Rare diseases

JAK inhibitors the ‘new therapeutic paradigm’ in ankylosing spondylitis

The oral Janus kinase (JAK) inhibitor, upadacitinib, is emerging as a potential new treatment option for patients with ankylosing spondylitis (AS) according to results from a phase 2/3 study.

The drug, which is not yet available in Australia, is approved in the US and Europe to treat rheumatoid arthritis (RA) but has recently been explored for the treatment of AS.

Published in The Lancet, findings from the SELECT-AXIS 1 study – the first randomised trial of upadacitinib versus placebo in patients with active ankylosing spondylitis – reveal that patients treated with the selective JAK1 inhibitor were significantly more likely than those given placebo to achieve the primary outcome of an ASAS40 response at week 14.

The primary outcome was met by 52% of the 93 patients treated with the JAK inhibitor compared to 26% of the 94 participants in the placebo arm.

According to researchers from the Netherlands, treatment with 15mg upadacitinib once daily led to statistically significant improvements in disease activity, function, and MRI-detected axial inflammation among biologic-naïve patients with ankylosing spondylitis and an inadequate response or intolerance to nonsteroidal anti-inflammatory drugs.

The significant differences in ASAS40 response rates between the two groups could be seen as early as two weeks and were maintained throughout 14 weeks.

Furthermore, patients given upadacitinib experienced significantly greater decreases in Spondyloarthritis Research Consortium of Canada MRI spine and sacroiliac joint scores, as well as ASDAS and BASFI scores, compared with those given placebo in a multiplicity-controlled analysis.

Investigators said that rates of adverse events were similar in the upadacitinib and placebo groups, adding that, ‘the safety profile was consistent with findings from upadacitinib studies in patients with rheumatoid arthritis and other indications.”

Overall, 62% and 55% of patients in the upadacitinib and placebo arms, respectively, experienced adverse events while 2% and 3% respectively experienced adverse events leading to treatment discontinuation. Infections occurred in 20% of patients given the JAK inhibitor and 28% of those in the placebo group.

Describing the study as ‘well constructed’ rheumatologist and Associate Professor at the University of NSW, Paul Bird, told the limbic the findings ‘open up a whole new therapeutic paradigm’ for patients with ankylosing spondylitis.

“The response we’re seeing here is in keeping with what we’re seeing with other agents like NSAIDs and biological DMARDs and we’re not seeing any safety signal, so this does look promising,” he said.

Noting that the patient profile seen in the study is ‘exactly what we see in clinical practice’ Associate Professor Bird said the study is generalisable but added that longer term data is needed to determine whether the effect is sustained.

Commenting on the role of MRI in the study, Associate Professor Bird said it was ‘good’ to see imaging outcomes used as well as clinical outcome measures.

“That might help us as clinicians on the way to knowing when to use imaging in our patients to see how they’re responding to treatment. At the moment we don’t do this and this study gives us data on how we might use imaging better to monitor outcomes in patients.”

As for where the drug sits in terms of a treatment algorithm, he expects TNF inhibitors will remain first line therapy.

“At the moment we have a lot of data on TNF inhibitors – much better long term safety data – so it would remain the mainstay of therapy however, for those patients who don’t respond to TNF inhibition they will be able to potentially move to this medication.

The other factor, he adds, is convenience.

“This is an oral medication as opposed to an injection and for a lot of younger people with ankylosing spondylitis that’s appealing.”

And according to Professor Bird, the excitement for the JAK inhibitors in ankylosing spondylitis could extend to the full spectrum of axial spondyloarthritis

“Ankylosing spondylitis is one end of the spectrum – usually male and more severe disease – but there is a huge number of people along the spondyloarthritis spectrum with different characteristics who don’t see a response to TNF inhibitor therapy that is as good as what we see in pure ankylosing spondylitis and for those people this provides an exciting alternative.”

In a linked comment accompanying the study, Associate Professor Maria Tektonidou from Laikon Hospital, Athens, Greece said: “head-to-head comparisons, as well as differences in safety, convenience, and cost, will help to determine the place of JAK inhibitors in the treatment algorithm of ankylosing spondylitis.”

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