Olokizumab improves signs, symptoms, physical function in methotrexate-refractory RA
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Olokizumab is associated with significant improvements in rheumatoid arthritis signs, symptoms and physical function in patients with inadequate response to methotrexate, according to data published in the Annals of the Rheumatic Diseases.
“A number of effective therapies with different modes of action are currently available for RA; however, many patients with active RA fail to achieve defined targets of therapy, namely low disease activity or remission,” Evgeniy Nasonov, MD, PhD, DMSci, at the Research Institute of Rheumatology of RAMS, in Moscow, Russia, and colleagues wrote. “The proinflammatory cytokine interleukin-6 plays a significant role in the pathogenesis of RA and two anti-IL-6 receptor (IL-6R) antibodies have been shown to be relatively safe and effective and are approved for treatment of RA.”
“Olokizumab (OKZ) is an anti-IL-6 monoclonal antibody that binds directly to IL-6 at a specific site and neutralizes its activity through blocking hexamer formation of the extracellular signaling complex inhibiting transmembrane signaling,” they added. “In early clinical studies it was shown that OKZ resulted in a rapid reduction in the level of IL-6 and C-reactive protein that lasted over an extended period of time due to OKZ’s long half-life of approximately 31 days.”
To analyze the efficacy and safety of olokizumab (R-Pharm) in patients with active RA despite receiving methotrexate, Nasonov and colleagues conducted a multicenter, placebo-controlled, double-blind, phase 3 trial. A total of 428 adults from 42 hospitals in Russia, Belarus and Bulgaria were randomly assigned 1:1:1 to receive either subcutaneous olokizumab 64 mg once every 2 weeks, the same dosage once every 4 weeks, or placebo. Participants in all groups also received methotrexate.
The primary efficacy endpoint was the proportion of participants who achieved the ACR20 response at week 12. Secondary endpoints included the percentage of participants who achieved DAS28 based on a CRP level of less than 3.2, the Health Assessment Questionnaire Disability Index (HAQDI) at week 12, the ACR50 response, and a Clinical Disease Activity Index (CDAI) of 2.8 or less at week 24. The researchers assessed safety and immunogenicity throughout the study.
According to the researchers, ACR20 responses were more frequent in the olokizumab groups — 63.6% among those who received the drug every 2 weeks and 70.4% in those treated every 4 weeks — than with placebo, at 25.9% (P < .0001 for both comparisons). In addition, there were significant differences in all secondary efficacy endpoints between those who received olokizumab and those in the placebo group.
Regarding safety, treatment-emergent serious adverse events were reported by more patients in the olokizumab groups, compared with the placebo arm, with infections being the most common. No participants developed neutralizing antidrug antibodies, according to the researchers.
“In this first phase 3 trial of OKZ in patients with active RA despite treatment with an adequate dose of [methotrexate], OKZ demonstrated significant improvements in signs and symptoms of RA, including in disability and quality of life measures, compared with [placebo],” Nasonov and colleagues wrote. “OKZ was reasonably well-tolerated over a period of 24 weeks with no unexpected safety findings.”
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David A. McLain, MD, MACR, FACP, FRCP
This is phase 3 data for olokizumab, a new humanized monoclonal antibody against the IL-6 ligand. Tocilizumab and sarilumab both target the IL-6 receptor; however, olokizumab has been shown to rapidly reduce IL-6 and CRP and has a long half-life of 31 days, whereas tocilizumab has a half-life of 6-18 days, and sarilumab a half-life of 21 days. Results of this trial met the primary and secondary endpoints at both doses of 64 mg once every 2 weeks and once every 4 weeks.
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