IL-6 Blocker Beats Anti-TNF in RA
Sarilumab superior to adalimumab as monotherapy
Nancy Walsh November 22, 2016
Senior Staff Writer, MedPage Today
The interleukin-6 receptor (IL-6R) blocker sarilumab given as monotherapy among patients with active rheumatoid arthritis (RA) was superior to adalimumab (Humira) monotherapy, a phase III trial found.
At week 24, the mean change from baseline in Disease Activity Score in 28 joints (DAS28) was -3.28 for those randomized to sarilumab compared with -2.20 among those given adalimumab, for a difference of -1.08 (95% CI -1.36 to -0.79, P<0.0001), according to Gerd R. Burmester, MD, of Charite-University Medicine in Berlin, and colleagues.
In addition, the likelihood of achieving DAS28 remission, defined as a score below 2.6, was almost three times higher at 12 weeks (OR 2.61, 95% CI 1.31-5.20) in the sarilumab group and five times greater at 6 months (OR 4.88, 95% CI 2.54-9.39, P<0.0001), the researchers reported online in Annals of the Rheumatic Diseases.
Clinical guidelines generally recommend that biologic agents be given in combination with methotrexate for RA, but up to one-third of patients currently use these therapies as monotherapy, either because of the inability to tolerate methotrexate or because the drug is contraindicated.
"Therapeutic targeting of the IL-6R has been a major advance in the effective treatment of RA, as IL-6R plays a key role in mediating the underlying disease pathophysiology and clinical manifestations of RA," Burmester and colleagues wrote.
Sarilumab is a monoclonal antibody that binds both soluble and membrane-bound IL-6R. Previous studies have shown efficacy among RA patients who had an inadequate response to methotrexate or tumor necrosis factor (TNF) inhibitors. In October, the FDA issued a complete response letter to developers Sanofi Genzyme and Regeneron Pharmaceuticals, stating that it would not approve sarilumab because of "certain deficiencies identified during a routine good manufacturing practice inspection of the Sanofi Le Trait facility where sarilumab is filled and finished."
Adalimumab is a TNF inhibitor that is approved for use in combination with conventional disease-modifying anti-rheumatic drugs and as monotherapy.
In a study known as MONARCH, which was sponsored by the two companies, the investigators sought to evaluate the efficacy of these two agents as monotherapy "to help better define strategies for the choice and optimal sequencing of available therapeutics suited for real-world clinical practice."
They enrolled 369 patients from 86 centers worldwide from 2015 to 2016, randomizing them to receive subcutaneous sarilumab, 200 mg every 2 weeks, or adalimumab, 40 mg also subcutaneously every 2 weeks. The patients were either intolerant of, or considered inappropriate candidates for, continued treatment with methotrexate, or inadequate responders if treated with an adequate methotrexate dose, the authors explained.
Patients' mean age was 52, mean disease duration was 7 years, and more than 80% were women.
Baseline DAS28 was 6.8, swollen joint count was 18, and tender joint count was 27.
A total of 90% of patients in the sarilumab group and 84% of those in the adalimumab group completed the 24-week double-blind phase of the trial.
By week 12, the change in DAS28 was -2.77 for the sarilumab group versus -1.88 in the adalimumab group, for a difference of -0.89 (95% CI -1.18 to -0.59, P<0.0001).
On the Clinical Disease Activity Index, which assesses clinical response without including acute-phase reactants such as erythrocyte sedimentation rate or C-reactive protein, more patients receiving sarilumab had achieved low disease activity at week 24 (41.8% versus 24.9%, P=0.0005) or remission (7.1% vs 2.7%, P=0.0468).
The proportions of patients who had 20%, 50%, and 70% responses on the criteria of the American College of Rheumatology at week 24 also were significantly higher in the sarilumab group, at 71.7%, 45.7%, and 23.4%, respectively, compared with 58.4%, 29.7%, and 11.9% (P≤0.0074 for all).
Improvements on the Health Assessment Questionnaire Disability Index also favored sarilumab, with changes from baseline of -0.61 versus -0.43, for a difference of -0.18 (95% CI -0.31 to -0.06, P=0.0037).
Those receiving sarilumab also had greater improvements at week 24 on the Short Form-36 Physical Component Score, while the groups showed similar benefits on the Short Form-36 Mental Component Score.
Approximately two-thirds of patients in both groups reported any adverse event, while the rates of serious adverse events were similar in the sarilumab and adalimumab groups (4.9% versus 6.5%). Infections were seen in 28.8% and 27.7%, respectively. One death occurred in the sarilumab group, from cardiac failure after aortic dissection and rupture of the papillary muscle.
Injection site reactions occurred in 9.2% of the sarilumab group and in 4.3% of the adalimumab group.
Neutropenia was reported in 13.6% of the sarilumab group and in 0.5% of the adalimumab group. Elevations of alanine aminotransferase of 1 to 3 times the upper limit of normal occurred in 33.7% of the sarilumab group and in 21.2% of the adalimumab group, with mean increases of 6.1 IU/L and 2.1 IU/L at week 24, respectively. Increases in serum lipids were observed in 1.6% of the sarilumab group compared with 4.3% of the adalimumab group.
"In MONARCH, changes in laboratory values in the sarilumab group, including neutropenia, liver transaminases, and total cholesterol, were expected class effects," the investigators noted.
"These data demonstrate that sarilumab improves signs and symptoms and functional disability of RA and is an appropriate, effective, and superior monotherapy compared with TNF-α inhibition for patients who are unsuitable candidates for continued treatment with methotrexate," they concluded.
A limitation of the study was the lack of information about radiographic outcomes.
The study was sponsored by Sanofi Genzyme and Regeneron Pharmaceuticals.
Burmester and co-authors disclosed relevant relationships with Sanofi Genzyme, Regeneron, AbbVie, Bristol-Myers Squibb, MedImmune, Merck, Pfizer, Roche, and UCB.