Lack of Dose Response Found for Experimental IL-6 Inhibitor in PsA

Data from a Phase 2b clinical trial supported the safety and efficacy of clazakizumab in active psoriatic arthritis (PsA) with or without methotrexate, according to results recently published in Arthritis & Rheumatology.¹ However, improvements in cutaneous manifestations were minimal, and no clear dose-response to treatment was found. 

Clazakizumab is a recombinant humanized antihuman interleukin-6 (IL-6) receptor monoclonal antibody. The study, led by Dr Philip Mease of Swedish Medical Center and the University of Washington in Seattle, was the first controlled trial to demonstrate a beneficial effect in targeting the IL-6 cytokine in PsA. 

The treatment of PsA improved substantially when therapies targeting anti-tumor necrosis factor-α (TNF-α) were added to the armamentarium. TNF- α inhibitors have been demonstrated to be efficacious across all PsA domains, including peripheral arthritis, axial involvement, enthesitis, dactylitis, plaque psoriasis and nail psoriasis.² 

However, a significant minority of patients either respond inadequately to TNF-α inhibitors or do not exhibit a sustained response,² leading to the investigation of additional pharmacotherapies that target alternate pathways.

Regarding the selection of IL-6 as a drug target in PsA, Dr Mease and colleagues noted that “serum levels of IL-6 are increased in patients with psoriasis, and the upregulation of pro-inflammatory cytokines, including IL-6, in PsA synovial tissue has been reported. In patients with PsA, IL-6 levels correlate with the number of affected joints, elevation of the erythrocyte sedimentation rate, and C-reactive protein. Additionally, there have been a few case reports of successful use of anti-IL-6 receptor biologic therapy to treat PsA, although results have been conflicting.”

The study comprised 2 phases: a 24-week double-blind period and a subsequent open-label, long-term extension period. In Part 1, 165 patients with active PsA who had responded inadequately to non-steroidal anti-inflammatory drugs and/or non-biologic disease-modifying antirheumatic drugs were randomized to subcutaneous placebo or clazakizumab 25 mg, 100 mg, or 200 mg every 4 weeks, with or without methotrexate. Patients who had previously received biologic therapies for PsA, as well as those with abnormal laboratory results, were excluded.

Part 2 consisted of a continuation of randomized treatment from part 1; however, patients with inadequate disease control were permitted to receive rescue therapy as long as it was not initiated within 4 weeks of the week 24 assessment.

The primary endpoint of the trial, defined as the proportion of patients with American College of Rheumatology (ACR) 20 response at week 16, was achieved for more than half (52.4%) of patients who received 100-mg clazakizumab compared with 29.3% those who received placebo. Secondary efficacy endpoints consisted of ACR 20 response at weeks 16 and 24. 

For patients in the 25 mg clazakizumab and 200 mg clazakizumab arms, ACR20 responses at week 16 were 46.3% and 39.0% respectively, results which were not statistically significant. Patients treated with clazakizumab demonstrated significantly improved musculoskeletal manifestations, including enthesitis as measured by SPARCC enthesitis index scores (assessing 18 entheses), and dactylitis as measured by numbers of dactylitic digits. 

Efficacy with clazakizumab treatment versus placebo was observed for other measures of joint disease, including ACR50, ACR70, and DAS28, but did not reach statistical significance.

After the study began, a new regulation stipulated that all new patients receive a stable oral dose of methotrexate in order to reduce the risk of radiographic progression over 24 weeks in patients not receiving active treatment. In an editorial in Nature Reviews Rheumatology, Dr Oliver FitzGerald of the Department of Rheumatology in Dublin’s St Vincent’s University Hospital speculated that the lack of demonstration of a dose response, the failure to demonstrate statistically significant improvements in ACR50 or ACR70 measures, and an unexpectedly high placebo response at week 20 may have been influenced by that change.³

Summary & Clinical Applicability

“The results from the phase IIb study of IL-6 blockade in PsA are sufficiently promising to continue the IL-6-targeting drug development programme,” wrote Dr FitzGerald in his editorial.

Dr FitzGerald suggested that a research focus on baseline predictors of treatment response might elucidate the role of IL-6 in PsA. “It may well turn out that there are patients with PsA, perhaps with certain disease characteristics, whose disease is a least partly driven by IL-6. The early identification of such patients and the introduction of appropriate IL-6-blocking therapy would help to prevent the long-term consequences of persistent inflammatory disease.”

Limitations & Disclosures

This study was supported and funded by Bristol-Myers Squibb.

References

1.     Mease P, Gottlieb AB, Berman A, et al. The Efficacy and Safety of Clazakizumab, an Anti-Interleukin-6  Monoclonal Antibody, in a Phase 2b Study of Adults with Active Psoriatic Arthritis. Arthritis Rheumatol. 2016;  Accepted article published online ahead of print, doi: 10.1002/art.39700

2.     Coates LC, Kavanaugh A, Mease PJ, et al. Group for Research and Assessment of Psoriasis and Psoriatic  Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis. Arthritis Rheumatol Hoboken NJ.  2016;68(5):1060-1071.

3.     FitzGerald O. Spondyloarthropathies: IL-6 blockade in psoriatic arthritis – a new therapeutic option? Nat Rev  Rheumatol. 2016;12(6):318-319.