A head-to-head comparison of ixekizumab vs. guselkumab in patients with moderate-to-severe plaque psoriasis: 24-week efficacy and safety results from a randomized, double-blinded trial

Abstract

Background: Significantly more patients with moderate-to-severe plaque psoriasis treated with the interleukin (IL)-17A inhibitor ixekizumab vs. the IL-23p19 inhibitor guselkumab in the IXORA-R head-to-head trial achieved 100% improvement in Psoriasis Area and Severity Index (PASI 100) at week 12.

Objectives: To compare skin and nail clearance and patient-reported outcomes for ixekizumab vs. guselkumab, up to week 24.

Methods: IXORA-R enrolled adults with moderate-to-severe plaque psoriasis, defined as static Physician's Global Assessment ≥ 3, PASI ≥ 12 and involved body surface area ≥ 10%. Statistical comparisons were performed using the Cochran-Mantel-Haenszel test stratified by pooled site. Time-to-first-event comparisons were performed using Kaplan-Meier analysis, and P-values were generated using adjusted log-rank tests stratified by treatment group. Cumulative days at clinical and patient-reported responses were compared by ancova. The trial was registered with ClinicalTrials.gov (NCT03573323).

Results: Of the 1027 patients randomly assigned, 90% completed the trial (465 of 520 ixekizumab and 459 of 507 guselkumab). As early as week 2 and through week 16, more patients on ixekizumab achieved PASI 100 (P < 0·01). At week 24, ixekizumab was noninferior to guselkumab (50% vs. 52%, difference -2·3%), with no statistically significant difference in PASI 100 (P = 0·41). More patients receiving ixekizumab showed completely clear nails at week 24 (52% vs. 31%, P = 0·007). The median time to first PASI 50/75/90 and PASI 100 were 2 and 7·5 weeks shorter, respectively, for patients on ixekizumab vs. guselkumab (P < 0·001). Patients on ixekizumab also had a greater cumulative benefit, with more days at PASI 90 and 100, with Dermatology Life Quality Index of 0 or 1, and itch free (P < 0·05). The frequency of serious adverse events was 3% for each group, with no new safety signals.

Conclusions: Ixekizumab was noninferior to guselkumab in complete skin clearance and superior in clearing nails at week 24. Ixekizumab cleared skin more rapidly in patients with moderate-to-severe plaque psoriasis, with a greater cumulative benefit, than guselkumab. Overall, the safety findings were consistent with the known safety profile for ixekizumab.

Figure 1

Disposition of the patients. Details are given according to the CONSORT statement for reporting randomized controlled trials.

Figure 2

Clinical endpoints through week 24 in the ixekizumab (IXE) and guselkumab (GUS) groups. The data are percentages with 95% confidence intervals (CIs). Proportions of patients achieving (a) 100% improvement in Psoriasis Area and Severity Index (PASI 100), (b) static Physician’s Global Assessment (sPGA) score of 0, (c) PASI 90, (d) PASI 75 and (e) PASI 50. The box in panel (a) indicates the primary endpoint (PASI 100 at week 12). Nonresponder imputation was used for missing data. The 95% CIs were constructed using the asymptotic method, without continuity correction (i.e. normal approximation to the binomial distribution). ***P < 0·001, **P < 0·01, *P < 0·05. A prespecified noninferiority test of IXE vs. GUS was performed for the proportion of patients achieving PASI 100 at week 24 (preset noninferiority margin: −11·4%). IXE was noninferior to GUS for PASI 100 at week 24: IXE 50%, GUS 52%, difference −2·3% (95% CI −8·4 to 3·8%). A portion of the data shown here was previously reported, including PASI 100 at weeks 4, 8 and 12; sPGA score of 0 at week 12; PASI 90 at weeks 4 and 8; PASI 75 at week 2 and PASI 50 at week 1. ³

Figure 3

Physician’s Global Assessment of Fingernail Psoriasis (PGA‐F) response at week 24 in the ixekizumab (IXE) and guselkumab (GUS) groups. Data are percentages with 95% confidence intervals. Nonresponder imputation was used for missing data. The 95% confidence intervals were constructed using the asymptotic method, without continuity correction (i.e. normal approximation to the binomial distribution). n = number of patients with PGA‐F ≥ 3 (left and centre columns) or number of patients with PGA‐F> 0 (right column).

