OP0002 Tofacitinib in Patients with Ankylosing Spondylitis: A Phase 2, 16-Week, Randomised, Placebo-Controlled, Dose-Ranging Study

Abstract

BackgroundTofacitinib is an oral JAK inhibitor that has been investigated for the treatment of ankylosing spondylitis (AS).ObjectivesTo investigate for the first time the effects of tofacitinib in adult patients (pts) with active AS.MethodsThis was a 16-week (wk), Phase 2, multicentre, randomised, double-blind, placebo (PBO)-controlled, dose-ranging study (NCT01786668) to investigate efficacy, safety and dose-response of tofacitinib in pts with AS. Pts fulfilling the modified New York criteria (central read) were randomised 1:1:1:1 to PBO or tofacitinib 2, 5 or 10 mg BID for 12 wks plus 4 wks follow-up. Primary efficacy endpoint was ASAS20 response rate at Wk 12 using a 3-parameter Bayesian Emax model by assuming a monotonic response. Secondary endpoints included ASAS40 response rate, AS disease activity score using C-reactive protein (ASDAS), Bath AS disease activity index 50% (BASDAI50) response rate, Bath AS functional index, Bath AS metrology index (linear method), Spondyloarthritis Research Consortium of Canada (SPARCC) score of sacroiliac (SI) joints and spine. Safety endpoints included adverse events (AEs) and laboratory outcomes.Results208 pts were randomised and 207 treated; 196 pts completed the study. 51 pts (PBO group) and 52 (each tofacitinib group) were included in analyses. Baseline demographics and disease characteristics were balanced between groups and typical of AS populations (87.4% HLA-B27 positive; 81.2% white; 69.1% male; mean age 42 years; mean disease duration 6.3 years; mean BASDAI 6.7).The table summarises safety and efficacy results. The ASAS20 Emax model showed tofacitinib 10 mg BID had a high response rate and its confidence bounds met a pre-specified efficacy decision rule. ASAS20 response rates by NRI were significantly greater with tofacitinib 5 mg BID vs PBO, compared with 2 or 10 mg BID. All tofacitinib groups had ASAS40, ASDAS and BASDAI50 improvements of similar magnitude vs PBO. Tofacitinib 2 mg BID did not differ vs PBO in remaining clinical efficacy measures or SPARCC scores. Tofacitinib 5 and 10 mg BID had greater clinical efficacy vs PBO, with minimal differences between doses, and significantly improved SPARCC SI joint and spine scores vs PBO.No tofacitinib-related safety issues unique to the AS population or new safety concerns were identified. Two treatment-related herpes zoster cases were reported (1 each with tofacitinib 2 and 10 mg BID). No cases of tuberculosis, malignancy, gastrointestinal perforation or death were reported. Dose-dependent changes in laboratory outcomes commonly reported in other tofacitinib studies were observed and returned to approximately baseline values by Wk 16.ConclusionsTofacitinib 5 and 10 mg BID demonstrated greater clinical and imaging efficacy vs PBO in reducing the signs and symptoms of AS in adults with active AS. Safety was similar to that reported for tofacitinib studies in other indications.AcknowledgementPreviously presented (van der Heijde D et al. Arthritis Rheumatol 2015; 67(S10): Abstr 5L) and reproduced with permission from A...

Tracking JAKs in spondyloarthritis: rationale and expectations

“…In this issue, Van der Heijde and colleagues1 report the results of a randomised, prospective, placebo-controlled, dose-ranging trial evaluating the short-term (12 weeks) symptomatic effect of a Janus kinase (JAK) inhibitor, tofacitinib. This well-conducted and optimally presented trial raised two important points: (1) a potential role of the JAK/signal transducer and activator of transcription (STAT) pathway in the pathophysiology of axial spondyloarthritis (SpA) and (2) the expected results allowing to anticipate that such compounds might be included in the armamentarium for axial SpA.…”

“…JAKs play a critical role in both innate and adaptive immunity, which has justified the large number of JAK inhibitors developed in the past decades in the field of cancer but also rheumatology 1 2. JAKs bind to the intracellular domain of a broad range of receptors.…”

“…As an example, tofacitinib has been approved for rheumatoid arthritis4–6 and has shown interesting profiles of efficacy with psoriasis7 and psoriatic arthritis;8 in axial SpA, the results reported in this issue by Van der Heijde et al 1 are promising but can be seen as less impressive than in other rheumatological conditions. The specificity of JAK inhibition and the prominent cytokine pathways involved in each condition might explain these unequal response profiles.…”

“…Nevertheless, this kind of compound is not available until now, and tofacitinib is the only JAK inhibitor that has received regulatory approval in rheumatology. Indeed, tofacitinib is probably not the best JAK inhibitor to efficiently target the IL-23 pathway according to in vitro experiments demonstrating that tofacitinib inhibits JAK1 and JAK3, with marginal inhibition of JAK2 and TYK2 1 3. Similar experiments have shown baricitinib with more specificity for JAK1 and JAK2 over JAK33 and should be, in this regard, more effective in inhibiting IL-23 signalling and the Th17 pathway, hypotheses that require demonstration in clinical trials.…”

“…The interpretation of the clinical relevance of the findings from Van der Heijde and colleagues1 might differ according to different perspectives, particularly pharmaceutical companies in charge of developing a specific compound for a specific disease and clinicians managing disease in daily practice. In this article, specifically table 2, describing the ‘Emax model-predicted ASAS20 response’, the data observed did not reach the a priori decided target in terms of ASAS20 treatment response at week 12.…”