DENVER – The emerging new era in the treatment of spondyloarthritis is combined blockade of tumor necrosis factor–alpha (TNF-alpha) and interleukin-17 using a bispecific antibody, Dr. Siba P. Raychaudhuri predicted at the annual meeting of the Spondyloarthritis Research and Treatment Network.
“This is the next generation of antibody therapies for spondyloarthritis,” said Dr. Raychaudhuri, a rheumatologist at the University of California, Davis.
Bruce Jancin/Frontline Medical News
Dr. Siba P. Raychaudhuri
This novel approach has a sound theoretical basis. Moreover, studies in mouse models, including models of rheumatoid arthritis (Arthritis Rheumatol. 2015 Jan;67[1]:51-62), have been positive. And proprietary bispecific anti-TNF-alpha/IL-17 antibodies are now in phase I and phase II clinical trials for various forms of spondyloarthritis, he noted.
The impetus for development of this new therapy is widespread agreement that while TNF inhibition has been a step forward in the treatment of axial spondyloarthritis, the efficacy is less than hoped for with these potent and costly agents.
“Things have been sort of gray for almost the last 10 years. All the evidence suggests we’re not getting full efficacy with anti-TNF therapy. We’re getting stuck at about a 60% ASAS 20 response,” he observed.
The explanation for this merely middling success rate appears to be that TNF inhibition induces a counterregulatory uptick in the IL-17 pathway. And in animal models, IL-17 is a key mediator of joint inflammation and destruction.
Dr. Raychaudhuri noted that brodalumab, an investigational human monoclonal antibody directed against IL-17 receptor A, has been shown “reasonably effective” in a phase II study in patients with psoriatic arthritis, which is part of the spondyloarthritis family of autoimmune diseases, achieving an ACR 20 response rate of 39% at week 12 in the high-dose arm (N Engl J Med. 2014 Jun 12;370[24]:2295-306).
The expectation is that by inhibiting both TNF-alpha and IL-17 using a bispecific protein composed of fragments of two different monoclonal antibodies, the result will be reduced growth and differentiation of proinflammatory T cells, decreased T cell migration, and synergistic clinical efficacy, compared with what’s attainable by addressing either target alone.
Dr. Raychaudhuri reported receiving research grants from or serving as a consultant to Abbott, Amgen, Celgene, UCB, and Janssen Biotech.