clear psoriasis plaques from the skin of patients has grown in response to accumulating evidence that residual skin disease can affect patients’ health-related QoL.4,5
In one study, clinicians reported that itch, flaking, and pain were the primary symptoms of psoriasis.6 In the same study, patients rated itch as the most important, most severe, and most troublesome psoriasis symptom.6 Furthermore, patients reported that itch negatively impacted their daily activities, concentration, sleep, and absenteeism and presenteeism, as well as emotions such as anxiety and embarrassment.6 It is particularly important for studies to assess the impact of psoriasis treatments on absenteeism and presenteeism because work productivity loss increases progressively with increasing dermatology life quality index (DLQI) scores and body surface area affected, and its associated costs contribute to the economic burden of psoriasis.7
Ixekizumab is a high-affinity monoclonal antibody that selectively targets interleukin-17A (IL-17A). IL-17A is a member of the family of proinflammatory IL-17 cytokines and plays an important role in the pathogenesis of psoriasis and other immune-related diseases.8 Two randomized, double-blinded, multicenter, phase 3 clinical studies of ixekizumab (UNCOVER-1 and UNCOVER-2) have shown greater efficacy than placebo and etanercept through 60 weeks of treatment in patients with moderate-to-severe plaque psoriasis.9,10 As psoriasis is a chronic disease with a cumulative burden if not treated, treatment should be efficacious and well tolerated long-term, particularly as drug exposure increases over time. The objective of this analysis was to report PROs for UNCOVER-1 and UNCOVER-2 in patients with moderate-to-severe plaque psoriasis through 5 years of treatment with ixekizumab.
In one study, clinicians reported that itch, flaking, and pain were the primary symptoms of psoriasis.6 In the same study, patients rated itch as the most important, most severe, and most troublesome psoriasis symptom.6 Furthermore, patients reported that itch negatively impacted their daily activities, concentration, sleep, and absenteeism and presenteeism, as well as emotions such as anxiety and embarrassment.6 It is particularly important for studies to assess the impact of psoriasis treatments on absenteeism and presenteeism because work productivity loss increases progressively with increasing dermatology life quality index (DLQI) scores and body surface area affected, and its associated costs contribute to the economic burden of psoriasis.7
Ixekizumab is a high-affinity monoclonal antibody that selectively targets interleukin-17A (IL-17A). IL-17A is a member of the family of proinflammatory IL-17 cytokines and plays an important role in the pathogenesis of psoriasis and other immune-related diseases.8 Two randomized, double-blinded, multicenter, phase 3 clinical studies of ixekizumab (UNCOVER-1 and UNCOVER-2) have shown greater efficacy than placebo and etanercept through 60 weeks of treatment in patients with moderate-to-severe plaque psoriasis.9,10 As psoriasis is a chronic disease with a cumulative burden if not treated, treatment should be efficacious and well tolerated long-term, particularly as drug exposure increases over time. The objective of this analysis was to report PROs for UNCOVER-1 and UNCOVER-2 in patients with moderate-to-severe plaque psoriasis through 5 years of treatment with ixekizumab.
MATERIALS AND METHODS
Study Design
The present report includes side-by-side data from the UNCOVER-1 (NCT01474512) and UNCOVER-2 (NCT01597245) studies. The study designs for these studies have been described previously.9,10 An active drug control (etanercept) was also included in UNCOVER-2. Both the studies included a blinded induction period from weeks 0–12. Patients in UNCOVER-1 (N=1296) were randomized in a 1:1:1 ratio to receive ixekizumab 80 mg every 2 weeks (Q2W), ixekizumab 80 mg every 4 weeks (Q4W), or placebo. In UNCOVER-2, patients (N=1224) were randomly assigned in a 2:2:2:1 ratio to receive ixekizumab Q2W, ixekizumab Q4W, etanercept 50 mg twice weekly, or placebo. In both studies, patients treated with ixekizumab received an initial loading dose of 160 mg. During the maintenance period (weeks 12–60) in both studies, static physician global assessment (sPGA) <2 responders were re-randomized in the same ratio to receive any study treatment, and non-responders were assigned to ixekizumab Q4W in both UNCOVER-1 and -2. Here, we report the efficacy results for patients who responded at week 12 (sPGA 0,1), were initially randomized to ixekizumab Q2W, who received ixekizumab Q4W during the maintenance period, completed week 60, and continued into the long-term extension periods (weeks 60–264) of UNCOVER-1 and -2. UNCOVER-1 was conducted in Australia, Canada, Denmark, Germany, Hungary, Italy, Japan, Poland, Romania, the United Kingdom, and the United States. UNCOVER-2 was conducted in Australia, Austria, Canada, the Czech Republic, France, Germany, the Netherlands, Poland, Romania, Spain, the United Kingdom, and the United States.
Both studies included in this analysis were compliant with ethical guidelines including the Declaration of Helsinki and other relevant laws and regulations. Each site’s ethical review committee or institutional review board approved the study protocols and all patients provided written informed consent.
