Impact of Ixekizumab Treatment on Itch and Psoriasis Area and Severity Index in Patients with Moderate-to-Severe Plaque Psoriasis: An Integrated Analysis of Two Phase III Randomized Studies

Abstract

Introduction: We evaluated baseline itch and its impact on the efficacy of ixekizumab (IXE) in clearing psoriasis and improving quality-of-life measures, and we explored the relationship between itch and psoriatic skin improvement.

Methods: Data were analyzed from two double-blind, randomized, controlled phase III studies (UNCOVER-2/3) comparing etanercept (ETN), IXE, and placebo (PBO) in patients with moderate-to-severe plaque psoriasis. Long-term analysis included UNCOVER-3 data from week 0 to week 156.

Results: At week 12, a clinically meaningful improvement in itch [Itch Numeric Rating Scale (NRS) reduction ≥ 4] was seen in 70.0%, 88.6%, and 90.8% of the IXE-treated patients in the baseline Itch NRS 4-6, 7-8, and 9-10 groups, respectively (all itch severity groups p < 0.001 versus ETN and PBO). Also, 68.9%, 67.1%, and 73.6% of the IXE-treated patients in the baseline Itch NRS 4-6, 7-8, and 9-10 groups, respectively, showed an improvement of ≥ 90.0% in the Psoriatic Area and Severity Index (PASI) at week 12 as compared to the baseline (PASI 90) (all itch severity groups p < 0.001 versus ETN and PBO). For most patients, itch reduction preceded psoriatic plaque improvement. Sustained effects of IXE on itch and PASI were observed during 3 years of treatment.

Conclusions: Regardless of baseline itch severity, IXE treatment provided a rapid improvement in itch followed by clinically meaningful improvements in psoriasis.

Funding: Eli Lilly and Company.

Trial registration: ClinicalTrials.gov identifiers, NCT01597245 and NCT01646177.

Keywords: IL-17A; Itch; Ixekizumab; Psoriasis.

Fig. 1

Impact of baseline psoriasis-associated itch severity on the Itch Numeric Rating Scale changes from baseline during the induction period (pooled data from UNCOVER-2 and 3; LSM) in patients with psoriasis-associated Itch NRS ≥ 4 at baseline (the LSM difference, 95% confidence interval, and p values were derived from a mixed effects model for repeated measures analysis including the fixed-effects treatment, study, visit, and treatment × visit, with the variance–covariance structure set to unstructured) (intent-to-treat population). Itch NRS 4–6, 7–8, and 9–10  indicate the Itch NRS scores at baseline. ETN etanercept, IXE ixekizumab, LSM least squares mean, NRS numeric rating scale, PBO placebo, Q2W every 2 weeks

Fig. 2

Impact of baseline Itch Numeric Rating Scale severity on the response rate for a clinically meaningful improvement in itch (i.e., ≥ 4 point reduction in Itch NRS) at week 12 in patients with psoriasis-associated Itch NRS ≥ 4 at baseline (intent-to-treat population); treatment p < 0.001, baseline Itch NRS category p < 0.001, treatment × baseline Itch NRS category (p = 0.253), Itch NRS 4–6, 7–8, and 9–10 indicate the Itch NRS score at baseline. ETN etanercept, IXE ixekizumab, NRS Numeric Rating Scale, PBO placebo, Q2W every 2 weeks. *p < 0.001 versus ETN and PBO

Fig. 3

Impact of baseline Itch Numeric Rating Scale severity on the response rate for complete itch resolution (i.e., Itch NRS = 0) at week 12 in patients with psoriasis-associated Itch NRS ≥ 1 at baseline (intent-to-treat population); treatment p < 0.001, baseline Itch NRS category p < 0.001, treatment × baseline Itch NRS category (p = 0.285) at the end of the induction period (pooled data from UNCOVER-2 and 3; NRI), Itch NRS 4–6, 7–8, and 9–10 indicate the Itch NRS score at baseline. ETN etanercept, IXE ixekizumab, NRI nonresponder imputation, NRS Numeric Rating Scale, PBO placebo, Q2W every 2 weeks. *p < 0.001 versus ETN and PBO

Fig. 4

Impact of baseline psoriasis-associated itch severity on the response rate for ≥ 90% improvement in Psoriasis Area and Severity Index from baseline at the end of the induction period (week 12) in patients with Itch Numeric Rating Scale ≥ 4 at baseline (intent-to-treat population). Pooled data from UNCOVER-2 and 3; NRI; treatment p < 0.001, baseline Itch NRS category p = 0.021, treatment × baseline Itch NRS category (p = 0.148). Itch NRS 4–6, 7–8, and 9–10 indicate the Itch NRS score at baseline. ETN etanercept, IXE ixekizumab, NRI nonresponder imputation, NRS Numeric Rating Scale, PASI Psoriasis Area and Severity Index, PASI 90 ≥ 90% improvement in PASI from baseline, PBO placebo, Q2W every 2 weeks. *p < 0.001 versus ETN and PBO

