SUMMARY  

• IXORA-R is a multicenter, randomized, double-blind, parallel-group phase IV study comparing the efficacy and safety of TREMFYA and ixekizumab for the treatment of adult patients with moderate to severe plaque psoriasis (PsO).^1,2
• The primary endpoint, a 100% improvement in Psoriasis Area Severity Index score (PASI 100) response at week 12 was achieved by a significantly greater proportion of patients in the ixekizumab group (41%) than in the TREMFYA group (25%) odds ratio (OR) 2.14 (95% confidence interval [CI] 1.63-2.81, P<0.001).¹
• At week 24, the proportion of patients achieving PASI 100 was similar in both treatment groups, (ixekizumab, 50% [260/520] vs TREMFYA, 52% [265/507]; P=0.41).²

CLINICAL DATA

IXORA-R

Blauvelt et al (2020)^1,2 evaluated the efficacy and safety of ixekizumab and TREMFYA in a multicenter, randomized, double-blind, parallel-group, head-to-head, phase IV study in 1027 patients with moderate to severe plaque PsO.

Study Design/Methods

• Eligible patients (≥18 years of age) had moderate to severe plaque PsO for ≥6 months, Psoriasis Area Severity Index (PASI) ≥12, static Physician’s Global Assessment (sPGA) score ≥3, body surface area (BSA) involvement ≥10%, and were candidates for phototherapy and/or systemic therapy.^1,2
• Patients were excluded if they had a predominant pattern of pustular, erythrodermic and/or guttate forms of PsO; a history of drug-induced PsO or a clinically significant flare of PsO during the 12 weeks before baseline; used tanning booths 4 weeks before baseline; used any biologic agent within specified periods prior to baseline; used any interleukin (IL)-23p19 antagonists; or had any condition or contraindication as addressed in the local labeling for TREMFYA.¹
• Patients were randomized in a 1:1 ratio to receive either subcutaneous (SC) TREMFYA 100 mg at weeks 0, 4, and every 8 weeks thereafter or SC ixekizumab 160 mg loading dose (two 80-mg injections) at week 0 followed by 80 mg every 2 weeks from week 2 to week 12 and then 80 mg every 4 weeks through week 24. To maintain blinding, patients in the TREMFYA group received 1 placebo injection at weeks 0, 2, 6, 8, 10 and 16.^1,2
• An interim analysis was conducted when all patients completed their week 12 study visit or early termination visit.¹
• Patients were assessed at baseline, weeks 1, 2, 4, 6, 8, 10, 12, 16, 20 and 24.^1,2
• The primary endpoint was the proportion of patients who achieved a PASI 100 response at week 12 (complete clearance). The sample size was estimated to have 98% power for testing the superiority of ixekizumab to TREMFYA at a two-sided 5% type I error rate. ^1,2
• Major secondary endpoints included the proportion of patients who achieved: PASI 50 at week 1; PASI 75 at week 2; PASI 90 at weeks 4 and 8; PASI 100 at weeks 4, 8, and 24; and sPGA score of 0 at week 12.¹
• Patient-reported outcomes were assessed using Patient’s Global Assessment of Disease Severity (PatGA), Dermatology Life Quality Index (DLQI), skin pain visual analogue scale (VAS), and the itch numeric rating scale (NRS).¹
• A multiple testing strategy was implemented for superiority testing of primary and major secondary endpoints. Nominal P-values are shown for all analyses.^1,2
• Missing data for binary measures were imputed as nonresponse.^1,2
• A prespecified noninferiority test of ixekizumab vs TREMFYA was performed for PASI 100 at week 24, with a preset noninferiority margin of -11.4%.²
• Exploratory and post hoc analysis were not adjusted for multiple comparisons.^1,2
• Safety data was collected at every visit through week 24 in all randomized patients who received at least one dose of study drug.²

Results

Patient Characteristics

• A total of 1027 patients were randomized to receive TREMFYA (n=507) or ixekizumab (n=520).¹
• Baseline demographics and disease characteristics were comparable between the treatment groups.¹
• At baseline, the mean BSA involved was 23.8% and 24.1%, and the mean PASI score was 19.3 and 19.5 in the TREMFYA and ixekizumab groups, respectively.¹
• At baseline, a total of 50% and 51%, 46% and 43%, and 5% and 6% of patients in the TREMFYA and ixekizumab groups reported sPGA scores of 3, 4, and 5, respectively.¹
• Of the 1027 patients randomized, 91% (459/507) of patients in the TREMFYA arm and 89% (465/520) of patients in the ixekizumab arm completed the study through week 24.²
• Through week 12, 25 TREMFYA-treated patients and 32 ixekizumab-treated patients discontinued study agent.¹
  • Reasons for discontinuation in the TREMFYA group were adverse events (AEs n=7), protocol deviations (n=5), loss to follow-up (n=5), patient withdrawal (n=4), other (n=2), screening failure (n=1), and lack of efficacy (n=1).
  • Reasons for discontinuation in the ixekizumab group were patient withdrawal (n=11), AEs (n=6), lost to follow-up (n=6), protocol deviations (n=3), other (n=3), lack of efficacy (n=2), and screening failure (n=1).

