Long-term use of sarilumab (Kevzara) among patients with rheumatoid arthritis (RA) has reflected a consistent safety profile whether given as combination therapy with a conventional disease-modifying antirheumatic drug (DMARD) or as monotherapy, a manufacturer-sponsored post hoc analysis found.
Among patients enrolled in eight clinical trials and long-term extension studies, overall incidence rates for serious adverse events have been 9.4 and 6.7 per 100 patient-years for combination therapy and monotherapy, respectively, according to Roy Fleischmann, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues.
And the incidence rates for serious infections were 3.7 and 1.0 per 100 patient-years, respectively, the investigators reported in Rheumatology.
Sarilumab binds the interleukin (IL)-6 receptor and thereby blocks multiple actions of this pro-inflammatory cytokine. It was approved by the FDA in 2017 for the treatment of adults with moderate to severe RA. As of January 2018, the medication had been used by 2,887 patients as combination therapy, and by 471 as monotherapy, with cumulative exposure of up to 7.3 years for the combination and 3.5 years for monotherapy.
The most common dosages have been 150 or 200 mg every 2 weeks, given subcutaneously. Patients included in the clinical trials could have had inadequate responses or intolerance to conventional DMARDs and/or tumor necrosis factor inhibitors.
In the overall patient population, mean age at baseline was 52, and more than 80% were women. Disease duration averaged 9 years, and more than 90% in the combination group were receiving methotrexate.
For laboratory abnormalities, leukopenia was seen in 21% and 20% of patients on combination and monotherapy, respectively. Absolute neutrophil counts below 1,000 cells/mm3, the level at which treatment reduction or stopping is recommended, were reported in 13% and 15%, most often during the first 6 months of treatment.
Elevations of alanine aminotransferase above 3 times the upper limit of normal occurred in 10% and 6% of patients in the combination and monotherapy groups, respectively, and again most often in the first 6 months. Liver enzyme abnormalities are a recognized effect of IL-6 blockade, and the increases seen with combination therapy may also reflect the hepatotoxic effects of methotrexate.
Lipid elevations were observed in rates of 6.1 and 2.2 per 100 patient-years with combination and monotherapy, similar to what has been seen with another IL-6 inhibitor, tocilizumab (Actemra), but the adjusted rates of major adverse cardiovascular events was similar to what is seen in the overall RA population.
In fact, "inhibition of IL-6 signaling might exert effects on cardiovascular risk outside any effects on lipid levels; advances in the understanding of the role of inflammation in atherosclerosis have led to the suggestion that targeting the actions of IL-6 might prove beneficial in reducing the inflammatory response implicated in development of coronary artery disease," Fleischmann and colleagues stated.
For infections, the most common serious infections seen with combination therapy were pneumonia, in 1.5%, cellulitis in 0.8%, and erysipelas in 0.3%. For monotherapy, no type of serious infection developed in more than one patient.
Opportunistic infections, including tuberculosis and herpes zoster, were reported at rates of 0.9 and 0.7 per 100 patient-years, and none of the zoster cases were disseminated.
No correlation was seen between infections and neutropenia, the authors noted.
"Consistent with previous analyses and with this class of therapy, neutropenia was common with sarilumab treatment," but patients who developed neutropenia had no greater incidence of infections or serious infections than those with normal neutrophil counts, they observed. There also was no correlation between severity of neutropenia and serious infections.
For malignancies, the exposure-adjusted incidence of any cancer was 0.7 per 100 patient-years in the combination group and 0.6 per 100 in the monotherapy group, and the adjusted standardized incidence ratios were not significantly different from those of the general population for either group.
Nine patients on combination therapy experienced gastrointestinal perforations; most had also received nonsteroidal anti-inflammatory drugs and corticosteroids. No perforations occurred among monotherapy patients.
"In conclusion, no new safety concerns emerged in this integrated analysis of up to 7 years' sarilumab treatment representing almost 9,000 years of cumulative exposure," the authors wrote, adding that safety follow-up continues for both combination and monotherapy.
A limitation of the analysis was the smaller number of patients treated with monotherapy in the clinical trials.
The study was funded by Sanofi Genzyme and Regeneron Pharmaceuticals.
The authors reported financial relationships with multiple companies, including Sanofi Genzyme, Regeneron, AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Celltrion, Serono, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Samsung, Sandoz, Taiho, UCB, Astellas, Boehringer Ingelheim, Daiichi, Galapagos, Gilead, Janssen, Takeda, Biogen, Novartis, Schering Plough, and Abbott.
Sarilumab, a fully human monoclonal antibody against
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