Study Population
Detailed eligibility criteria have been published.9,11 Briefly, eligible patients were aged 18 years or older and had a diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomization), involvement of 10% or greater body surface area at both screening and baseline visits, at least a moderate clinical severity as measured by sPGA ≥3, a psoriasis area and severity index (PASI) score of ≥12, and were candidates for phototherapy, systemic therapy, or both. Prior therapy with biologics was permitted except for prior use of etanercept, which was an exclusion criterion in UNCOVER-2.
Assessments
Efficacy outcome measurements included the proportion of patients achieving improvement in itch numeric rating scale ≥4-point improvement from baseline (itch NRS ≥4), itch NRS 0 for patients with baseline itch NRS >0, skin pain visual analog (VAS) scale 0, DLQI 0,1, and mean change from baseline in the psoriasis skin appearance bothersomeness (PSAB) measure. The PSAB measure asks patients to indicate how bothered they are by the 3 dimensions of skin appearance (redness or discoloration, areas or thickness, and scaling or flakiness) due to psoriasis skin plaques included in the physician-assessed PASI.12 Each dimension is rated on an 11-point NRS ranging from 0 (not bothered at all) to 10 (extremely bothered). The 3-item scores were summed for a total score ranging from 0 to 30, with higher scores indicating more bothersomeness due to skin appearance. Additionally, mean change from baseline in the short form health survey (SF-36) physical (PCS) or mental component summaries (MCS) along with individual domains were measured, as well as work productivity activity impairment (WPAI) psoriasis item scores. The clinical meaningfulness of improvements in WPAI psoriasis item scores for work productivity loss and work activity impairment was assessed by determining the minimal clinically importance difference (MCID), using a cutoff of 20% as previously described.13
The present report includes side-by-side data from the UNCOVER-1 (NCT01474512) and UNCOVER-2 (NCT01597245) studies. The study designs for these studies have been described previously.9,10 An active drug control (etanercept) was also included in UNCOVER-2. Both the studies included a blinded induction period from weeks 0–12. Patients in UNCOVER-1 (N=1296) were randomized in a 1:1:1 ratio to receive ixekizumab 80 mg every 2 weeks (Q2W), ixekizumab 80 mg every 4 weeks (Q4W), or placebo. In UNCOVER-2, patients (N=1224) were randomly assigned in a 2:2:2:1 ratio to receive ixekizumab Q2W, ixekizumab Q4W, etanercept 50 mg twice weekly, or placebo. In both studies, patients treated with ixekizumab received an initial loading dose of 160 mg. During the maintenance period (weeks 12–60) in both studies, static physician global assessment (sPGA) <2 responders were re-randomized in the same ratio to receive any study treatment, and non-responders were assigned to ixekizumab Q4W in both UNCOVER-1 and -2. Here, we report the efficacy results for patients who responded at week 12 (sPGA 0,1), were initially randomized to ixekizumab Q2W, who received ixekizumab Q4W during the maintenance period, completed week 60, and continued into the long-term extension periods (weeks 60–264) of UNCOVER-1 and -2. UNCOVER-1 was conducted in Australia, Canada, Denmark, Germany, Hungary, Italy, Japan, Poland, Romania, the United Kingdom, and the United States. UNCOVER-2 was conducted in Australia, Austria, Canada, the Czech Republic, France, Germany, the Netherlands, Poland, Romania, Spain, the United Kingdom, and the United States.
Both studies included in this analysis were compliant with ethical guidelines including the Declaration of Helsinki and other relevant laws and regulations. Each site’s ethical review committee or institutional review board approved the study protocols and all patients provided written informed consent.
Study Population
Detailed eligibility criteria have been published.9,11 Briefly, eligible patients were aged 18 years or older and had a diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomization), involvement of 10% or greater body surface area at both screening and baseline visits, at least a moderate clinical severity as measured by sPGA ≥3, a psoriasis area and severity index (PASI) score of ≥12, and were candidates for phototherapy, systemic therapy, or both. Prior therapy with biologics was permitted except for prior use of etanercept, which was an exclusion criterion in UNCOVER-2.
Assessments
Efficacy outcome measurements included the proportion of patients achieving improvement in itch numeric rating scale ≥4-point improvement from baseline (itch NRS ≥4), itch NRS 0 for patients with baseline itch NRS >0, skin pain visual analog (VAS) scale 0, DLQI 0,1, and mean change from baseline in the psoriasis skin appearance bothersomeness (PSAB) measure. The PSAB measure asks patients to indicate how bothered they are by the 3 dimensions of skin appearance (redness or discoloration, areas or thickness, and scaling or flakiness) due to psoriasis skin plaques included in the physician-assessed PASI.12 Each dimension is rated on an 11-point NRS ranging from 0 (not bothered at all) to 10 (extremely bothered). The 3-item scores were summed for a total score ranging from 0 to 30, with higher scores indicating more bothersomeness due to skin appearance. Additionally, mean change from baseline in the short form health survey (SF-36) physical (PCS) or mental component summaries (MCS) along with individual domains were measured, as well as work productivity activity impairment (WPAI) psoriasis item scores. The clinical meaningfulness of improvements in WPAI psoriasis item scores for work productivity loss and work activity impairment was assessed by determining the minimal clinically importance difference (MCID), using a cutoff of 20% as previously described.13
