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A randomised phase IIb study of mavrilimumab, a novel GM–CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis
  1. Gerd R Burmester1,
  2. Iain B McInnes2,
  3. Joel Kremer3,
  4. Pedro Miranda4,
  5. Mariusz Korkosz5,
  6. Jiri Vencovsky6,
  7. Andrea Rubbert-Roth7,
  8. Eduardo Mysler8,
  9. Matthew A Sleeman9,
  10. Alex Godwood9,
  11. Dominic Sinibaldi10,
  12. Xiang Guo10,
  13. Wendy I White10,
  14. Bing Wang11,
  15. Chi-Yuan Wu11,
  16. Patricia C Ryan10,
  17. David Close9,
  18. Michael E Weinblatt12
  19. on behalf of the EARTH EXPLORER 1 study investigators
  1. 1Department of Rheumatology and Clinical Immunology, Charité—University Medicine Berlin, Free University, and Humboldt University Berlin, Berlin, Germany
  2. 2Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, UK
  3. 3Center for Rheumatology, Albany Medical College, Albany, New York, USA
  4. 4Universidad de Chile and Hospital San Juan de Dios, Santiago, Chile
  5. 5Division of Rheumatology, Department of Internal Medicine and Gerontology, Jagiellonian University Medical College, Krakow, Poland
  6. 6Institute of Rheumatology, Charles University, Prague, Czech Republic
  7. 7Department of Internal Medicine, University of Cologne, Cologne, Germany
  8. 8Organizacion Medica de Investigación, Buenos Aires, Argentina
  9. 9MedImmune, Cambridge, UK
  10. 10MedImmune, Gaithersburg, Maryland, USA
  11. 11MedImmune, Mountain View, California, USA
  12. 12Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts, USA
  1. Correspondence to Dr Gerd R Burmester, Director, Department of Rheumatology and Clinical Immunology, Charité—University Medicine Berlin, Free University, and Humboldt University Berlin Charitéplatz 1, Berlin 10117, Germany; Gerd.Burmester{at}charite.de

Abstract

Objectives Despite the therapeutic value of current rheumatoid arthritis (RA) treatments, agents with alternative modes of action are required. Mavrilimumab, a fully human monoclonal antibody targeting the granulocyte–macrophage colony-stimulating factor receptor-α, was evaluated in patients with moderate-to-severe RA.

Methods In a phase IIb study (NCT01706926), patients with inadequate response to ≥1 synthetic disease-modifying antirheumatic drug(s), Disease Activity Score 28 (DAS28)−C reactive protein (CRP)/erythrocyte sedimentation rate ≥3.2, ≥4 swollen joints despite methotrexate (MTX) were randomised 1:1:1:1 to subcutaneous mavrilimumab (150, 100, 30 mg), or placebo every other week (eow), plus MTX for 24 weeks. Coprimary outcomes were DAS28−CRP change from baseline to week 12 and American College of Rheumatology (ACR) 20 response rate (week 24).

Results 326 patients were randomised (150 mg, n=79; 100 mg, n=85; 30 mg, n=81; placebo, n=81); 305 completed the study (September 2012–June 2013). Mavrilimumab treatment significantly reduced DAS28−CRP scores from baseline compared with placebo (change from baseline (SE); 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; all dosages compared with placebo).

Significantly more mavrilimumab-treated patients achieved ACR20 compared with placebo (week 24: 73.4%, 61.2%, 50.6% vs 24.7%, respectively (p<0.001)). Adverse events were reported in 43 (54.4%), 36 (42.4%), 41 (50.6%) and 38 (46.9%) patients in the mavrilimumab 150, 100, 30 mg eow and placebo groups, respectively. No treatment-related safety signals were identified.

Conclusions Mavrilimumab significantly decreased RA disease activity, with clinically meaningful responses observed 1 week after treatment initiation, representing a novel mechanism of action with persuasive therapeutic potential.

Trial registration number NCT01706926; results.

  • Rheumatoid Arthritis
  • Cytokines
  • Treatment

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Footnotes

  • Handling editor Tore K Kvien

  • GRB and IBM contributed equally.

    DC and MEW are joint senior authors.

  • Contributors GRB contributed to the study design, interpretation and generation of data, manuscript preparation and review; IBM contributed to study design, interpretation, manuscript preparation and review; JK contributed to study design, data analysis and interpretation, and manuscript preparation and review; PM contributed to data collection, review and interpretation; MK contributed to data collection and manuscript review; JV contributed to study design, data collection, analysis and interpretation, and manuscript preparation and review; AR-R contributed to study design, interpretation of data, manuscript preparation and review; EM contributed to protocol assessment, data analysis and interpretation, and manuscript preparation and review; MAS contributed to study design, data analysis and interpretation and manuscript preparation and review; AG contributed to study design and set-up, data cleaning, analysis and interpretation, and manuscript preparation and review; DS contributed to study design, data cleaning, analysis and interpretation, and manuscript preparation and review; XG contributed to data collection, analysis and interpretation, and manuscript preparation and review; WIW contributed to study design, data analysis and interpretation, and manuscript preparation and review; BW contributed to study design, data analysis and interpretation, and manuscript preparation and review; C-YW contributed to study design, data collection, and manuscript preparation and review; PCR contributed to study design, data collection, analysis and interpretation, and manuscript preparation and review; DC contributed to study design and conduct, data analysis and interpretation, and manuscript preparation and review; MEW contributed to study design and set-up, data analysis and interpretation, and manuscript preparation and review.

  • Funding The study was funded by AstraZeneca/MedImmune.

  • Competing interests 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.

  • Ethics approval Institutional Review Board/Independent Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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