In a phase-3 clinical trial, patients with psoriatic arthritis for whom standard-of-care pharmaceutical treatments have provided no lasting relief, experienced a significant reduction in symptoms, when they were given a new drug, ixekizumab.
The 24-week randomised, double-blind, placebo-controlled trial was conducted at 109 centres in 10 countries and involved more than 300 adults for whom available biologic drugs – the standard of care for this painful autoimmune condition – had lost their efficacy or lacked it in the first place.
Left untreated or treated unsuccessfully, psoriatic arthritis can progress to induce severe joint and bone damage and functional disability, said Dr Mark Genovese, Stanford professor of immunology and rheumatology and the study's senior author.
In the trial, known as SPIRIT-P2, 314 patients received regular injections of either a biologic drug, ixekizumab, or a placebo for 24 weeks. The trial was sponsored by Eli Lilly & Co, the drug's manufacturer.
Treatment with ixekizumab resulted in more than 50% of the participants having at least a 20% reduction in the number of tender and swollen joints, significantly outperforming the placebo, said Genovese. Few serious adverse events were reported for patients receiving the drug or the placebo, he said.
About one in 200 adults in developed countries lives with psoriatic arthritis. Like the more common rheumatoid arthritis, which affects nearly 2% of the population, psoriatic arthritis is an inflammatory autoimmune disease whose symptoms – including stiffness, pain and swelling of several joints – typically emerge between the ages of 30 and 50.
The two syndromes differ, though, in their constellation of symptoms. For example, psoriatic arthritis manifests most often in the lower extremities and is associated with the autoimmune skin condition called psoriasis, in which raised red, scaly patches appear on the skin. Although psoriatic rashes most often precede the onset of the arthritic stage, the reverse can also be the case.
Three of the 10 top-selling drugs in the US in dollar sales – adalimumab, etanercept and infliximab – are biologics prescribed for psoriatic arthritis as well as for the more common rheumatoid arthritis. These three drugs share a common property: They block the action of a pro-inflammatory substance called tumor necrosis factor. Secreted by various immune cells, TNF stimulates the immune response and accompanying inflammation.
However, despite the availability of TNF inhibitors, "only about half of psoriatic arthritis patients who are given TNF inhibitors get better," said Genovese.
Although the ultimate cause of the disease remains unknown, there was a good clinical rationale for hoping it might be responsive to ixekizumab. For the last decade or so, Genovese said, another pro-inflammatory substance called IL-17 has been drawing the attention of immunologists focusing on psoriasis and psoriatic arthritis.
Ixekizumab works by blocking IL-17. The drug, an injectable monoclonal antibody, is already commercially available for the treatment of psoriasis, for which it has been remarkably effective, said Genovese. And in an earlier Lilly-sponsored phase-3 trial, ixekizumab was shown to be effective for psoriatic arthritis patients who had not yet been treated with biological drugs such as TNF inhibitors. (Another approved monoclonal antibody that targets IL-17, secukinumab, was approved in 2016 for psoriatic arthritis.)
Over the 24-week duration of the latest trial, 109 participants received ixekizumab every two weeks; 94 received placebo injections every two weeks; and 111 alternated every two weeks between getting injections of ixekizumab and the placebo.
While 19.5% of patients who received only the placebo injections were judged to have met the trial's specified clinical endpoint – at least a 20% reduction in the number of tender and swollen joints – the response rate among those getting the real drug every four weeks was 53.3%. Those getting the drug every two weeks didn't do any better and were slightly more prone to side effects, such as a mild reaction at the injection site.
Although any treatment that works by blocking the immune system's ability to mount an inflammatory response should be carefully monitored for its potential to render the body vulnerable to infectious disease, there were few observed differences in this category between recipients of placebo versus active drug given every four weeks, Genovese said.
Summary
Background: Patients who have had inadequate response to tumour necrosis factor inhibitors have fewer treatment options and are generally more treatment refractory to subsequent therapeutic interventions than previously untreated patients. We report the efficacy and safety of ixekizumab, a monoclonal antibody that selectively targets interleukin-17A, in patients with active psoriatic arthritis and previous inadequate response to tumour necrosis factor inhibitors.
