Background/Purpose: GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through the activation, differentiation, and survival of macrophages and neutrophils. Mavrilimumab (CAM-3001) is a human monoclonal antibody targeting the alpha subunit of GM-CSF receptor which MedImmune is developing as a novel treatment for RA.  Because GM-CSF plays a role in the regulation of pulmonary surfactant homeostasis (Trapnell and Whitsett, Ann Rev Physiology, 2002:775-802), lung toxicity is a potential concern for biologics such as mavrilimumab which inhibit GM-CSF receptor signaling. As a result, additional attention was given to the potential impact of lung toxicity during the development of mavrilimumab.

Methods: Nonclinical safety of mavrilimumab was evaluated in several repeat dose studies in cynomolgus monkeys.  Comprehensive toxicity parameters were assessed in each study, and treatment duration ranged from 4 to 26 weeks.  All animal studies were performed under approved protocols at AAALAC-accredited labs.  In the recently completed Ph2a clinical study EARTH (Burmester et al., ARD 2012 ) intensive respiratory monitoring included chest X-rays, forced expiratory volume (FEV1), forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO) and dyspnea scores. Serum biomarkers of lung damage, surfactant protein D (SP-D) and Krebs von den Lungen-6 (KL-6) were measured using commercially available immunoassays (BioVendor, LLC; Candler, NC).

Results: Mavrilimumab has an acceptable safety profile in monkeys with no changes in any parameters other than microscopic findings in lung.  In several studies, minimal accumulation of foamy alveolar macrophages was observed.  This finding was reversible following a dose-free recovery period and was considered non-adverse.  At very high dose levels (≥30 mg/kg), in a 26-week repeat IV dose study, the presence of lung foreign material, cholesterol clefts, and granulomatous inflammation was also observed in a few animals and was considered adverse.  These dose and time related changes in lung were consistent with mavrilimumab inhibitory effects on lung macrophage function arising from exaggerated pharmacology.  Overall, a clean no-observed-adverse-effect-level (NOAEL) without any effects in lung was established and provided adequate clinical safety margins. In EARTH, mavrilimumab demonstrated good clinical activity with no clinically significant or persistent changes in the lung function tests performed.  Likewise, the serum biomarkers of lung damage, SP-D and KL-6, showed no clinically significant changes following mavrilimumab treatment.

Conclusion: These results suggest that suppressing macrophage activity by targeting GM-CSF receptor alpha may be a novel approach with an acceptable safety profile for the treatment of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-of-mavrilimumab-in-cynomolgus-monkeys-relevance-of-nonclinical-findings-in-lung-to-human-safety/