The human monoclonal antibody MOR103, which targets granulocyte-macrophage colony-stimulating factor, was well tolerated and exhibited a satisfactory safety profile in the first human study assessing it for the treatment of active, moderate rheumatoid arthritis.
The phase I/II clinical trial was designed to determine the safety of multiple doses of MOR103, but the findings also "provided suggestive evidence for the efficacy of this agent," said Dr. Frank Behrens of the division of rheumatology, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany, and his associates. In exploratory analyses, they found that MOR103 produced significant improvement across all efficacy variables and had a rapid onset of action, compared with placebo.
Their results establish proof of concept for the use of antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in the treatment of RA, and "suggest that MOR103 has the potential to become a novel and valuable therapeutic option," the investigators said.
The GM-CSF molecule is thought to play a critical role in both initiating and exacerbating RA, and MOR103, a high-affinity recombinant human IgG1 antibody, blocks its receptors by binding to the GM-CSF epitope. In this industry-sponsored double-blind study of three doses of MOR103, 96 patients with active, moderate RA were treated and followed at 26 medical centers in Europe.
A total of 24 patients received 0.3 mg/kg MOR103; 22 received 1.0 mg/kg MOR103; 23 received 1.5 mg/kg MOR103; and 27 received matching placebo infusions every week for 4 weeks. All were followed for a further 16 weeks.
Adverse effects occurred more often during the study period in patients who received active treatment (42 of 69; 60.9%) than in those who received placebo (12 of 27; 44.4%). However, none of the adverse effects were considered to be definitely or even probably related to treatment, and all were of mild or moderate intensity.
Three adverse effects occurred more frequently in the active-treatment groups than in the placebo group: fatigue, cough, and RA exacerbations. However, the disease flares occurred after treatment ended and were considered to be related to drug withdrawal. There were no infusion reactions, but one case of rash and one case of fatigue were thought to be possibly related MOR103.
All of these differences "should be interpreted with caution because they are based on small subject numbers," Dr. Behrens and his associates said (Ann. Rheum. Dis. 2014 [doi:10.1136/annrheumdis-2013-204816]).
High levels of GM-CSF autoantibodies are known to be associated with idiopathic pulmonary alveolar proteinosis, so the study participants’ serum surfactant D levels were monitored and pulmonary function tests were performed at frequent intervals. There were no clinically important changes in these measures or in any other laboratory values between active treatment and placebo.
In an exploratory analysis, scores regarding swollen and tender joints on the Disease Activity Score-28 joints (DAS-28) improved rapidly and robustly with the two higher doses of MOR103, compared with placebo. Improvements also were seen on the European League Against Rheumatism response criteria, American College of Rheumatology improvement criteria, patients’ self-assessments of pain, the Health Assessment Questionnaire-Disability Index (HAQ-DI), and the Functional Assessment of Chronic Illness Therapy (FACIT).
Serial MRIs were performed to assess synovitis and bone edema and erosions. No significant differences were observed between active treatment and placebo groups.
Larger clinical trials are warranted to further assess the safety and efficacy of MOR103 for RA, the researchers said.
This study was funded by MorphoSys AG. Many of the investigators reported receiving grants and/or fees from MorphoSys AG. Two authors are employees of the company. No other conflicts of interest were reported.