions

Infections: In the first 16 weeks, infections occurred in 22.1% of the SKYRIZI group (90.8 events per 100 patient-years) compared with 14.7% of the placebo group (56.5 events per 100 patient-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 Trials PsO-1 and PsO-2, through Week 52, the rate of infections (73.9 events per 100 patient-years) was similar to the rate observed during the first 16 weeks of treatment.

Safety T hrough 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 trial discontinuation included pneumonia.

Plaque Psoriasis of the Scalp or Genital Area

The overall safety profile observed in clinical trials of adults with moderate-to-severe plaque psoriasis of the scalp or genital area treated with SKYRIZI is generally consistent with the safety profile observed in previous clinical trials of adults with moderate-to-severe plaque psoriasis [see Clinical Studies (14.1 )] .

Adverse Reactions in Pediatric Subjects 6 Years of Age and Older with Plaque Psoriasis

The safety of SKYRIZI was evaluated in a four-part trial that included 137 pediatric subjects 6 years of age and older with moderate-to-severe plaque psoriasis [see Clinical Studies (14.1 )] . Overall, the safety profile observed in pediatric subjects 6 years of age and older treated with SKYRIZI for up to 52 weeks was consistent with the safety profile observed in adult subjects with moderate-to-severe plaque psoriasis.

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 trials (CD-1, CD-2) and a randomized, double-blind, placebo-controlled, dose-finding trial (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 trial (CD-3) [see Clinical Studies (14.3 )] .

In the two induction trials (CD-1, CD-2) and the dose finding trial (CD-4), 620 subjects received the SKYRIZI intravenous induction regimen at Weeks 0, 4 and 8. In the maintenance trial (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 trials 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 trials and at a higher rate than placebo are shown in Table 4.

Adverse reactions reported in >3% of subjects in the maintenance trial and at a higher rate than placebo are shown in Table 5.

Specific Adverse Drug Reactions

• Infections: In the maintenance trial (CD-3) through Week 52, the rate of infections was 32.3% (50.2 events per 100 patient-years) in subjects who received SKYRIZI 180 mg and 36.6% (60.8 events per 100 patient-years) in subjects who received SKYRIZI 360 mg compared to 36.4% (60.3 events per 100 patient-years) in subjects who received placebo after SKYRIZI induction. The rate of serious infections was 2.6% (2.7 events per 100 patient-years) in subjects who received SKYRIZI 180 mg and 5.6% (7.4 events per 100 patient-years) in subjects who received SKYRIZI 360 mg compared to 2.1% (2.4 events per 100 patient-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 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 trial (UC-1) and a randomized, double-blind, placebo-controlled, dose-finding trial (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 trial (UC-2) [see Clinical Studies (14.4 )].

In the induction trials (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 trial (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 trials (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 trial (UC-2) and at a higher rate than placebo are shown in Table 6.

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 trials (UC-1 and UC-3) and maintenance trial (UC-2) were similar to the rates in subjects with CD who received SKYRIZI compared to subjects who received placebo in the induction trials (CD-1, CD-2, and CD-4) and maintenance trial (CD-3).

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

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.

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

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 (C _max ) and trough concentration (C _trough ) 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 C _max and C _trough are estimated to be 156 mcg/mL and 38.8 mcg/mL, respectively, during Weeks 8-12; and the steady state median C _max and C _trough are estimated to be 14 mcg/mL and 4.1 mcg/mL, respectively for 180 mg or 28 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 C _max and C _trough are estimated to be 350 and 87.7 mcg/mL, respectively, during the induction period (Weeks 8-12); and the steady state median C _max and C _trough 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, C _max 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

Pediatric Patients

• Plaque Psoriasis: Risankizumab-rzaa exposures in pediatric subjects 6 years of age and older with plaque psoriasis receiving weight-based dosing regimens were consistent with those in adults. At the recommended dosing regimens evaluated in these subjects, estimated median steady-state peak and trough plasma concentrations were 15.7 and 2.3 mcg/mL, respectively, in subjects weighing less than 40 kg, and 11.1 and 1.6 mcg/mL, respectively, in subjects weighing 40 kg or greater.

Geriatric Patients

Risankizumab-rzaa exposures (C _trough ) 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 in adult patients.

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).

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the trials described below with the incidence of ADA in other trials, including those of SKYRIZI or other risankizumab products.

Moderate-to-Severe Plaque Psoriasis

By Week 52, approximately 24% (263/1079) of adults treated with SKYRIZI at the recommended dosage 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.

In pediatric subjects 6 years of age and older, approximately 15% (13/88) of subjects treated with SKYRIZI at the recommended dose developed antibodies to risankizumab-rzaa by Week 52. Of the 13 subjects who developed antibodies to risankizumab-rzaa, approximately 15% (2.3% of all subjects treated with SKYRIZI) had antibodies that were classified as neutralizing. Due to the small number of subjects who developed antibodies to risankizumab-rzaa, it is difficult to determine the impact of the antibodies on pharmacokinetics, pharmacodynamics, safety, and/or effectiveness.

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.

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).

Adults with Moderate-to-Severe Plaque Psoriasis

Four multicenter, randomized, double-blind trials [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 trial subjects had a history of diagnosed psoriatic arthritis.

Across all trials, 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.

Trials PsO-1 and PsO-2

In trials 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 trials 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 7.

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 trials 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.

Trial PsO-3

Trial 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.

