Treatment of rheumatoid arthritis with olokizumab combined with methotrexate led to significantly more patients with improved signs and symptoms than did methotrexate plus placebo in circumstances where previous treatment with one or more tumor necrosis factor (TNF) inhibitors yielded inadequate responses, results from a phase 3 randomized trial show.
At the week 12 primary endpoint, 40.6% of patients receiving placebo had at least 20% improvement in American College of Rheumatology response criteria (ACR 20), compared with 60.9% of patients receiving olokizumab 64 mg every 2 weeks and 59.6% of patients receiving olokizumab 64 mg every 4 weeks (P <.01 for both comparisons), senior author Roy M. Fleischmann, MD, of the University of Texas Southwestern Medical Center in Dallas and colleagues reported in Annals of the Rheumatic Diseases.
Dr. Roy M. Fleischmann
Dr. Fleischmann said that given the existing literature on the investigational interleukin (IL)-6 inhibitor olokizumab shows that it is superior to placebo and noninferior to adalimumab (Humira) in patients who have an inadequate response to methotrexate and that it was superior to methotrexate alone for patients who have failed one or more TNF inhibitors in this current trial, the most likely use of olokizumab in clinical practice if it is approved is for those with inadequate responses to TNF inhibitors.
“If olokizumab is approved in the U.S., it is a reasonable choice when considering an inhibitor of IL-6. As it does affect IL-6 directly, rather than the receptor, much less protein needs to be administered with a convenient dosing interval of either every 2 or 4 weeks subcutaneously,” Dr. Fleischmann said in an interview.
The 24-week, double-blind, multicenter study, dubbed Clinical Rheumatoid Arthritis Development for Olokizumab (CREDO 3), involved 161 patients receiving 64 mg of olokizumab subcutaneously every 4 weeks, 138 receiving 64 mg of olokizumab subcutaneously once every 2 weeks, and 69 receiving placebo. At week 16, the researchers randomized participants in the placebo group to receive either olokizumab regimen.
All patients received methotrexate, and NSAIDs and glucocorticoids (< 10 mg/day prednisone or equivalent) were allowed in stable doses. Mean age was about 53 years across all three arms, and females accounted for the majority for each arm.
Significantly more patients in both olokizumab arms achieved the main secondary endpoint of Disease Activity Score in 28 joints based on C-reactive protein less than 3.2 at week 12, compared with placebo.
Notably, patients who moved from placebo at week 16 experienced improvement that was sustained over the remaining 8 weeks.
Serious treatment-emergent adverse events with olokizumab occurred in 3.2% receiving the drug every 4 weeks and in 7% receiving it every 2 weeks but in none who received placebo.
The study’s limitations included the high placebo response rate, the short timeframe for placebo, and its fairly small sample size, which limits the generalizability of the results, the authors noted.
Expert commentary
There are currently two biologics on the market that inhibit the IL-6 receptor, tocilizumab (Actemra), and sarilumab (Kevzara), but olokizumab is unique in that “it does not block the receptor. It binds directly to the cytokine,” noted Larry Moreland, MD, a professor of medicine and orthopedics in the division of rheumatology at the University of Colorado at Denver in Aurora, who was not involved in the study.
Tocilizumab and sarilumab had a similar clinical trial portfolio when they were studied in people who failed anti-TNF therapy, so this is the standard study a company would do prior to seeking approval, Dr. Moreland said.
“The fact that there is another IL-6 blocker that is showing promise means that there are more opportunities for researchers and clinicians to use these agents not only for rheumatoid arthritis but also hopefully study them in other diseases,” he said.
The CREDO 3 trial was sponsored by R-Pharm. Some of the authors are employees of R-Pharm. Dr. Fleischmann and some of his coauthors reported financial ties to R-Pharm and other pharmaceutical companies. Dr. Moreland reported having no relevant competing interests.