Figure 4

Visual improvement of skin and nails after treatment with ixekizumab (IXE) or guselkumab (GUS). (a) IXE patient 1 had a baseline Psoriasis Area and Severity Index (PASI) of 27·4 and achieved 86% and 98% improvement after 12 and 24 weeks of IXE, respectively. GUS patient 2 had a baseline PASI of 33·8 and achieved 89% and 98% improvement after 12 and 24 weeks of GUS, respectively. (b) IXE patient 3 had a baseline PASI of 13·7 and achieved 93% and 96% improvement after 12 and 24 weeks of IXE, respectively. GUS patient 4 had a baseline PASI of 15·0 and achieved 89% and 100% improvement after 12 and 24 weeks of GUS, respectively. Percentage PASI improvements for patients 1, 2, 3 and 4 are shown in Table S1 (see Supporting Information). (c) Patient scores on the Physician’s Global Assessment of Fingernail psoriasis (PGA‐F) were 3 at baseline and 1 after 24 weeks of IXE.

Figure 5

Comparison of the speed of improvement in clinical and patient‐reported outcomes. (a) Median percentage improvement from baseline in Psoriasis Area and Severity Index (PASI). Data are shown as the median percentage with interquartile range. Modified baseline observation carried forward was used for missing data. Dashed lines mark 50%, 75%, 90% and 100% thresholds for improvement in PASI. (b) Median time to first achievement of PASI 50/75/90/100, Dermatology Life Quality Index (DLQI) of 0 or 1 and itch numerical rating scale (NRS) score of 0. Data are shown as the median (95% confidence interval) and were determined using Kaplan–Meier analyses. The intention‐to‐treat population was used for all analyses except for itch NRS score of 0, which used the intention to treat with baseline Itch NRS > 0. P ≤ 0·001 for each pair of medians compared in panel (b) based on adjusted log‐rank test stratified by treatment. GUS, guselkumab; IXE, ixekizumab.

Figure 6

Cumulative benefit of ixekizumab (IXE) vs. guselkumab (GUS) for clinical and patient‐reported outcomes. Cumulative days of the indicated response over the 24‐week study for 100% and ≥ 90% Psoriasis Area and Severity Index (PASI) improvement, DLQI of 0 or 1, and itch numerical rating scale (NRS) score of 0 for IXE vs. GUS treatments. Data are shown as the least squares mean for normalized area‐under‐the‐curve measurements, with 100% representing the maximum area for each measure, multiplied by the 168‐day study duration. Error bars show 95% confidence intervals. ***P < 0·001, **P < 0·01, *P < 0·05 vs. GUS. P‐values were calculated using ancova analysis after adjusting for baseline scores and pooled sites.

Figure 7

Effect of period (42‐day intervals) of achievement of first 100% improvement in Psoriasis Area and Severity Index (PASI 100) on cumulative benefit for Dermatology Life Quality Index (DLQI) of 0 or 1, regardless of drug. Days from randomization to first achieved PASI 100 vs. cumulative days of DLQI score of 0 or 1 over the 24‐week study. The data are shown as the least squares mean for normalized area‐under‐the‐curve measurements, with 100% representing the maximum area for each measure, multiplied by the 168‐day study duration. Error bars show 95% confidence intervals. ^# P < 0·05 vs. 85–126 days; ^† P < 0·01 vs. 127‐184 days; ^‡ P < 0·001 vs. No PASI 100. P‐values were calculated using ancova analysis after adjusting for baseline scores and pooled sites.