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JAK inhibition as a treatment option for ankylosing spondylitis

Presented by
Prof. Atul Deodhar, Oregon Health & Science University, USA
ACR 2020

Tofacitinib demonstrated very promising results for oral treatment of active ankylosing spondylitis in a phase 3 trial. New safety risks were not detected.

Several types of immune cells playing a role in the pathogenesis of spondyloarthritis use JAK pathways [1]. Hence, not surprisingly, JAK inhibitors such as tofacitinib have already shown promising results in phase 2 trials for ankylosing spondylitis (AS) and therefore have potential to become a therapeutic option for this indication in the future [2,3].

The oral JAK inhibitor tofacitinib is now investigated in phase 3 for the treatment of AS [4]. This randomised, placebo-controlled, double-blind study included 269 adult patients with active AS, who met the modified New York criteria in centrally read radiographs. All patients had inadequate response or were intolerant to treatment with at least 2 non-steroidal anti-inflammatory drugs (NSAIDs). A primary analysis of the still ongoing trial was reported.

Over 16 weeks, study subjects were either treated with twice daily 5 mg tofacitinib or placebo. In the following open-label extension, all patients received 5 mg tofacitinib twice daily until week 48. The primary endpoint was defined as Assessment in Ankylosing Spondylitis (ASAS)20 response at week 16. The key secondary endpoint was ASAS40 achievement. Furthermore, 4 groups of endpoints for efficacy were evaluated at week 16, including change in various outcome types. Safety data was available up to week 48.

Baseline patient characteristics were: 85% males, the average age was 41, symptom duration was ~13 years, Ankylosing Spondylitis Disease Activity Score (ASDAS) was 3.8 for the group receiving tofacitinib and 3.9 for the group receiving placebo. “The majority of patients (80%) were naïve to biologic disease-modifying antirheumatic drugs (DMARDs) and 20% were inadequate responders to TNF inhibitors or had experienced biologic DMARDs in the past,” explained Prof. Atul Deodhar (Oregon Health & Science University, USA).

The rate of patients achieving an ASAS20 response at week 16 was 56.4% with tofacitinib and 29.4% with placebo (P<0.0001; see Figure). Furthermore, the percentage of ASAS40-responding patients at week 16 was significantly higher in those treated with tofacitinib (40.6%) than in those receiving placebo (12.5%; P<0.0001). ASDAS was significantly reduced by 1.36 for tofacitinib versus 0.39 for placebo (P<0.001). Comparisons for the ASAS components as well as various other secondary endpoints including CRP reduction were all significant in favour of tofacitinib treatment.

Figure. Tofacitinib in ankylosing spondylitis: primary and key secondary endpoints were achieved [4]

ASAS, Assessment in Ankylosing Spondylitis; BID, twice daily.

Concerning safety up to week 16, adverse events (AEs) were registered for 54.1% in the tofacitinib and 51.5% in the placebo group, with rates for serious AEs of 1.5% and 0%, respectively. Study discontinuation due to AEs at week 16 was low: 2.3% for tofacitinib versus 0.7% for placebo. “There were no unexpected side effects in this study,” said Prof. Deodhar. Concerning safety up to week 48, he further elaborated: “There were no malignancies, no thromboembolic events, no major adverse cardiac events, and no gastrointestinal perforations.”

In conclusion, the study met its primary and secondary endpoints with the demonstration of significant superiority of tofacitinib over placebo in the treatment of active AS and adds to the body of literature supporting the efficacy of JAK inhibition in AS and the seronegative spondyloarthropathies.

  1. Veale DJ, et al. Rheumatology (Oxford). 2019;58:197-205
  2. Van der Heijde D, et al. Ann Rheum Dis. 2017;76:1340-7.
  3. Poddubnyy D, Sieper J. Curr Rheumatol Rep. 2020;22:47
  4. Deodhar A, et al. Tofacitinib for the treatment of adult patients with ankylosing spondylitis: primary analysis of a phase 3, randomized, double-blind, placebo-controlled study. L11, ACR Convergence 2020, 5-9 Nov.

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