Treatment-Resistant Psoriatic Arthritis Improved by Ixekizumab

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Although TNF inhibitors can be highly effective, up to 40% of patients with PsA have a suboptimal response to these agents.
Although TNF inhibitors can be highly effective, up to 40% of patients with PsA have a suboptimal response to these agents.

Ixekizumab was found to benefit patients with psoriatic arthritis (PsA) showing poor response to conventional treatment when administered over a 2- or 4-week period, according to a double-blind randomized placebo-controlled trial published in the Lancet.1

Tumor necrosis factor (TNF) inhibitors have become standard therapy in patients with PsA. Although TNF inhibitors can be highly effective, up to 40% of patients with PsA have a suboptimal response to these agents. Other patients have tolerance issues or acquire resistance. Ixekizumab is a monoclonal antibody that targets interleukin-17A, an inflammatory cytokine overexpressed in patients with PsA. It is approved in the United States for moderate to severe plaque psoriasis but not for PsA.

In this study, researchers sought to evaluate the safety and efficacy of ixekizumab in a phase 3 trial (SPIRIT-P2 trial; ClinicalTrials.gov Identifier: NCT02349295) of patients with active PsA who responded poorly or could not tolerate TNF inhibitors.

A total of 363 adults with PsA from 10 countries throughout Asia, Australia, Europe, and North America were recruited and randomly assigned to receive ixekizumab every 2 (n=123) or 4 (n=122) weeks or placebo (n=118). Enrollment was limited to patients who had an inadequate response to or an intolerance of TNF inhibitors and a history of plaque psoriasis. Among these patients, 56% had an inadequate response to 1 TNF inhibitor, 35% had an inadequate response to 2 TNF inhibitors, and 9% could not tolerate TNF inhibitors.

Patients in the ixekizumab cohorts received a loading dose of 160 mg (given as 2 subcutaneous injections) on day 1, then a single 80-mg injection every 2 or 4 weeks for the remainder of the study. The primary end point was the percentage of patients with sustained 20% improvement in American College of Rheumatology response criteria (ACR-20) at 24 weeks.

Approximately half the study participants (44% in the placebo group, 49% and 59% in the ixekizumab every 4- and 2 weeks groups, respectively) were taking conventional disease-modifying anti-rheumatic drugs (DMARDs) at baseline and were permitted to continue concomitant DMARDs throughout the study. At week 16, patients who had an inadequate response to ixekizumab were required to add concomitant DMARDs or modify their DMARD regimen; patients taking placebo were re-randomly assigned to one of the ixekizumab arms.

Safety and efficacy outcomes were evaluated at weeks 1, 2, and 4, and every 4 weeks thereafter. Overall, 87% of patients completed all 24 weeks of treatment. At 24 weeks, 53% of patients who received ixekizumab every 4 weeks had an ACR-20 response compared with 48% of patients who received ixekizumab every 2 weeks and 20% of patients given placebo (P <.0001 for both). The percentage of patients taking ixekizumab who had an ACR-20 response was consistent when patients were stratified according to TNF inhibitor history. Patients in the ixekizumab arms were significantly more likely to show improvement from baseline in the Health Assessment Questionnaire-Disability Index and to have minimal disease activity at week 24 than patients taking placebo. Resolution of enthesitis at 24 weeks was not improved by either ixekizumab regimen.

In patients taking ixekizumab, the most common treatment-related adverse events were injection-site reactions, upper respiratory tract infection, nasopharyngitis, sinusitis, and oropharyngeal pain. However, most cases were mild or moderate. Of note, 8% of patients taking ixekizumab developed grade 1 neutropenia and 1% of patients had grade 2 neutropenia.

The researchers concluded that “Both dosing regimens of ixekizumab…were superior to placebo treatment in improving the signs and symptoms of active PSA and several of its manifestations” in patients who had a suboptimal experience with TNF inhibitors. They noted that their findings support evidence from other studies that have shown interleukin-17A to play a role in the pathogenesis of PsA.

Summary & Clinical Accessibility

Ixekizumab appears to improve symptoms in patients with PsA who have either shown a suboptimal response to TNF inhibitors or have developed a tolerance to them. Although not approved in the United States for PsA, ixekizumab is approved for plaque psoriasis and may have some benefit in patients with plaque psoriasis and comorbid PsA who cannot be treated with TNF inhibitors.

Limitations & Disclosures

This study was limited by its short duration, but the 3-year extension phase is expected to provide better insight into the safety and efficacy of ixekizumab. The study also did not evaluate radiographic progression of the disease.

Eli Lilly and Company funded the study and provided the drug being tested. Several of the authors received grants or personal fees from Eli Lilly and Company, and an Eli Lilly employee provided writing support. Three authors are employees and stockholders of Eli Lilly and Company.


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Reference

  1. Nash P, Kirkham B, Okada M, et al. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomized, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial [published online May 24, 2017]. Lancet. doi:10.1016/S0140-6736(17)31429-0 
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