Summary Basis of Decision for Skyrizi

 

Clinical Pharmacology

Risankizumab, the medicinal ingredient in Skyrizi, is a modified monoclonal antibody based on the structure of immunoglobulin G1 (IgG1). Risankizumab binds to and inhibits interleukin (IL)-23, a naturally occurring cytokine with key roles in inflammatory and immune responses. In cell-based assays, the binding of risankizumab to IL-23 has been shown to inhibit IL-23 signalling, including the release of another pro-inflammatory cytokine, IL-17. Risankizumab binds specifically to IL-23, and does not bind to the closely related IL-12.

Population pharmacokinetic and exposure-response models for risankizumab were developed based on data from seven clinical trials: two Phase I trials, one Phase II trial, and four Phase III trials.

Following subcutaneous administration, exposure to risankizumab was observed to increase in a linear and dose-proportional manner across the range of doses tested (fixed dose: 18 mg to 300 mg; body-weight dose: 0.25 mg/kg to 1 mg/kg). Based on population pharmacokinetic analyses, peak plasma concentrations were achieved between three and 14 days after administration and the estimated absolute bioavailability of risankizumab was 89%. Both the volume of distribution and clearance were observed to increase with body weight. Based on the population pharmacokinetic estimates, a typical plaque psoriasis patient (90 kg) is expected to achieve a steady-state at 16 weeks. At steady state, the estimated mean peak concentration (± standard deviation [SD]) was 11.9 ± 3.06 mcg/mL, and the estimated mean trough concentration was 1.91 ± 1.17 mcg/mL. Although the exact process through which risankizumab is metabolized remains unclear, it is believed that it undergoes degradation into smaller peptides and amino acids, similar to endogenous immunoglobulin G (IgG) antibodies. The half-life of risankizumab in patients with plaque psoriasis is approximately 28 days. Changes due to hepatic or renal impairment were not studied. However, risankizumab is not expected to rely on the hepatic cytochrome P450 enzymes for metabolism, or on the renal system for elimination.

Population pharmacokinetic analyses revealed that an anti-drug antibody (ADA) titer of at least 128 and body weight greater than 100 kg were covariates which reduced exposure to risankizumab by approximately 30%; however, neither covariate appeared to significantly impact safety or efficacy. No dose adjustments are recommended, as the data demonstrate that the safety and efficacy of risankizumab remain consistent across most subpopulations analyzed.

For further details, please refer to the Skyrizi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Evidence supporting the clinical efficacy of Skyrizi was provided primarily through four pivotal, randomized, double-blind Phase III trials: ULTIMMA-1, ULTIMMA-2, IMMHANCE, and IMMVENT. Collectively, these trials enrolled 2,109 adult patients with moderate to severe plaque psoriasis who were candidates for systemic therapy or phototherapy. Randomization was stratified by weight (≤100 kg vs. >100 kg) and by prior exposure to tumour necrosis factor (TNF) antagonists (0 vs. 1). All four trials followed the recommended dosing regimen for Skyrizi, in which 150 mg are administered as two 75 mg subcutaneous injections at Week 0, Week 4, and every 12 weeks thereafter.

In ULTIMMA-1, ULTIMMA-2, and IMMHANCE, the co-primary endpoints comparing Skyrizi to placebo at Week 16 were:

• the proportion of patients who achieved at least a 90% reduction from baseline in the Psoriasis Area and Severity Index (PASI 90) composite score, and
• the proportion of patients who achieved a static Physician Global Assessment (sPGA) of clear or almost clear

In IMMVENT, the co-primary endpoints at Week 16 were the proportions of patients who achieved PASI 90 and sPGA of clear or almost clear, comparing Skyrizi to adalimumab.

ULTIMMA-1 and ULTIMMA-2

ULTIMMA-1 and ULTIMMA-2 were replicate studies in which Skyrizi was compared to a placebo and to ustekinumab, another biologic authorized for the treatment of psoriasis. Across both studies, 997 patients were randomized in a 3:1:1 ratio to receive Skyrizi (number of patients [n] = 598), the placebo (n = 200), or ustekinumab (n = 199). For patients receiving ustekinumab, doses were dependent on body weight (45 mg for those weighing ≤100 kg or 90 mg for this weighing >100 kg). All treatments were administered at Week 0, Week 4, and every 12 weeks thereafter. At Week 16, patients in the placebo group began treatment with Skyrizi, while patients randomized to the Skyrizi or ustekinumab treatment groups continued to receive their originally assigned treatment up to 52 weeks.

The co-primary endpoints were achieved in both studies. The difference in the PASI 90 composite score between the Skyrizi and placebo treatment groups at Week 16 was 70.3% in ULTIMMA-1 (95% confidence interval [CI]: 64.0, 76.7) and 72.5% in ULTIMMA-2 (95% CI: 66.8, 78.2). The treatment difference for sPGA of clear or almost clear response between the Skyrizi and placebo groups at Week 16 was 79.9% in ULTIMMA-1 (95% CI: 73.5, 86.3) and 78.5% in ULTIMMA-2 (95% CI: 72.4, 84.5).

