Efficacy and safety of ixekizumab in the treatment of various domains of psoriasis and psoriatic arthritis

The use of interleukin-17 (IL-17) inhibitors, tumor necrosis factor inhibitors, and Janus kinase (JAK) inhibitors have recently been approved by the Group for Research and Assessment for Psoriasis and Psoriatic Arthritis (GRAPPA) for the treatment of all patients with psoriatic arthritis (PsA).¹ Ixekizumab (IXE) is a human monoclonal antibody that binds IL-17 and inhibits the release of pro-inflammatory cytokines and chemokines.¹

IXE was first approved in 2016 by the U.S. Food and Drug Administration (FDA) for the treatment of patients with moderate to severe plaque psoriasis,² followed by its approval for treatment of patients with active PsA in 2017³ and treatment of the pediatric population with moderate to severe plaque psoriasis in 2020.⁴ In addition, the National Institute for Health and Care Excellence recommended IXE for treating moderate to severe plaque psoriasis in 2017⁵ and PsA in 2018.⁶

Several trials have reported the safety and efficacy of IXE for different indications of psoriasis and PsA in different populations. Here, we summarize the key findings from some of these trials covering the efficacy of safety data of IXE for different domains of psoriasis and PsA.        

Psoriatic arthritis^1,7

An integrated safety analysis by Deodhar et al.¹ included patient data from four clinical trials (SPIRIT‑P1, NCT01695239; SPIRIT‑P2, NCT02349295; SPIRIT‑P3, NCT02584855; and SPIRIT‑H2H, NCT03151551) in patients who had active PsA and had received at least one dose of IXE. A total of 1,401 patients with a cumulative IXE exposure of 2,247.7 patient-years were included. The cohort had a mean age of 49.1 years, and just over half (51.5%) of the patients were female. Most patients (80.7%) reported treatment-emergent adverse events (TEAEs), although these were either mild (32.9%) or moderate (39.7%). Over half of the patients reported infections, again these were typically mild or moderate. The most common TEAEs, mostly infections, included injection site reaction (18.6%), nasopharyngitis (14.4%), upper respiratory tract infection (13.3%), bronchitis (6.5%), sinusitis (5.5%), urinary tract infection (4.9%), and pharyngitis (3.9%). The exposure-adjusted incidence rate (EAIR) per 100 patient years was 6.0 for serious adverse events. TEAEs showed an increased trend during the first year of IXE exposure (EAIR, 87.0) and decreased over time (EAIR, 67.3 in Year 3).¹

The frequency of serious infections was low (2%) and continued to be comparatively stable for each of the 1-year periods. Low EAIR was observed for malignancies (0.7), inflammatory bowel disease (0.1), depression (1.6), and major adverse cerebro-cardiovascular events (0.5). The frequencies of opportunistic infections and Candida infections were also low (EAIR, 1.8 and 2.0, respectively).¹ 

Eder et al.⁷ investigated the differences in responses to IXE between male and female patients with PsA. Their analysis included pooled data from the SPIRIT-P1 and SPIRIT-P2 phase III trials, which randomized patients to IXE 80 mg every 4 weeks (Q4W), 80 mg every 2 weeks (Q2W), and placebo for 24-weeks. A total of 679 patients were included, of which 45.7% were male and the mean age was 51 years. Comparison of baseline characteristics showed that female patients were older (51.9 years vs 49.9 years) and also had a higher body mass index (31.2 kg/m² vs 29.9 kg/m²) in the IXE Q4W arm compared with male patients. Lower creatinine-reactive protein levels (p = 0.037) at baseline were observed in female patients in the IXE Q2W arm compared with male patients. Finally, significantly higher Health Assessment Questionnaire Disability Index (HAQ-DI) scores were noted in female patients across all arms (placebo, p < 0.001; IXE Q4W, p = 0.003; IXE Q2W, p = 0.003) and higher Leeds Enthesitis Index (LEI) scores were recorded in female patients in the placebo arm (p = 0.021) and the IXE Q4W arm (p = 0.031) compared with male patients.⁷

Efficacy of IXE was measured as the proportion of patients achieving ≥20%, ≥50%, or ≥70% improvement from baseline through Week 156 according to the American College of Rheumatology (ACR) criteria, minimal disease activity (MDA), and Disease Activity Index for Psoriatic Arthritis (DAPSA). Female patients had significantly lower response rates through Week 156 for ACR50, ACR70, MDA, and DAPSA low disease activity response rates. Female patients treated with IXE also reported minimal improvement particularly for pain, Patient’s Global Assessment (PtGA), and HAQ-DI compared with their male counterparts.⁷