Methods: In this double-blind, multicentre, randomised, placebo-controlled, phase 3 study (SPIRIT-P2), patients were recruited from 109 centres across ten countries in Asia, Australia, Europe, and North America. Patients were aged 18 years or older, had a confirmed diagnosis of psoriatic arthritis for at least 6 months, and had a previous inadequate response, distinguished by being refractory to therapy or had loss of efficacy, or were intolerant to tumour necrosis factor inhibitors. Patients were randomly assigned (1:1:1) by a computer-generated random sequence to receive a subcutaneous injection of 80 mg ixekizumab every 4 weeks or every 2 weeks after a 160 mg starting dose or placebo. The primary endpoint was the proportion of patients who attained at least 20% improvement in the American College of Rheumatology response criteria (ACR-20) at week 24. This study is registered with ClinicalTrials.gov, number NCT02349295.
Findings: Between March 3, 2015, to March 22, 2016, 363 patients were randomly assigned to placebo (n=118), ixekizumab every 4 weeks (n=122), or ixekizumab every 2 weeks (n=123). At week 24, a higher proportion of patients attained ACR-20 with ixekizumab every 4 weeks (65 [53%] patients; effect size vs placebo 33·8% [95% CI 22·4–45·2]; p<0·0001) and ixekizumab every 2 weeks (59 [48%] patients; 28.5% [17·1–39.8]; p<0·0001) than did patients with placebo (23 [20%] patients). Up to week 24, serious adverse events were reported in three (3%) patients with ixekizumab every 4 weeks, eight (7%) with ixekizumab every 2 weeks, and four (3%) with placebo; no deaths were reported. Infections were reported in 47 (39%) patients with ixekizumab every 4 weeks, 47 (38%) with ixekizumab every 2 weeks, and 35 (30%) with placebo. Three (2%) serious infections, all in patients in the ixekizumab every 2 weeks group, were reported.
Interpretation: Both the 2-week and 4-week ixekizumab dosing regimens improved the signs and symptoms of patients with active psoriatic arthritis and who had previously inadequate response to tumour necrosis factor inhibitors, with a safety profile consistent with previous studies investigating ixekizumab.
Authors
Peter Nash, Bruce Kirkham, Masato Okada, Proton Rahman, Benard Combe, Gerd-Ruediger Burmester, David H Adams, Lisa Kerr, Chin Lee, Catherine L Shuler, Mark Genovese, Khalid Ahmed, Jeffrey Alper, Nichol Barkham, Ralph E Bennett, Francisco Javier Blanco García, Ricardo Blanco Alonso, Howard B Blumstein, Michael S Brooks, Gerd-Rüdiger Burmester, Patricia Cagnoli, Paul H Caldron, Alain Cantagrel, Der-Yuan Chen, Melvin A Churchill, Christine E Codding, Benard Combe, Peter MG Deane, Jose Del Giudice, Atul A Deodhar, Rajat K Dhar, Eva Dokoupilova, Rita M Egan, Andrea Everding, Eva Galíndez, Mark Genovese, David H Goddard, Alice Gottlieb, Philippe Goupille, Robert M Griffin, Ramesh C Gupta, Stephen Hall, Kalpita Hatti, Mary P Howell, Yu-Huei Huang, Ramina Jajoo, Namieta M. Janssen, Uta Kiltz, Alan J. Kivitz, Steven J. Klein, Mariusz P. Korkosz, Roshan Kotha, Joel M Kremer, Cummins Lue, José Luis Marenco de la Fuente, Helena Marzo-Ortega, Jordi Gratacós Masmitja, Philip J Mease, Pier Luigi Meroni, Eric C Mueller, Anupama C Nandagudi, Peter Nash, Antonio Fernández-Nebro, Clark M Neuwelt, Ana Maria Orbai, Meera R Oza, Deborah L Parks, Debendra Pattanaik, Maria E Rell-Bakalarska, David Rosmarin, Euthalia Roussou, Anna I Rychlewska-Hanczewksa, David H Sikes, Michael T Stack, Prashanth Sunkureddi, Hasan Tahir, Diamant Thaçi, Tsen-Fang Tsai, Anthony M Turkiewicz, Leonore Unger, Raúl Veiga Cabello, Ulf Wagner, Cheng-Chung Wei, Alvin F Wells, Peter Youssef, Agnieszka Zielinska
[link url="http://med.stanford.edu/news/all-news/2017/05/drug-for-refractory-psoriatic-arthritis-shows-promise-in-clinical-trial.html"]Stanford University Medical Centre material[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31429-0/fulltext"]The Lancet article summary[/link]