MAUI, HAWAII – Arguably the most exciting therapeutic development in axial spondyloarthritis in the past year was the demonstrated efficacy and safety of the investigational oral selective Janus kinase 1 inhibitor filgotinib in the setting of active ankylosing spondylitis, speakers agreed at the 2019 Rheumatology Winter Clinical Symposium.
“This is big, big news,” commented symposium director. “This is going to be a big deal.”
Other recent clinical trials of note in axial spondyloarthritis (SpA) highlighted by Dr. Kavanaugh and, professor of medicine at Northwestern University, Chicago, included a positive phase 3 study of certolizumab pegol (Cimzia) in nonradiographic SpA, two positive phase 3 trials of the interleukin-17A antagonist ixekizumab (Taltz) in radiographic SpA, a positive phase 2b trial of the dual IL-17A/F antagonist bimekizumab, and publication of three surprisingly negative phase 3 trials of the IL-12/23 inhibitor ustekinumab (Stelara).
TORTUGA was a phase 2b, double-blind, multicenter trial of 116 European patients with active ankylosing spondylitis nonresponsive to NSAIDs who were randomized to oral filgotinib at 200 mg once daily or placebo for 12 weeks. Filgotinib reduced the Ankylosing Spondylitis Disease Activity Score (ASDAS) by a mean of 1.47 points from baseline, a significantly better result for the primary outcome than the 0.57-point decrease in controls ().
Dr. Ruderman was also favorably impressed with the oral Janus kinase 1 (JAK1) inhibitor’s performance on the secondary outcome measures, including a mean 2.41-point reduction from baseline on the Bath Ankylosing Spondylitis Disease Activity Index, compared with a 1.44-point decrease in controls, with the difference being significant from week 8 onward. The filgotinib group also did significantly better on validated measures of physical function, spinal mobility, physical function, quality of life, peripheral arthritis, fatigue, and spinal and sacroiliac joint inflammation as assessed by MRI.
One patient in the filgotinib group, a smoker, developed pneumonia and another experienced deep venous thrombosis.
The study results are an exciting development because SpA treatments with new mechanisms of action are sorely needed. NSAIDs are considered first-line pharmacotherapy at present, with various tumor necrosis factor (TNF) inhibitors as well as the IL-17 inhibitor secukinumab (Cosentyx) the only approved biologic alternatives.
“This is the most impressive data I’ve seen that JAK inhibitors are effective in ankylosing spondyloarthritis,” commented, professor of rheumatology and director of the University of Leeds (England) Musculoskeletal Biomedical Research Center.
TORTUGA was the first positive phase 2 trial of a selective JAK1 inhibitor in SpA. However, Dr. Kavanaugh noted that while a phase 2 trial of tofacitinib (Xeljanz) failed to meet its “very convoluted” primary endpoint, the JAK1/3 inhibitor was positive for key secondary endpoints, including favorable MRI changes. And a phase 3 trial of tofacitinib in SpA is underway.
A key remaining question pending the outcome of definitive phase 3 trials is whether specificity of JAK enzyme inhibition matters or if a class effect is at work, according to Dr. Kavanaugh, professor of medicine at the University of California, San Diego.