Mavrilimumab for Moderate-to-Severe RA

Researchers in Germany found that rheumatoid arthritis patients treated with mavrilimumab had significantly reduced disease activity and greater American College of Rheumatology 20 response rates compared with placebo.

This study appears in the February 17 online issue of Annals of the Rheumatic Diseases.

The study was a phase IIb, randomized, double-blind, placebo-controlled trial conducted with 326 patients, aged 18-80, with moderate-to-severe adult-onset rheumatoid arthritis. Patients from 14 countries were recruited between September 2012 and June 2013, and were eligible for the study if they had inadequate response of at least one synthetic disease-modifying anti-rheumatic drug; a Disease Activity Score 28 (DAS28); a CRP  erythrocyte sedimentation rate of at least 3.2 and more than four swollen joints despite methotrexate therapy.

Patients were randomized in a 1:1:1:1 ratio to subcutaneous mavrilimumab (150, 100, 30 mg), or placebo every other week, plus methotrexate for 24 weeks.

Led by Gerd Burmester, M.D., from the University Medicine Berlin, Free University, and Humboldt University Berlin, the primary outcomes of this study were change in DAS28−CRP from baseline to week 12, and the American College of Rheumatology 20 response rate (ACR20) at week 24.

The results showed that patients treated with mavrilimumab had significantly lower DAS28−CRP scores from baseline compared with placebo. The changes from baseline were as follows: 150 mg: −1.90 (0.14), 100 mg: −1.64 (0.13), 30 mg: −1.37 (0.14), placebo:−0.68 (0.14); p<0.001. In addition, significantly more patients treated with mavrilimumab (150, 100, and 30 mg) achieved ACR20 at week 24 compared with placebo: 73.4 percent, 61.2 percent, 50.6 percent vs. 24.7 percent, respectively; p<0.001.

“Data from this study demonstrate that mavrilimumab, particularly at a dosage of 150 mg every other week, provides a rapid, effective and well tolerated potential treatment for patients with RA,” wrote Dr. Burmester and colleagues.

Despite improvements in biological therapies for patients with rheumatoid arthritis, approximately 50 percent of patients do not reach low disease activity levels within 12 months of anti-tumor necrosis factor-α therapy and approximately 80 percent of patients do not achieve a Disease Activity Score 28 of less than 2.6.  These statistics suggest that novel biologics that target different signaling pathways are needed to improve disease control and related outcomes for patients with rheumatoid arthritis.

Granulocyte–macrophage colonystimulating factor (GM−CSF) is a novel therapeutic target for autoimmune and inflammatory diseases. As a proinflammatory multifunctional cytokine, GM−CSF may play a key role the pathogenesis of rheumatoid arthritis via activation, differentiation and survival of macrophages, dendritic cells and neutrophils. Moreover, prior research has shown that signaling through the GM−CSF receptor-α subunit has been demonstrated to have a role in animal models of arthritis as well as modulation of pain pathways.

Mavrilimumab is a fully human monoclonal antibody that blocks the GM−CSF receptor and is in clinical development to target this pathway. Previous clinical studies have already demonstrated the safety, tolerability, and efficacy of mavrilimumab. However, these studies have been of shorter duration than the current study that evaluated endpoints for 24 weeks.

“This proof-of-concept study confirms that inhibition of GM−CSF activity is a promising and novel therapeutic approach for patients with RA, including those who do not adequately respond to currently available therapies,” wrote Dr. Burmester and his team.

Disclosures:

This research was funded by AstraZeneca/MedImmune.

GRB is a consultant and has received lecture fees from Abbvie, Bristol-Myers Squibb, MSD, Pfizer, Roche, UCB; IM has received grants and personal fees from Abbvie, AstraZeneca, Bristol-Myers Squibb, Janssen, MedImmune, MSD, Pfizer, UCB; JK is a shareholder and employee of Corrona; has received grants from Abbvie, Amgen, Genentech, Lilly, Pfizer; and is a consultant for Abbvie, Amgen Genentech, Lilly, Pfizer, BMS and MedImmune; PM has received grants from

MedImmune; JV is a consultant for Biotest and Samsung Bioepics and has participated in speaker bureaus for Abbvie, MSD, Pfizer, UCB, Roche; AR-R received honoraria for consultation and lectures from Abbvie, Amgen, Chugai, Roche, UCB, MSD, Pfizer, Lilly, Sanofi, Novartis, BMS; EM has received a grant from Organizicion medica de Investigacion; MAS was formerly a full-time employee of MedImmune, a wholly owned subsidiary of AstraZeneca; AG, DS, XG, WIW, BW, C-YW, PCR and DC are employees of MedImmune and hold AstraZeneca shares; MEW has received research grants from Bristol-Myers Squibb, Crescendo Bioscience and UCB, and is a consultant for Abbvie, Amgen, AstraZeneca, Bristol-Myers Squibb, Corrona, Crescendo Bioscience, Genentech/Roche, Janssen, Lycera, Lilly, MedImmune, Merck, Pfizer, Regeneron, Sanofi, UCB.

References:

Gerd R Burmester, Iain B McInnes, Joel Kremer, et al. “A randomised phase IIb study of mavrilimumab, a novel GM–CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis,” Annals of the Rheumatic Diseases. Published online February 17, 2017. DOI: 10.1136/annrheumdis-2016-210624