Efficacy

• At week 12, a PASI 100 response was achieved by a significantly greater proportion of patients in the ixekizumab group (41% [215/520]) than in the TREMFYA group (25% [126/507]); treatment difference: 16.5 percentage points (95% confidence interval [CI] 10.8-22.2); odds ratio: 2.14 (95% CI, 1.63-2.81); P<0.001.¹
• Major secondary endpoints are described in Table: IXORA-R Primary and Major Secondary Endpoints - Intent-to-Treat Population Through Week 12.

• At week 24, similar percentages of patients receiving TREMFYA and ixekizumab achieved PASI 100 (52% [265/507] vs 50% [260/520]; P=0.41).This superiority test was last in the hierarchical testing scheme therefore does not affect the other major secondary endpoints.²
• At week 24, the PASI 100 result for ixekizumab was noninferior to TREMFYA with a treatment difference of -2.3% (95% CI, -8.4 to 3.8).²

Patient-Reported Outcomes

• At week 1, more ixekizumab-treated patients reported PatGA scores of 0 or 1 vs TREMFYA-treated patients (7% [36/520] vs 2% [10/507]; P<0.001).¹
  • The greatest differences between ixekizumab and TREMFYA in patient-reported PatGA scores of 0 or 1 occurred at weeks 4 and 6 (P<0.001) and remained significant through week 12 (P=0.011).
• More ixekizumab-treated patients reported DLQI of 0 or 1 (ie, no impact of disease on quality of life) as early as week 4 vs TREMFYA-treated patients (34% [175/520] vs 21% [106/507]; P<0.001).¹
• Of patients with baseline skin pain VAS scores >0, more ixekizumab-treated patients vs TREMFYA-treated patients reported skin pain VAS score of 0 (no skin pain) at week 8 (23% [118/505] vs 15% [70/479]; P<0.001).¹
• Significant differences were reported for ixekizumab vs TREMFYA through week 12 for PatGA (0, 1) (P<0.001), DLQI (0, 1) (P=0.029), and for itch NRS score of 0 (P<0.001).¹
• At week 4 through week 16, an itch NRS score of 0 was reported in more ixekizumab treated patients compared to TREMFYA treated patients (41% [210/515] vs 33% [164/495]; P<0.05).²
• For patients who achieved a sPGA score of 0 or 1, PGA score or 0 or 1 and a DLQI score of 0 or 1, there were no significant difference noted among ixekizumab treated patients and TREMFYA treated patients from week 16 through week 24.²

Speed of onset of treatment effects

• Ixekizumab treated patients reached the 50%, 75%, 90%, and 100% PASI improvement thresholds more rapidly than TREMFYA treated patients.²
• The median time to first achievement of PASI 50 and PASI 75 was 2 weeks sooner for ixekizumab treated patients than TREMFYA treated patients (P<0.001).²
• The median time to achievement of PASI 90 was 2.1 weeks sooner with ixekizumab treated patients than TREMFYA treated patients (P<0.001).²
• The median time to achievement of PASI 100 was 7.5 weeks sooner with ixekizumab treated patients versus TREMFYA treated patients (12.6 weeks vs 20.1 weeks; P<0.001).²
• The median times at which ixekizumab treated patients improved quality of life (DLQI of 0 or 1) and eliminated itch (NRS of 0) was sooner than that of TREMFYA treated patients (6.3 weeks vs 12.1 weeks; P=0.002) and (16.1 weeks vs 20.3 weeks; P=0.001), respectively.²

Cumulative benefit of treatment

• Patients receiving ixekizumab experienced more days of complete clearance, days of almost complete clearance, days without psoriasis impacting their quality of life and days without itch than patients treated with TREMFYA.²
  • PASI 100: 55.6 days vs 42.2 days; P<0.001
  • PASI 90: 95.2 days vs 78.6 days; P<0.001
  • DLQI of 0 or 1: 84.9 days vs 77.4 days; P=0.026
  • Itch NRS of 0: 51.2 days vs 41.5 days; P=0.002
• An analysis exploring the benefit of achieving PASI 100 response early vs late showed that achieving a PASI 100 response earlier was associated with more days of DLQI of 0 or 1, regardless of treatment.²

Safety

• Safety data including the proportion of patients reporting treatment-emergent adverse events (TEAEs) and AEs leading to discontinuation were reported for TREMFYA- and ixekizumab-treated patients through week 24 (Table: Safety Outcomes - Safety Population Through Week 24).²
• Reports of injection-site reactions were greater in ixekizumab-treated patients with a frequency of 13% (67/519) and 4% (19/506) in TREMFYA-treated patients. Most injection-site reactions were classified as mild to moderate.²

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 24 December 2024.

Data included in this response are from a head-to-head clinical trial of TREMFYA in patients with moderate to severe plaque psoriasis.