Moderate to severe psoriasis⁸

Efficacy of IXE of nail and skin clearance was studied by Elewski et al.³ in an analysis of head-to-head IXE trials with other biologics (etanercept, guselkumab, adalimumab, and ustekinumab) for moderate to severe psoriasis and PsA. The analysis included data from the UNCOVER-1 (NCT01474512) and UNCOVER-2 (NCT01597245) trials, which were combined after 12 weeks, and UNCOVER-3 (NCT01646177), IXORA-R (NCT03573323), IXORA-S (NCT02561806), and SPIRIT-H2H (NCT03151551) trials. Complete resolution of psoriasis was defined as 100% improvement from baseline (a Psoriasis Areas and Severity Index [PASI] of 100) and complete resolution of nail psoriasis as either Physician’s Global Assessment (PGA) five-point scale of 0 or Nail Psoriasis Severity Index (NAPSI) of 0. The trial populations were largely similar at baseline, though differences were observed, such as lower psoriasis duration in SPIRIT-H2H and a lower proportion of males in IXORA-R and SPIRIT-H2H compared with the other trial populations.

IXE resulted in a significantly greater simultaneous clearance of nail and skin at 12 weeks compared with etanercept (UNCOVER-2, p < 0.0001; UNCOVER-3, p < 0.001). IXE also showed a numerically greater simultaneous nail and skin clearance compared with guselkumab in IXORA-R (p = 0.079 at 24 weeks) and a statistically significant clearance compared with ustekinumab in IXORA-S (p < 0.001 at 24 weeks; p < 0.001 at 52 weeks) and adalimumab in SPIRIT-H2H (p = 0.006 at 24 weeks; p = 0.007 at 52 weeks). Across the five head-to-head trials, IXE accomplished a higher rate of simultaneous nail and skin clearance (28.6–45.9% and 40.5–51.4% of patients by Weeks 24 and 52, respectively), which strengthens the existing evidence on IXE’s ability to achieve high levels of efficacy in multiple domains of psoriatic disease.

Pediatric moderate to severe plaque psoriasis⁹

IXORA-PEDS (NCT03073200), a trial with a double blind randomized 12-week period followed by treatment of both arms with IXE in a 48-week open label maintenance period then an extension period through to Week 108, was undertaken by Paller et al.⁴ IXORA-PEDS aimed to evaluate the long-term efficacy and safety of IXE for moderate to severe psoriasis in pediatric patients. Participants were aged 6 to <18 years with moderate to severe plaque psoriasis defined by PASI ≥12, static PGA (sPGA) score ≥3, and a psoriasis-affected body surface area of ≥10% at baseline. Efficacy endpoints at Week 108 included the percentage of patients who achieved PASI75, PASI90, or PASI100, a sPGA score of 0 (indicating clear or no signs) or 1 (indicating almost clear or intermediate between mild and clear signs of psoriasis), and an improvement of ≥4 points from baseline in the Itch Numeric Rating Scale (NRS).

A total of 171 patients, with a mean age of 13.5 years, were included. Patients achieved and sustained the efficacy endpoints through Week 108, with 91.7%, 79.0%, and 55.1% of patients achieving PASI75, PASI90, and PASI100, respectively. Similarly, a sPGA score of 0 or 1 was achieved by 78.3% and a sPGA score of 0 was achieved by 52.4% of patients. An Itch NRS improvement of ≥4 points was reported by 78.5% of patients. Clearance of nail psoriasis, palmoplantar psoriasis, scalp psoriasis, and genital psoriasis was reported by 68.1%, 90.0%, 76.2%, and 87.5% of patients, respectively. Mild and moderate TEAEs were experienced by 40.3% and 6.1% of patients, respectively, while 7.7% reported serious adverse events. A total of 2.6% of patients discontinued treatment due to an AE. There were no new cases of Candida infections reported, and treatment-emergent infections were reported by 74% of patients.

Conclusion

This summary of the key data from clinical trials evaluating the safety and efficacy of IXE demonstrates that IXE offers improvements across patient-reported outcomes and objective measures of complete skin clearance of psoriasis, including clearance in challenging-to-treat body parts, as well as in the pediatric population with moderate to severe plaque psoriasis The safety and tolerability of IXE provides clinically meaningful evidence to physicians who treat patients in the long-term with PsA. High response rates of simultaneous nail and skin clearance were observed with IXE compared with other biologics (etanercept, guselkumab, ustekinumab, and adalimumab) for patients with moderate to severe psoriasis and PsA.

Understanding the differences in response rates between male and female patients with PsA is needed to improve outcomes in patients with prior inadequate response. Further studies are also needed to investigate the effect of IXE on additional patient-reported outcomes and the effectiveness and safety of IXE in children with psoriasis in real-world settings.