Background/Purpose: GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through effects on macrophages and neutrophils. Mavrilimumab (CAM-3001) is a human monoclonal antibody targeting the alpha subunit of GM-CSF receptor. Marvrilimumab was recently evaluated in RA subjects in a phase 2a study (EARTH). Results reported from the European (EU) cohort demonstrated that mavrilimumab may provide clinical benefit to patients with moderate to severe RA (Burmester GR, et al. ARD 2012). Here, we describe final data from EARTH comparing results in the EU and Japanese (JA) cohorts. Biomarker (BM) assessments were also performed to elucidate mechanistic aspects of mavrilimumab.

Methods: Mavrilimumab (10, 30, 50 or 100 mg) or placebo was administered SC every other week to subjects with moderate/severe RA (DAS28 > 3.2) on stable methotrexate for 12 weeks followed by a 12 week drug free follow up period. A multi-biomarker disease activity (MBDA) score was calculated using the validated Vectra ®DA algorithm and used to track the effect of the drug on disease activity over time. An additional multi-BM-based algorithm (MBSD) was used to assess the impact of mavrilimumab on markers known to be associated with progressive joint damage. The relative ability of different mavrilimumab doses, over time, to saturate GM-CSF receptors in whole blood was examined by flow cytometry using receptor occupancy assay (ROA) in the EU cohorts.

Results: In the EARTH study, mavrilimumab demonstrated good clinical activity with generally similar responses in the EU and JA cohorts. In the overall population, the primary endpoint (DAS28-CRP reduction ≥1.2 at Week 12) was met. Improvements were seen as early as week 2 and persisted through the 12 week follow up especially in the 100 mg dose group. The MBDA score decreased significantly as early as day 8 (p<0.05) and remained suppressed during the entire treatment period in cohorts from both EU and JA. Additional samples from the 100 mg EU cohort showed that suppression of the MBDA was maintained for a minimum of 4 weeks after the last dose. Individual components of the MBDA score, as well as additional BMs in the EU cohort showed that CRP, SAA, IL-6, IL-2RA and MDC were significantly decreased on days 8, 15, 88 and 113 in the 100 mg cohort compared to placebo. Lesser or no changes were observed with the 10 mg cohort. There was an early and sustained dose-related inhibition of the joint damage composite index MBSD observed in the EU cohort. In the JA cohort a significant decrease was also observed when comparing treatment group to placebo group. The ROA results showed the 10 mg dose was sub-optimal in its ability to saturate GM-CSF receptor. This sub-optimal effect was reflected in the BM analysis and in the clinical efficacy endpoints.

Conclusion: Promising clinical safety and efficacy results of mavrilimumab support further clinical development at doses greater than 10 mg. Mechanistically, the drug suppressed both acute phase and inflammatory blood markers. Tracking of disease activity by MBDA showed a clear biomarker-based dose-response relationship. The association of MBSD decline with radiographic damage will be assessed in an on-going phase 2b study.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/biomarkers-associated-with-rheumatoid-arthritis-disease-activity-including-joint-damage-correlate-with-changes-in-clinical-response-in-subjects-treated-with-mavrilimumab-at-doses-above-10-mg/