GlaxoSmithKline (GSK) has recently provided the latest developments in the phase otilimab III clinical development project, ContRAst.otilimab, a monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor (GM-CSF), is currently being evaluated under the ContRAst program for the potential treatment of moderate to severe rheumatoid arthritis (RA). The program enrolled patients with extensively refractory RA who were inadequate or refractory to existing therapies.
The first two trials from the ContRAst project, the ——ContRAst-1 trial and the ContRAst-2 trial, reached the statistically significant primary endpoint of ACR20 response: at week 12 of patients with inadequate response to methotrexate (ContRAst-1 trial) (ContRAst-1 trial), otilimab response was achieved in DMARD compared with placebo.
The ——ContRAst-3 trial from ContRAst Project Trial 3 did not reach the statistically significant primary endpoint of ACR20 response: In patients with insufficient response to biological DMARD and / or Janus kinase inhibitors (JAK inhibitor), otilimab treatment showed no statistically significant improvement in ACR20 response at week 12 compared to placebo.
Although the ContRAst-1 and ContRAst-2 trials have reached their primary end point, the demonstrated efficacy is unlikely to alter patient care in this refractory patient population. Efficacy and safety data assessment of the ContRAst program is ongoing, but the limited efficacy demonstrated does not support an appropriate benefit / risk profile of otilimab as a potential therapy for rheumatoid arthritis (RA). Therefore, GSK has decided not to conduct regulatory submissions. The full results of the Phase ContRAst 3 project will be submitted for journal publication in 2023.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by pain, joint swelling, stiffness, joint destruction, and disability. The disease affects 24.5 million people worldwide. Despite the use of disease-modifying antirheumatic drugs (DMARD), a significant number of patients are still unresponsive or underresponsive. Therefore, drugs with different mechanisms of action are needed for more effective treatment.
otilimab (formerly GSK3196165) is a whole-human monoclonal antibody that inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF), a protein central role in a wide range of immune-mediated diseases (including rheumatoid arthritis). GM-CSF acts on cells, including macrophages (an immune cell type that plays a key role in the inflammatory process), causing inflammation, joint damage, and pain.otilimab neutralizes the biological function of GM-CSF by blocking the interaction of GM-CSF with its cell-surface receptors.
In 2013, GSK acquired exclusive global rights from MorphoSys AG to develop and commercialize otilimab in all therapeutic areas. The Phase ContRAst 3 program, announced in July 2019, aims to compare two doses of otilimab (90mg and 150mg, subcutaneous once weekly) with placebo, tofacitinib (tofacitinib, a JAK inhibitor; 5mg capsule twice daily), and sarilumab (an anti-IL-6 mAb, 200mg, subcutaneous every other week), all combined with methotrexate or conventional DMARD. The primary endpoint of each trial was the proportion of patients achieving an ACR20 response at week 12 of treatment (as compared to placebo).