Fig. 5

Impact of baseline psoriasis-associated itch severity on the response rate for absolute Psoriasis Area and Severity Index score ≤ 2 at week 12 in patients with Itch Numeric Rating Scale ≥ 4 at baseline (intent-to-treat population). Treatment p < 0.001, baseline Itch NRS category p = 0.009, treatment × baseline Itch NRS category (p = 0.183) at the end of the induction period (pooled data from UNCOVER-2 and 3; NRI). Itch NRS 4–6, 7–8, and 9–10 indicate the Itch NRS score at baseline. ETN etanercept, IXE ixekizumab, NRI nonresponder imputation, NRS Numeric Rating Scale, PASI Psoriasis Area and Severity Index, PBO placebo, Q2W every 2 weeks. *p < 0.001 versus ETN and PBO

Fig. 6

Impact of baseline psoriasis-associated itch severity on order of first response based on a ≥ 90% improvement in Psoriasis Area and Severity Index from baseline and a ≥ 4 point improvement in Itch Numeric Rating Scale from baseline at the end of the induction period (12 weeks) in patients with psoriasis-associated Itch NRS ≥ 4 at baseline (intent-to-treat population). Pooled data from UNCOVER-2 and 3; a simultaneous response is defined as the first response in both itch and PASI occurring at the same visit; Itch NRS 4–6, 7–8, and 9–10 indicates the Itch NRS score at baseline. BS baseline, IXE Q2W ixekizumab 80 mg every 2 weeks, n total number of patients in each subgroup to achieve both a ≥ 4 point improvement in Itch NRS and PASI 90 at some point before week 12, NRS numerical rating scale, PASI Psoriasis Area and Severity Index, PASI 90 ≥ 90% improvement in PASI from baseline

Fig. 7

Impact of baseline psoriasis-associated itch severity on response rates for Dermatology Life Quality Index scores 0 or 1 at the end of the induction period (week 12) in patients with psoriasis-associated Itch Numeric Rating Scale ≥ 1 at baseline (intent-to-treat population). Pooled data from UNCOVER-2 and 3; NRI; treatment p < 0.001, baseline Itch NRS category p < 0.001, treatment × baseline Itch NRS category (p = 0.652). Itch NRS 4–6, 7–8, and 9–10 indicate the Itch NRS score at baseline. DLQI Dermatology Life Quality Index, ETN etanercept, IXE ixekizumab, NRI nonresponder imputation, NRS numeric rating scale, PBO placebo, Q2W every 2 weeks. *p < 0.001 versus ETN and PBO

Fig. 8

Impact of baseline itch severity on the response rate for a ≥ 4-point reduction on the Itch Numeric Rating Scale in patients with psoriasis-associated Itch NRS ≥ 4 at baseline (intent-to-treat population) (all treatments combined, UNCOVER-3; MI). For the itch reduction, fewer patients in the Itch NRS 4–6 baseline severity subgroup achieved clinically meaningful improvements compared to those in the Itch NRS 7–8 subgroup at weeks 24, 60, and 108 and compared to those in the Itch NRS 9–10 subgroup at weeks 12, 60, 108, and 156. Itch NRS 4–6, 7–8, and 9–10 indicate the Itch NRS score at baseline

Fig. 9

Impact of baseline itch severity on the response rate for a ≥ 90% improvement in Psoriasis Area and Severity Index from baseline in patients with psoriasis-associated Itch NRS ≥ 4 at baseline (intent-to-treat population) (all treatments combined, UNCOVER-3; MI). For itch reduction, fewer patients in the Itch NRS 4–6 baseline severity subgroup achieved clinically meaningful improvements compared to those in the Itch NRS 7–8 subgroup at weeks 24, 60, and 108 and compared to those in the Itch NRS 9–10 subgroup at weeks 12, 60, 108, and 156. Itch NRS 4–6, 7–8, and 9–10 indicate the Itch NRS score at baseline. MI multiple imputation, NRS Numeric Rating Scale, PASI Psoriasis Area and Severity Index, PASI 90 ≥ 90% improvement in PASI from baseline, PBO placebo, Q2W every 2 weeks, Q4W every 4 weeks

Fig. 10

Impact of baseline itch severity on the response rate for absolute PASI scores ≤ 2 during the long-term extension period (IXE Q2W/IXE Q4W treatment) in patients with psoriasis-associated Itch NRS ≥ 4 at baseline (intent-to-treat population) (all treatments combined, UNCOVER-3; MI). For itch reduction, fewer patients in the Itch NRS 4–6 baseline severity subgroup achieved a clinically meaningful improvement compared to those in the Itch NRS 7–8 subgroup at weeks 24, 60, and 108 and compared to those in the Itch NRS 9–10 subgroup at weeks 12, 60, 108, and 156. Itch NRS 4–6, 7–8, and 9–10 indicate the Itch NRS score at baseline. IXE ixekizumab, MI multiple imputation, NRS Numeric Rating Scale, PASI Psoriasis Area and Severity Index, Q2W every 2 weeks, Q4W every 4 weeks