BIRMINGHAM, ENGLAND (FRONTLINE MEDICAL NEWS) – A “durable clinical response and stabilization of structural damage” was observed at 3 years of follow-up in the Long Term Evaluation of Sarilumab in Rheumatoid Arthritis Patients (SARIL-RA-EXTEND) study.

Désirée van der Heijde, MD, PhD , who reported the findings of the EXTEND study at the British Society for Rheumatology annual conference, noted that the benefit was seen regardless of the initial treatment that had been given at baseline.

The study was an open-label, multicenter, uncontrolled extension of the previously reported SARIL-RA-MOBILITY trial that had shown that sarilumab added to methotrexate not only improved disease control at 24 weeks but also improved physical function at 16 weeks, and reduced radiological progression at 1 year ( Arthritis Rheumatol. 2015;67:1424-37 ).

The aim of the EXTEND trial was to examine the continuity of response to sarilumab seen in the MOBILITY trial, said Dr. van der Heijde, professor of rheumatology at Leiden (The Netherlands) University Medical Center.

Sarilumab is a fully human (IgG1) monoclonal antibody that binds to interleukin (IL)-6 receptors, both soluble and membrane-bound, and thus inhibits IL-6-mediated signaling through the soluble IL-6R alpha and membrane-bound IL-6R alpha receptors. It is undergoing regulatory approval in the United States, European Union, and Japan, but was recently approved in Canada for treatment of adult patients with moderate to severe rheumatoid arthritis (RA) who have had an inadequate response to one or more biologic or nonbiologic disease-modifying antirheumatic drugs (DMARDs) ( Drugs. 2017;77:705-12 ).

In the MOBILITY trial, 1,197 patients who were being treated with methotrexate but who had an inadequate response were randomized to receive placebo (n = 398) or sarilumab given subcutaneously every 2 weeks at one of two doses: 150 mg (n = 400) or 200 mg (n = 399).

EXTEND allowed patients completing this trial who still had active disease to continue or start (if they had been given placebo) treatment with sarilumab at a dose of 200 mg given every 2 weeks, with dose reduction to 150 mg every 2 weeks if needed, in addition to methotrexate. A total of 901 patients participated in the extension study.

“In the MOBILITY trial, all three groups were very balanced, and if you then take the patients who entered the EXTEND trial, they are very similar to the patients who also were randomized into MOBILITY,” Dr. van der Heijde said.

This was a fairly typical RA population, she observed: About 80% were female, the mean age was 50 years, and the mean duration of RA was 9 years. About 20%-25% had prior treatment with a DMARD, more than 80% were rheumatoid factor or anti-CCP antibody positive. There were similar mean C-reactive protein (CRP) levels between the groups, and the 28-joint disease activity score (DAS28) with CRP was around 6, and Clinical Disease Activity Index (CDAI) score around 40.

Radiographs that were taken at baseline, at the end of year 2, and at the end of year 3 were reread by two independent readers and scored together in one session. Data had to be extrapolated for 29 patients who did not have a radiographs taken at year 3 but who had been seen during the third year of treatment.

The significant radiographic inhibition seen at the end of the MOBILITY trial in both the 150-mg and 200-mg active treatment groups was sustained in the EXTEND study.

“There is a small progression between year 2 and 3, and this progression is quite similar in all the three treatment arms,” Dr. van der Heijde reported, nothing that all patients were taking 200 mg of sarilumab at this point.

The mean change in the modified total Sharp score (mTSS) from year 2 to 3 was 0.35 in the patients who had originally been randomized to the placebo arm, 0.64 in patients originally randomized to 150 mg sarilumab every 2 weeks, and 0.44 in those originally taking 200 mg sarilumab every 2 weeks.

From baseline to year 3, the mean change in mTSS were a respective 3.3, 1.9, and 0.8.

“If you present the data in a different way, like the percentage of patients showing no progression, you see the differentiation between the patients who started on placebo versus those who were started on sarilumab 150 mg or 200 mg,” said Dr. van der Heijde.

At year 2, 67%, 59%, and 48% of patients treated with sarilumab 200 mg, sarilumab 150 mg, or placebo, respectively had no progression in mTSS (signified by a change from baseline of 0.5 points or more).

At year 3, corresponding rates were a respective 75%, 55%, and 49%.

DAS-28-CRP response at year 3 was similar across the initial treatment groups, Dr. van der Heijde observed. Reductions seen in the MOBILITY trial were clearly continued, she said. The percentage of patients achieving DAS-28-CRP of less than 2.6 was 22%, 34%, and 36% of placebo, sarilumab 150-mg, and sarilumab 200-mg treated patients at the end of the MOBILITY study. At the end of year 2, the corresponding numbers were 60%, 62%, and 62%, and by year 3, not much had changed in the percentage of patients achieving DAS-28-CRP of less than 2.6: 58% for placebo, 62% for sarilumab 150 mg, and 68% for sarilumab 200 mg.

Similar results were seen for patients achieving a CDAI of 2.8 or lower at years 2 and 3 in the extension study.

Treatment-emergent adverse events (TEAEs) occurred in 89.7% of patients over 3 years. One in five (20%) patients experienced serious adverse events, with 23% of patients discontinuing treatment because of TEAEs. There were 9 (0.8%) deaths during the trial.

TEAEs that occurred at rates of 5% or higher in any treatment group were neutropenia in 19.4%, increased alanine aminotransferase in 13.0%, and upper respiratory tract infections in 12.7%.

There were some changes in laboratory values, Dr. van der Heijde said, but “most of the changes were very small” and in line with the effects expected with IL-6 inhibition.

The study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals. Dr. van der Heijde and coauthors disclosed receiving consulting fees, research grants, or both from multiple pharmaceutical companies, including the sponsors of the study. Dr. van der Heijde is director of Imaging Rheumatology.


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