PHILADELPHIA – Treatment with the interleukin-6 receptor antagonist sarilumab (Kevzara), along with a 14-week taper of glucocorticoids, proved to have significant efficacy in patients with relapsing polymyalgia rheumatica (PMR) who were resistant to glucocorticoids in a phase 3 trial.
No new safety concerns were found with sarilumab in the multicenter, randomized, double-blind, placebo-controlled SAPHYR trial. Sarilumab is approved in the United States for the treatment of moderate to severe active rheumatoid arthritis in adults who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs.
The results, presented at the annual meeting of the American College of Rheumatology by Robert Spiera, MD, director of the Scleroderma, Vasculitis, and Myositis Center at the Hospital for Special Surgery in New York, included clinically meaningful improvement in quality-of-life scores.
The disease, which primarily affects people over age 65, can cause widespread aching and stiffness. It’s one of the most common inflammatory diseases among older adults.
PMR is relatively easy to treat with glucocorticoids, but relapses are common, which means long courses of glucocorticoid therapy and the side effects that come with them.
Need for a steroid-sparing therapy
“We recognize that a steroid-sparing drug in polymyalgia rheumatica seems to be an unmet need,” Dr. Spiera said at the meeting.
The trial, sponsored by Sanofi, included active, refractory PMR patients who flared within 3 months of study entry while on at least 7.5 mg/day of prednisone or the equivalent. They were randomly assigned (1:1) to 52 weeks of treatment with subcutaneous sarilumab 200 mg every 2 weeks plus the rapid 14-week glucocorticoid tapering regimen or were given placebo every 2 weeks plus a more traditional 52-week tapering of glucocorticoids.
COVID hampered recruitment
Recruitment was stopped early because of complications during the COVID-19 pandemic, so between October 2018 and July 2020, 118 of the intended 280 patients were recruited, and 117 were treated (sarilumab = 59, placebo = 58). Median age was 69 years in the treatment group and 70 among those taking placebo.
Of the 117 treated, only 78 patients (67%) completed treatment (sarilumab = 42, placebo = 36). The main reasons for stopping treatment were adverse events – including seven with sarilumab and four with placebo – and lack of efficacy (sarilumab = four, placebo = nine).
The primary outcome was the proportion of patients who reached sustained remission at 52 weeks, defined as disease remission by week 12 and no disease flare, normal C-reactive protein (CRP), and adherence to the glucocorticoid taper during weeks 12-52.
The researchers found that sustained remission was significantly higher in the sarilumab arm versus the control group (28.3% versus 10.3%; P = .0193).
IL-6 inhibitors lower CRP, but if you take CRP out of the definition, Dr. Spiera said, “we still saw this difference: 31.7% of patients treated with sarilumab and 13.8% treated with placebo and a longer taper achieved that endpoint.”
Forty-four percent lower risk of flare with sarilumab
Patients in the sarilumab group also had 44% lower risk of having a flare after achieving clinical remission versus the comparator group (16.7% versus 29.3%; hazard ratio, 0.56; 95% confidence interval, 0.35-0.90; P = .0153).
Patient-reported outcomes, which included physical and mental health scores and disability index results, favored sarilumab.
The incidence of treatment-emergent adverse events (TEAEs) was numerically higher in the sarilumab group, compared with the control group (94.9% versus 84.5%). TEAEs included neutropenia (15.3%) and arthralgia (15.3%) in the sarilumab group and insomnia (15.5%) in the comparator arm.
However, the frequency of serious AEs was higher in the control group, compared with the sarilumab arm (20.7% versus 13.6%). No deaths were reported, and, importantly in this age group treated with concurrent glucocorticoids and an IL-6 inhibitor, Dr. Spiera said, “there were no cases of diverticulitis requiring intervention.”
Dr. Spiera was asked about a seemingly low remission rate. He answered that the bar was very high for remission in this study.
Patients had to achieve remission by week 12 and with the rapid 14-week taper. “That means by week 12 the sarilumab arm patients were only on 2 mg of daily prednisone or its equivalent,” he said.
Patients had to maintain that for another 40 weeks, he noted, adding, “I think especially in the context of quality of life and function indices, these were important results.”
Sebastian E. Sattui, MD, director of the University of Pittsburgh Medical Center vasculitis clinic, told this news organization that prolonged use of glucocorticoids in patients with PMR remains an important concern and the need for other options is critical.
“Around 30% of patients with PMR remain on prednisone 5 years after diagnosis,” he said. “Low-dose glucocorticoids are still associated with significant morbidity. Until recently, there has been a paucity of high-quality data regarding the use of steroid-sparing agents in PMR. “
He noted that the SAPHYR trial data are promising “with sarilumab being successful in achieving remission while minimizing glucocorticoids in patients with relapsing PMR.” The clinically meaningful improvement in patient-reported outcomes was just as important, he added.
The main unanswered question is whether the disease-modifying ability of sarilumab will continue after it is stopped, Dr. Sattui said.
Dr. Spiera is a consultant for Sanofi, which funded the trial. He also disclosed financial relationships with GlaxoSmithKline, Boehringer Ingelheim, Corbus, InflaRx, AbbVie/Abbott, Novartis, Chemocentryx, Roche, and Vera. Dr. Sattui has received research support from AstraZeneca and has done unpaid consulting work for Sanofi.
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