1926 - Cam-3001; a Novel Human Monoclonal Antibody against GM-CSFR-á, in Subjects with Rheumatoid Arthritis (RA): Results of a Phi Study

Tuesday, October 20, 2009: 3:30 PM
Auditorium (Pennsylvania Convention Center)
Gerd-R. Burmester, Charite, University Medicine Berlin Free University and Humboldt University of Berlin, Berlin, Germany, Frank Wagner, Charité Research Organisation GmbH, Berlin, Germany, Berlin, Germany, Eugen Feist, Charite University Hospital, Berlin, Germany, Matthew Sleeman, MedImmune Ltd, Cambridge, United Kingdom, Fabio Magrini, Medimmune, Cambridge, United Kingdom and Barbara White, Medimmune, Gaithersburg, MD
Presentation Number: 1926

GM-CSF is thought to play a significant role in RA. Elevated levels of GM-CSF have been shown in tissue biopsies and synovial fluid from arthritic patients. Furthermore, recombinant GM-CSF has shown to exacerbate disease in RA patients undergoing treatment for neutropenia (1). Using phage display we developed a human monoclonal antibody (CAM-3001) to the GM-CSFR alpha chain that neutralizes GM-CSF activity. We describe the results of a Phase I single ascending dose of CAM-3001 in RA.
Purpose: The primary objective was to assess the safety and tolerability of CAM-3001 in patients with RA. Other objectives included the pharmacokinetics of CAM-3001 and the effect on biomarkers of systemic inflammation.
Method: Thirty-two subjects with mild or inactive RA (DAS28 ≤4.8) on stable methotrexate (≥3 months) received single i.v. doses of CAM-3001 or placebo in ascending doses of 0.01 and 0.03, 0.1, 0.3, 1, 3, or 10 mg/kg. Safety was assessed throughout the study by evaluation of clinical and laboratory parameters.
Results: Adverse events were generally mild or moderate, and balanced between placebo and active treatments with no dose-relationship. There were two treatment-emergent serious adverse events (bilateral hernia, and breast cancer), neither of which was considered related to study drug. Mild transient neutropenia was seen in two subjects, and mild transient elevation of hepatic enzymes was also seen in two subjects. One subject experienced moderate urticaria of the face and neck during the infusion. Pulmonary function was also monitored and showed no clinically significant changes over the study period. Although the study was not designed to demonstrate clinical efficacy, post-hoc analysis of individual subjects with elevated CRP (>5mg/L) and ESR (>20mm/hr) at baseline showed reductions in CRP or normalization of ESR within the first 3 weeks post infusion, suggesting a potential benefit in RA. The pharmacodynamic activity of CAM-3001 pre and post dosing was also confirmed using an ex vivo GM-CSF-induced SOCS3 RT-PCR assay.
Conclusion: This is the first reported clinical study of a monoclonal antibody targeting the GM-CSF pathway in patients with rheumatoid arthritis. In this study, we show that CAM-3001 has an acceptable safety profile. Furthermore, the effects observed on acute phase reactants following single infusion of CAM-3001 suggest a potential effect on disease activity. This will be formally investigated in future clinical studies.
References: 1) Hamilton JA Nat Rev Immunol 2008; 8: 533-44. 2) Pereira J. Acta Haematol 1994;92: 154-56.

 

Sponsored by MedImmune.


Keywords: rheumatoid arthritis (RA)

Disclosure: G. R. Burmester, None; F. Wagner, None; E. Feist, None; M. Sleeman, MedImmune, 3 ; F. Magrini, Medimmune Ltd, 3 ; B. White, Medimmune LLC, 3 .