Treatment differences between Skyrizi and ustekinumab were evaluated as secondary endpoints. The difference in the PASI 90 composite scores between the Skyrizi and ustekinumab groups was 33.5% in ULTIMMA-1 (95% CI: 22.7, 44.3), and 27.6% in ULTIMMA-2 (95% CI: 16.7, 38.5) at Week 16. At Week 52, the difference was 38.3% in ULTIMMA-1 (95% CI: 27.9, 48.6) and 30.2% in ULTIMMA-2 (95% CI: 19.6, 40.9). At Week 16, the difference in sPGA of clear or almost clear response between the Skyrizi and ustekinumab groups was 25.1% in ULTIMMA-1 (95% CI: 15.2, 35.0) and 22.3% in ULTIMMA-2 (95% CI: 12.0, 32.5).

IMMHANCE

IMMHANCE evaluated the efficacy of Skyrizi compared to a placebo in 507 patients. In the first part of the trial, patients were randomized in a 4:1 ratio to receive either Skyrizi (n = 407) or the placebo (n = 100) according to the recommended dosage regimen. The co-primary endpoints were achieved by Week 16. At this point, the difference in the PASI 90 composite score between the Skyrizi and placebo treatment groups was 70.8% (95% CI: 65.7, 76.0). The difference in patients who achieved an sPGA of clear or almost clear was 76.5% (95% CI: 70.4, 82.5).

IMMVENT

IMMVENT evaluated the efficacy of Skyrizi compared to adalimumab, another biologic authorized for the treatment of psoriasis. In the first part of the trial, 605 patients were randomized in a 1:1 ratio to be treated with either Skyrizi (n = 301) or adalimumab (n = 304) for the first 16 weeks. Skyrizi was administered according to the recommended dosage regimen. Patients treated with adalimumab received 80 mg at the start of the trial (Week 0) and then 40 mg every other week starting at Week 1.

At Week 16, patients in the adalimumab treatment group either continued receiving the same treatment or switched to Skyrizi depending on their response:

• patients with less than a 50% reduction from baseline in the Psoriasis Area and Severity Index (<PASI 50) composite score switched to Skyrizi.
• patients with a reduction between 50% and <90% from baseline were re-randomized to either continue treatment with adalimumab or switch to Skyrizi.
• patients who achieved PASI 90 continued treatment with adalimumab.

Both co-primary endpoints were achieved by Week 16. The difference in the PASI 90 composite score between the Skyrizi and adalimumab treatment groups was 24.9% (95% CI: 17.5, 32.4). The difference in patients who achieved an sPGA of clear or almost clear was 23.3% (95% CI: 16.6, 30.1). Results were consistent during the second part of the trial, after some patients were switched to receive Skyrizi.

Indication

Sponsor's proposed indication	Health Canada-approved indication
Skyrizi (risankizumab injection) is indicated for the treatment of moderate to severe plaque psoriasis in adults.	Skyrizi (risankizumab injection) is indicated for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

The proposed indication was revised to more accurately reflect the patient population in the clinical trials.

For more information, refer to the Skyrizi Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The data reviewed for the safety evaluation of Skyrizi were derived from nine clinical trials, including the four Phase III pivotal trials (ULTIMMA-1, ULTIMMA-2, IMMHANCE, and IMMVENT) described in the Clinical Efficacy section. These nine trials included 2,234 patients treated with Skyrizi, with 1,208 of these patients (54%) exposed to Skyrizi 150 mg for at least one year.

In studies that included a placebo-controlled period, upper respiratory tract infections were the most common adverse events, reported in 13% of Skyrizi-treated patients and 10% of placebo-treated patients. The overall rate of infection was 22% in patients receiving Skyrizi, and 15% in patients receiving the placebo.

Serious adverse events which occurred during the clinical trials include infections in 22 patients, hypersensitivity (erythema multiforme) in one patient, depression in two patients, and a suicide attempt by one patient.

Treatment with any therapeutic protein is naturally accompanied by the risk of immunogenicity (the development of anti-drug antibodies [ADAs]). After 52 weeks of treatment, anti-risankizumab antibodies were detected in 24% of patients, and found to have a neutralizing effect in 14% of patients.

The data available at the time of review was not sufficient to thoroughly evaluate the long-term effects of Skyrizi, including the risks of malignancies and cardiovascular disorders. The sponsor has committed to monitoring these risks in a planned long-term prospective cohort study.

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Skyrizi, and to promote its safe and effective use. For more information, refer to the Skyrizi Product Monograph, approved by Health Canada and available through the Drug Product Database.