London, United Kingdom—Ixekizumab (Taltz) achieved clinically significant improvement in the signs and symptoms of psoriatic arthritis (PsA), including arthritis, dactylitis, and enthesitis, as well as skin improvements, during a 28-week extension phase of a 24-week, double-blind, phase 3 trial called SPIRIT-P1 (totaling 52 weeks).1
“The 52-week data show consistent responses to ixekizumab, and a low frequency of serious adverse events,” said Philip J. Mease, MD, Swedish Medical Center, and University of Washington, Seattle during a presentation at the 2016 European League Against Rheumatism (EULAR) Annual Congress. “We are pleased to show consistence of effect and good safety with this agent.”
Ixekizumab, an immunoglobulin G4 monoclonal antibody, binds specifically and with high affinity to interleukin (IL)-17A, the proinflammatory cytokine. Following a double-blind, placebo-controlled, 24-week study, ixekizumab was superior to placebo in achieving ≥20% improvement per American College of Rheumatology (ACR20) criteria in disease-modifying antirheumatic drug (DMARD)-naïve patients with active PsA.
In March 2016, ixekizumab was approved by the FDA for the treatment of adult patients with moderate-to-severe plaque psoriasis. The side effect profile of ixekizumab was reassuring in a large database of patients with psoriasis, Dr Mease told listeners.
Investigators behind SPIRIT-P1 randomized 417 DMARD-naïve patients with active PsA to 4 different subcutaneous treatment arms: 160 mg followed by 80 mg given once every 2 or 4 weeks, adalimumab 40 mg (active control arm), or placebo (control arm); they were treated for 24 weeks.
In the active control arm, if there was an inadequate response, background therapy could be adjusted. If patients receiving placebo responded inadequately, they could be randomized to ixekizumab every 2 or 4 weeks.
At 24 weeks, patients in the 2 ixekizumab arms continued with their assigned treatments; those in the adalimumab arm begin receiving ixekizumab at week 24 or 32, following an 8-week washout period, and patients being given placebo were started on ixekizumab at week 16 or 24.
During the extension phase, 191 patients were treated with ixekizumab every 4 weeks; 190 were given the drug every 2 weeks.
Patients enrolled in the trial were aged ≥18 years, with active PsA for ≥6 months, characterized by the presence of ≥3 swollen or tender joints, and >1 joint erosion.
Baseline demographics and disease characteristics of patients in the extension phase were well-balanced. “For example, about 40% of patients had active dactylitis and 50% to 60% had active enthesitis in both arms,” noted Dr Mease
A total of 304 patients completed the extension phase trial. Improvements from baseline were seen across all trial measures: ACR 20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI), Disease Activity Score 28−C-reactive protein (DAS28-CRP), Psoriasis Area and Severity Index (PASI) 75/90/100, Leeds Enthesitis Index, and Leeds Dactylitis Index-Basic.
The ACR20 response achieved at 24 weeks in both ixekizumab arms was maintained at week 52; ACR50/70 responses were also maintained at week 52. Dr Mease described these responses as being strong.
Patients receiving adalimumab who were switched to ixekizumab also maintained or increased their ACR responses. Those originally in the placebo arm who were switched to ixekizumab quickly caught up and achieved almost similar responses to patients originally randomized to receive ixekizumab every 4 or 2 weeks.
At week 52, patients in both ixekizumab arms had an ACR20 of approximately 67%. ACR50 was achieved in 52.9% of the group receiving ixekizumab every 4 weeks, and 48.9% of the 2-week group; rates of ACR70 were 33.5% and 34.7%, respectively.
Responses to the HAQ-DI were similar in both arms, reflecting a substantial improvement: –0.48 change. “We consider a change of –0.35 significant,” Dr Mease explained.
DAS28-CRP results were similar in both arms, as were those for PASI 75 (approximately 72% in both arms). Similar improvements in enthesitis and dactylitis were also observed in both ixekizumab arms, he said, adding that approximately 40% of patients in each arm achieved minimal disease activity.
The safety profile was similar to that of week 24 in the SPIRIT-P1 and phase 3 UNCOVER studies of patients with plaque psoriasis. Several cases of candidiasis were reported in the 2-week arm over the first 24 weeks. During the extension phase, very few serious adverse events were reported, and most were potentially unrelated to treatment.
Lab abnormalities that emerged were easily treatable. There were no reports of suicide or suicide attempts.
Ixekizumab in Patients with Plaque Psoriasis
During the EULAR meeting, results of 3 phase 3 trials of ixekizumab in a total of 3736 patients with moderate-to-severe plaque psoriasis were published in the New England Journal of Medicine.2
Results of UNCOVER-1, UNCOVER-2, and UNCOVER-3 showed that ixekizumab was effective in treating moderate-to-severe plaque psoriasis through week 60. The investigators stated that the efficacy and safety of ixekizumab beyond 60 weeks of treatment are unknown.
In these 3 trials, patients were monitored for cardiovascular events because of the concern that low serum levels of IL-17 could lead to myocardial infarctions and affect the stability of atherosclerotic plaque. During the 12-week induction periods, the risk for adverse cardiovascular deaths did not differ between ixekizumab-treated patients and those receiving placebo.
Among all of the patients who received ixekizumab during weeks 0 through 60, there were 2 confirmed deaths due to vascular causes, and 1 death attributed to unknown causes. In addition, 11 patients experienced inflammatory bowel disease (IBD) while taking ixekizumab, and an additional 3 reported having IBD while taking placebo after an ixekizumab induction phase.
The investigators in these trials said that further study is needed to understand the relationship between IL-17A inhibitors and IBD.
- Mease PJ, van der Heijde D, Ritchlin CT, et al. A randomized, double-blind, active- and placebo-controlled phase 3 study of efficacy and safety of ixekizumab, adalimumab, and placebo therapy in patients native to biologic disease modifying anti-rheumatic drugs with active psoriatic arthritis. Presented at: 2016 European League Against Rheumatism Annual Congress; June 8-10, 2016; London, United Kingdom. http://acrabstracts.org/abstract/a-randomized-double-blind-active-and-placebo-controlled-phase-3-study-of-efficacy-and-safety-of-ixekizumab-adalimumab-and-placebo-therapy-in-patients-naive-to-biologic-disease-modifying-anti/. Accessed June 12, 2016.
- Gordon KB, Blauvelt A, Papp KA, et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016 Jun 8. Epub ahead of print.