Moderate-to-Severe Plaque Psoriasis of the Scalp or Genital Area (Trial PsO-5)

The efficacy of SKYRIZI was assessed in a multicenter, randomized, double-blind, placebo-controlled trial [PsO-5 (NCT05969223)] that enrolled subjects 18 years of age and older with moderate-to-severe plaque psoriasis of the scalp (Trial 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 plaque psoriasis of the genital area (Trial G), defined as static Physician’s Global Assessment of Genitalia (sPGA-G) ≥3 (“moderate”) at baseline. All subjects had BSA ≥1% and sPGA ≥3 (“moderate”) at baseline.

In trial PsO-5, 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 of the Scalp

PsO-5 Trial 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) and 10% of the subjects were 65 years of age and older. Fifty-six (56)% of the subjects were male, 83% were White, 8% were Black or African American, and 5% were Asian; for ethnicity, 36% of the subjects 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 the remaining subjects. Median baseline BSA involvement was 11%. Baseline 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 results are presented in Table 8.

Plaque Psoriasis of the Genital Area

PsO-5 Trial 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 (65)% of the subjects were male, 90% were White, 4% were Asian, and 2% were Black or African American; for ethnicity, 29% of the subjects identified as Hispanic or Latino. At baseline, 62% of the subjects had moderate plaque psoriasis of the genital area (sPGA-G of 3) and 38% had severe or very severe plaque psoriasis of the genital area (sPGA-G of 4 or 5). Baseline BSA involvement was ≥10% for 63% of the subjects and <10% for the remaining subjects. Median baseline BSA involvement was 11%. Baseline 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 results are presented in Table 9.

Pediatric Subjects with Moderate-to-Severe Plaque Psoriasis

The safety and efficacy of SKYRIZI were assessed in a four-part trial [PsO-6 (NCT04435600)] [see Use in Specific Populations (8.4 ) ] . The trial included a randomized, efficacy assessor-blinded, active treatment-controlled cohort of 82 pediatric subjects 12 years of age and older with moderate-to-severe plaque psoriasis defined as BSA involvement of ≥10% with sPGA score of ≥3 or a PASI score ≥12.

Subjects were randomized 2:1 to receive SKYRIZI (N = 54) or ustekinumab (N = 28). Subjects weighing 40 kg or greater received SKYRIZI 150 mg and subjects weighing less than 40 kg received SKYRIZI 55 mg at Week 0, Week 4, and every 12 weeks thereafter.

Fifty-six (56)% of subjects were female, 83% were White, 10% were Asian, and 5% were Black or African American; for ethnicity, 17% of subjects identified as Hispanic or Latino. At baseline, 82% of subjects had a sPGA score of 3 (“moderate”) and 9% of subjects had a sPGA score of 4 (“severe”). Subjects had a median baseline PASI score of 15.7, and a median baseline BSA of 18%. A total of 4% of subjects had received prior biologic therapy.

The co-primary endpoints were sPGA score of 0 (“clear”) or 1 (“almost clear”) and at least a 2-point improvement from baseline, and PASI 75 at Week 16. The duration of treatment was up to 68 weeks.

The efficacy results are presented below (see Table 10).

Maintenance of Response

Subjects originally treated with SKYRIZI who achieved sPGA of 0 or 1 at Week 16 were re-randomized to continue SKYRIZI every 12 weeks through Week 52 or were withdrawn from treatment. For subjects who were re-randomized and also had at least a 2-point improvement in sPGA from baseline at Week 16, 95% (18/19) of the subjects continuing SKYRIZI had sPGA of 0 or 1 and at least a 2-point improvement from baseline at Week 52 compared with 39% (7/18) for those withdrawn from SKYRIZI.

The safety and efficacy of SKYRIZI were assessed in 1407 subjects in 2 randomized, double-blind, placebo-controlled trials (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 trials 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 trials, 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 trials 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 trials, 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 trials, treatment with SKYRIZI resulted in significant improvement in measures of disease activity compared with placebo at Week 24. See Tables 11 and 12 for key efficacy results.

In both trials, 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 trial PsA-1 through Week 24 is shown in Figure 1.

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

The results of the components of the ACR response criteria for both trials are shown in Table 13.

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 trials, patients treated with SKYRIZI showed statistically significant improvement from baseline in physical function compared with placebo as assessed by HAQ-DI at Week 24 (Table 13 ). The mean difference (95% CI) from placebo in HAQ-DI change from baseline at Week 24 was -0.20 (-0.26, -0.14) in trial PsA-1 and -0.16 (-0.26, -0.07) in trial PsA-2.

In both trials, 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 trials, 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 trials 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 trials at week 24 compared to placebo. In both trials at Week 24, subjects treated with SKYRIZI showed improvements in FACIT-Fatigue scores compared with subjects who received placebo.

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

In two 12-week induction trials (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 14 and Table 15 ). 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.

Trial CD-3

The maintenance trial 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 trials 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 16 ).

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.

Induction Trial ( Trial UC-1)

In the 12-week induction trial (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 17 ). Key secondary endpoints included clinical response, endoscopic improvement, and histologic endoscopic mucosal improvement (see Table 17 ).

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 Trial UC-2

The maintenance trial (UC-2; NCT03398135) evaluated 547 subjects who received one of three SKYRIZI induction regimens, including the 1,200 mg regimen, for 12 weeks in Trials 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 18 ). Key secondary endpoints included corticosteroid-free clinical remission, endoscopic improvement, and histologic endoscopic mucosal improvement (see Table 18 ).

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%).