Rapid Onset of Clinical Benefit Is Associated with a Reduction in Validated Biomarkers of Disease in Patients with Rheumatoid Arthritis Treated with Mavrilimumab, a Human Monoclonal Antibody Targeting GM-CSFRα: Analysis of the Randomized Phase 2b EARTH EXPLORER 1 Study

McInnes IB1, Burmester GR2, Kremer J3, Miranda P4, Korkosz M5, Vencovsky J6, Rubbert-

Roth A7, Mysler E8, Close D9, Sleeman M9, Godwood A9, Sandbach S9, Ryan P10 , Sinibaldi

D10, White W10, Defranoux N11, and Weinblatt M12

1. Glasgow Biomedical Research Centre, Glasgow, UK

2. Charité – University Medicine Berlin, Department of Rheumatology and Clinical

Immunology Free University and Humboldt University Berlin, Germany

3. Center for Rheumatology, Albany, NY, USA

4. Universidad de Chile and Hospital San Juan de Dios, Santiago, Chile

5. Division of Rheumatology, Jagiellonian University Hospital, Krakow, Poland

6. Institute of Rheumatology, Charles University, Prague, Czech Republic

7. Department of Internal Medicine, University of Cologne, Cologne, Germany

8. Organizacion Medica de Investigación, Buenos Aires, Argentina

9. MedImmune, Cambridge, UK

10. MedImmune, Gaithersburg, MD, USA

11. Crescendo Bioscience, South San Francisco, CA, USA

12. Division of Rheumatology, Immunology and Allergy Brigham and Women’s Hospital,

Boston, MA, USA

Background/Purpose Macrophages are pivotal to rheumatoid pathogenesis and their inflammatory products drive

many of the signs and symptoms of disease. Mavrilimumab inhibits macrophage activation

and survival via blockade of granulocyte-macrophage colony-stimulating factor receptor-α

(GM-CSFRα) and has previously shown a rapid (2 week) and sustained clinical benefit in

patients with RA. We present data from the EARTH EXPLORER 1 study examining speed of

clinical response to mavrilimumab, and effect on the multi-biomarker disease activity

(MBDA) score after week 1 (1 dose).

Methods This was a Phase 2b, 24-week, randomized, double-blind, placebo (PBO)-controlled study

(NCT01706926). Patients with adult-onset RA (18–80 years; DAS28-CRP >3.2; ≥4 swollen

joints; inadequate response to ≥1 DMARD) received mavrilimumab (30, 100, or 150 mg) or

PBO, administered subcutaneously every 2 weeks + methotrexate (7.5–25.0 mg/week).

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Efficacy assessments included DAS28-CRP, ACR responses, CRP, ESR, swollen joint

count (SJC), tender joint count (TJC) and pain. MBDA score was calculated using the

validated Vectra®DA algorithm, based on serum concentration of 12 biomarkers, to track the

effect of mavrilimumab on disease over time. Additional assessments were conducted on

MBDA biomarker components.

Results Overall, 326 patients with mean (SD) DAS28-CRP 5.8 (0.9) were randomized to

mavrilimumab (30, 100, or 150 mg) or PBO (n=81, 85, 79, and 81, respectively). At week 1

(first assessment), all mavrilimumab doses showed significant reductions from baseline in

DAS28-CRP (p<0.001 vs PBO; Figure A), with treatment benefit increasing to week 12.

Significant improvements for 150 mg vs PBO were seen at week 1 for CRP, ESR, SJC, TJC,

and pain (Table). Effects of mavrilimumab 150 mg were near maximal vs PBO for CRP,

ESR, and pain at week 1, and sustained (week 24). SJC and TJC for 150 mg improved from

baseline (week 1) and continued to improve (week 12); this was sustained until week 24.

Rapid onset of clinical benefit was paralleled with reduction in MBDA score; 100 and 150 mg

showed early (week 1) and sustained (week 24) significant changes in MBDA score vs PBO

(p<0.01; Figure B), with greater decreases in DAS28-CRP responders vs non-responders

(week 12). Approximately ≥50% decreases in serum IL-6, CRP, and serum amyloid-A

protein levels were observed at week 1 and maintained during treatment.

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Conclusion

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By targeting activated macrophages via inhibition of GM-CSFRα, mavrilimumab substantially

reduced patients’ RA disease activity from first (week 1; 1 dose) to final assessment,

evaluated by multiple clinical endpoints and biomarkers.

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