Background Preclinical and animal models have identified GM-CSF as a key cytokine in rheumatoid arthritis (RA). Mavrilimumab (CAM-3001), a human mAb targeting GM-CSFRα, is being evaluated for the treatment of RA.
Objectives To investigate the efficacy and safety of 3-month treatment with ascending doses (10–100 mg q2w) of mavrilimumab in adult subjects with RA in combination with methotrexate.
Methods Eligible subjects had moderate–severe disease activity (DAS28-CRP ≥3.2) of ≥3 mos disease duration, were receiving stable doses of MTX (7.5–25 mg/week), and were positive for ACPA and/or RF. A total of 233 subjects (mavrilimumab 158; placebo (PBO) 75) with active RA were randomised 2:1 to subcutaneous mavrilimumab (10, 30, 50, or 100 mg) or PBO. Subjects received the study drug every other wk for 12 wks, followed by a 12-wk follow-up (f/u) period. The primary endpoint was the proportion of mavrilimumab-treated subjects achieving a DAS28-CRP decrease ≥1.2 from baseline vs PBO at wk 12. Secondary endpoints included DAS28-CRP remission, ACR20/50/70, and HAQ-DI over time. All responder analyses were conducted using nonresponder imputation. Safety assessments included the incidence of adverse events (AEs and SAEs), and laboratory parameters.
Results Of the 233 subjects, 216 (93%) (mavrilimumab 149 [94%]; PBO 67 [89%]) completed the study; 1 (0.4%) mavrilimumab and 2 (0.9%) PBO discontinued due to AEs. By wk 12, 55.7% of mavrilimumab-treated subjects met the primary endpoint (DAS28-CRP reduction of ≥1.2) vs 34.7% PBO subjects (p=0.003). Onset of response generally occurred within 2 wks. The 100 mg group showed significant improvement compared with PBO in the primary endpoint (66.7 vs 34.7%; p=0.001) and ACR20 (69.2 vs 40.0%; p=0.005) that was sustained over the 12-wk f/u period (59.0 vs 33.3%; p=0.010 and 56.4 vs 30.7%; p=0.009, respectively); similarly, the proportion of subjects achieving a HAQ-DI improvement of ≥0.25 (74.4 vs 48.0%; p=0.009) was sustained over the 12-wk f/u (66.7 vs 46.7%; p=0.049). DAS28-CRP remission rates at 12 wks were significantly improved compared to PBO in the 100-mg group (23.1 vs 6.7%; p=0.016) but the effect was not sustained throughout the end of the f/u period (7.7 vs 9.3%; p=1.000). AEs were generally mild or moderate in intensity; the most common events included decrease in CO diffusing capacity (mavrilimumab 19 [11.9%]; PBO 5 [6.3%]), nasopharyngitis (mavrilimumab 10 [6.3%]; PBO 2 [2.5%]) and upper respiratory tract infections (mavrilimumab 6 [3.8%]; PBO 4 [5.1%]). No significant hypersensitivity reactions, serious or opportunistic infections, or clinically significant changes in pulmonary parameters were reported. SAEs were reported in 4 (2.5%) mavrilimumab subjects and 1 (1.3%) PBO and were not treatment-related.
Conclusions Mavrilimumab showed a rapid (within 2 wks) and significant clinical effect vs PBO, especially in the higher (100 mg) dose cohort. DAS28 response and ACR20 was maintained for 12 wks after cessation of mavrilimumab 100 mg. The sustained clinical activity along with an acceptable safety profile supports further clinical development of this new anti-GM-CSFRα mAb.
The study was funded by MedImmune, Ltd.
Disclosure of Interest G. Burmester Consultant for: MedImmune, M. Weinblatt Consultant for: Medimmune, I. McInnes: None Declared, O. Barbarash: None Declared, E. Esfandieri Employee of: Medimmune, M. Sleeman Employee of: MedImmune, A. Godwood Employee of: Medimmune, F. Magrini Employee of: Medimmune
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