Two Important Negative Trials in Ankylosing Spondylitis

Jonathan Kay, MD


June 28, 2012

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Hello. I'm Jonathan Kay, Professor of Medicine at the University of Massachusetts Medical School and Director of Clinical Research in the Division of Rheumatology at University of Massachusetts Memorial Medical Center, both in Worcester, Massachusetts. Welcome to my Medscape blog.

I am in Berlin, Germany, where I have been attending EULAR (The European League Against Rheumatism) Congress 2012. Today, Professor Joachim Sieper of Berlin presented 2 very interesting abstracts addressing the inhibition of interleukin-6 (IL-6) in the treatment of ankylosing spondylitis. We know that rheumatoid arthritis is a disease in which IL-6 plays an important role. IL-6 drives production of C-reactive protein, an acute-phase reactant that is elevated in many patients with active rheumatoid arthritis. Also, IL-6 is present in the joints of patients with active rheumatoid arthritis. Inhibition of IL-6 with tocilizumab, a monoclonal antibody directed against the IL-6 receptor, very effectively treats rheumatoid arthritis disease activity in individuals with early disease that is naive to methotrexate, in those who are inadequately responsive to methotrexate, and in those who are inadequately responsive to tumor necrosis factor (TNF) inhibition.

Levels of circulating IL-6 have been detected in patients with active ankylosing spondylitis and have also been recovered from the sacroiliac joints of patients with ankylosing spondylitis. Thus, it would make sense that IL-6 is an important driver of inflammation in ankylosing spondylitis.

Ankylosing spondylitis is a disease that is exquisitely responsive, in most patients, to TNF inhibition, which suggests that IL-6 inhibition might also be an effective form of therapy for this disease. With this preclinical information, 2 clinical trials were undertaken to investigate IL-6 inhibition in the treatment of ankylosing spondylitis.

One trial investigated the use of tocilizumab for the treatment of patients with active ankylosing spondylitis[1] and the other investigated sarilumab[2], a fully human antibody to the alpha chain of the IL-6 receptor, also for the treatment of patients with active ankylosing spondylitis. Both studies were phase 2, international, multicenter, randomized, double-blind, placebo-controlled trials, and they enrolled very similar patient populations. Patients were in their early 40s, predominantly male, most of them had the HLA-B27 antigen, and they had Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores > 4, with mean BASDAI scores upon study entry that were significantly above the cutoff of 4. The primary endpoint in these studies was 20% improvement in assessment of ankylosing spondylitis (ASAS 20) clinical response. Secondary endpoints included ASAS 40, improvement in BASDAI scores, and other measures of ankylosing spondylitis disease activity.

The tocilizumab study compared 8 mg/kg intravenously monthly with placebo in a 12-week, randomized, double-blind, placebo-controlled trial. The other study looked at 5 different dosing regimens of the subcutaneous monoclonal antibody sarilumab -- 100 mg subcutaneously every 2 weeks, 150 mg subcutaneously every 2 weeks, 100 mg subcutaneously weekly, 200 mg subcutaneously every 2 weeks, and 150 mg weekly -- compared with placebo. The baseline characteristics of patients in that trial were very similar to those of patients in the tocilizumab study. Both studies enrolled about 50 patients in each arm and both studies had similar rates of dropout among patients on placebo and among patients in the drug-treated arms. The reasons for discontinuation were similar and were not clearly due to toxicity or lack of efficacy.

The surprising finding in both studies was that the drugs tocilizumab and sarilumab were not effective in treating ankylosing spondylitis. In fact, placebo-treated patients exhibited greater improvement in some measures than did drug-treated patients. In the sarilumab trial, MRI of the spine was performed before and after treatment. The posttreatment MRIs showed more disease activity than the pretreatment MRIs. Thus, both studies concluded that IL-6 inhibition was ineffective for the treatment of ankylosing spondylitis, and further development of both agents for the treatment of ankylosing spondylitis was stopped.

Typically, a negative trial could be blamed on vagaries of the trial design or problems with study enrollment or study conduct. However, the presentation of 2 negative trials of drugs with the same mechanism of action and with very similar study design and very similar patient populations suggests that the target IL-6 is not a major player in the pathogenesis of ankylosing spondylitis. Thus, these 2 negative trials are very important for teaching us more about the pathophysiology of ankylosing spondylitis, which appears to be a disease that is driven by TNF but not by IL-6.

It is not often that negative trials are interesting for this reason, but the presentation of these 2 trials of negative results in ankylosing spondylitis were very instructive and interesting.

Thank you for your attention. I welcome your comments and suggestions regarding my Medscape blog, and I look forward to seeing you again.


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