Continuous dosing versus interrupted therapy with ixekizumab: an integrated analysis of two phase 3 trials in psoriasis

Abstract

Background: Continuous treatment is recommended for patients with moderate-to-severe psoriasis; however, treatment may need to be interrupted in routine clinical practice.

Objective: To assess outcomes in patients continuously treated with ixekizumab versus those who interrupted therapy and were subsequently retreated with ixekizumab (IXE).

Methods: This analysis used data pooled from two phase 3 trials, UNCOVER-1 and UNCOVER-2. Patients were randomized to placebo (PBO), IXE every 4 (Q4W) or IXE every 2 weeks (Q2W) for 12 weeks. Patients with a static Physician's Global Assessment (sPGA) 0, 1 at Week 12 were rerandomized to IXEQ4W, IXE every 12 weeks (not presented) or PBO. We examined outcomes in patients who were continuously treated (IXEQ2W/IXEQ4W; IXEQ4W/IXEQ4W) or withdrawn (IXEQ2W/PBO; IXEQ4W/PBO), and in patients who were withdrawn and retreated with IXEQ4W for 24 weeks after disease relapse (sPGA ≥3).

Results: A total of 1226 treated patients achieved an sPGA 0, 1 at Week 12 and entered the maintenance phase; of these patients, 402 and 416 were rerandomized to PBO and IXEQ4W, respectively. Among patients interrupting treatment, 157 (82.2%) of IXEQ4W/PBO and 176 (83.4%) of IXEQ2W/PBO had an sPGA ≥3 by Week 60; median time to relapse was approximately 20 weeks irrespective of induction dose. At Week 60, continuously treated patients maintained high levels of PASI and sPGA responses (90.0% PASI 75 IXEQ2W/IXEQ4W; 81.9% sPGA 0, 1 IXEQ2W/IXEQ4W, non-responder imputation). After 24 weeks of retreatment with IXEQ4W (IXEQ2W/PBO/IXEQ4W and IXEQ4W/PBO/IXEQ4W), 87.0% (107 of 123) and 95.1% (97 of 102) (observed), respectively, of patients recaptured PASI 75 and 70.7% (104 of 147) and 82.3% (107 of 130) (observed) recaptured an sPGA 0, 1. Overall, adverse events in continuously treated and retreated patients were comparable.

Conclusion: High levels of response were sustained with continuous ixekizumab treatment through 60 weeks. Most patients who were withdrawn experienced disease relapse, and most of those patients recaptured response after 24 weeks of retreatment.

Figure 1

Study Diagram. The study diagram is shown. In UNCOVER‐1 and UNCOVER‐2, the 12‐week induction period was followed by a 48‐week randomized withdrawal (maintenance) period (weeks 12–60), whereby ixekizumab responders at Week 12 (sPGA = 0 or 1) were rerandomized to placebo (withdrawal group), IXEQ4W (continuously treated groups) or ixekizumab 80 mg every 12 weeks (IXEQ12W; not included in analyses). Patients in the withdrawal group who experienced disease worsening (sPGA ≥3 [relapse]) during the maintenance period received open‐label IXEQ4W (retreatment group). Although the maintenance period ended at Week 60, additional data from the long‐term extension period were used up to and including Week 84 to allow for 24 weeks of retreatment. At the time of this database lock, all patients completed Week 60. Not all retreated patients had the opportunity to receive 24 weeks of retreatment. ETN, etanercept; IXE Q2W, ixekizumab 80 mg every 2 weeks; IXE Q4W, ixekizumab 80 mg every 4 weeks; IXEQ12W, ixekizumab 80 mg every 12 weeks; n, number in group; PBO, placebo; R, randomize.

Figure 2

Response at Week 60 in Patients Continuously Treated and Withdrawn from Ixekizumab. Per cent responders using non‐responder imputation is shown. (a) IXEQ2W; (b) IXEQ4W. The numbers above the bars are the per cent responders. IXE, ixekizumab; PASI 75, 75% reduction in the Psoriasis Area and Severity Index; PASI 90, 90% reduction in the Psoriasis Area and Severity Index; PASI 100, 100% reduction in the Psoriasis Area and Severity Index; PBO, placebo; Q2W, every 2 weeks; Q4W, every 4 weeks; sPGA, static Physician's Global Assessment.

Figure 3

Mean PASI and Itch NRS Score Over Time. Data, including the induction period, are from sPGA 0,1 responders at Week 12. (a) PASI; (b) Itch NRS. The number of patients in each group at each time is shown at the bottom of the graph. NRS, Numeric Rating Scale; IXEQ2W, 80 mg ixekizumab every 2 weeks; IXEQ4W, 80 mg ixekizumab every 4 weeks; PASI, Psoriasis Area and Severity Index; PBO, placebo; IXE Q2W, ixekizumab 80 mg every 2 weeks; IXE Q4W, ixekizumab 80 mg every 4 weeks; sPGA, static Physician's Global Assessment; Q2W, every 2 weeks; Q4W, every 4 weeks.

Figure 4

Efficacy in Relapsed and Retreated Patients. (a) sPGA; (b) PASI. Patients were treated with ixekizumab 80 mg Q2W. At Week 12, responders (sPGA 0, 1) were rerandomized to placebo. At relapse, patients were retreated with ixekizumab 80 mg Q4W. Relapse Week 0 includes all relapse patients regardless of which week the relapse occurred. The PASI summary includes only PASI 75 non‐responders at relapse Week 0. The x‐axis shows retreatment week. Percent responders (observed) with 95% CIs are shown. The upper and lower error bars represent the high and low values, respectively, of the 95% CI. CI, confidence interval; Q2W, every 2 weeks; Q4W, every 4 weeks; PASI 75, 75% reduction in the Psoriasis Area and Severity Index; PASI 90, 90% reduction in the Psoriasis Area and Severity Index; PASI 100, 100% reduction in the Psoriasis Area and Severity Index; PBO, placebo; sPGA, static Physician's Global Assessment.

Figure 5

PASI Response Over Time by Treatment‐emergent Antidrug Antibody Status. Date are from LOCF responders at Week 12 (sPGA 0, 1) who relapsed (sPGA ≥3) during maintenance period and received IXEQ4W retreatment (UNCOVER‐1 and UNCOVER‐2 pooled data set). TE‐ADA positive = either in the induction period or in the retreatment period; TE‐ADA negative = in both the induction period and the retreatment period. The IXEQ2W/PBO + IXEQ4W group is shown. The upper and lower error bars represent the high and low values, respectively, of the 95% CI. IXE Q2W, 80 mg of ixekizumab every 2 weeks; IXE Q4W, 80 mg of ixekizumab every 4 weeks; LOCF, last observation carried forward; PASI, Psoriasis Area and Severity Index; PBO, placebo; sPGA, static Physician's Global Assessment; TE‐ADA, treatment‐emergent antidrug antibody.