‘Great journey ahead’ for JAK inhibitors in rheumatic conditions: BSR 2022

Medicines

By Selina Wellbelove

16 May 2022

The future of JAK inhibitors as treatments for rheumatic and musculoskeletal diseases looks promising despite recent safety signals, but rheumatologists will need to be mindful of patient comorbidities to secure the best treatment outcomes, a UK conference has heard.

Professor Patrick Kiely, Professor of Practice in Clinical Rheumatology at St George’s University Hospitals NHS Trust, London, told the British Society for Rheumatology’s recent annual conference that there were no adverse events showing in the clinical data that would “wipe out” the entire JAK inhibitor class, nor a particular drug, but he reminded rheumatologists “to be very mindful of specific comorbidities, particular with MACE and cancer, and manage those alongside [the] drug of choice”.

With regard to efficacy, there is “little doubt” of “a great journey ahead” for JAK inhibitors in rheumatic conditions, he said.

Across the four conditions JAK inhibitors are already licensed for – rheumatoid arthritis (RA), psoriatic arthritis (PsA, ankylosing spondyloarthritis (AS) and juvenile idiopathic arthritis (JIA) – clinical data has shown comparability and/or superiority versus bDMARDs across the board, he noted.

And while to date there has been little success for JAK inhibitors in treating systemic lupus erythematosus (SLE), with Lilly recently pulling the plug an baricitinib after a disappointing performance in late-stage trials, Prof. Kiely believes there is still hope for the drug class within this indication.

“I don’t think the story is over for lupus,” he said. “The first attempt with baricitinib has not been a success,” but “there is still a Phase II study underway of updacitinib with a BTK inhibitor”, which could provide an alternative treatment pathway.

JAK inhibition also evidently remains an attractive target for pharma, and there are a lot of diseases where there is interest in application of a JAK inhibitors to the management of patients, he said.

For example, indications coming through the pipeline include upadacitinib in Phase IIII for Crohn’s disease, Giant Cell Arteritis (GCA) and Takayasu Arteritis (TAK), baricitinib in Phase II for juvenile idiopathic arthritis, Polymyalgia rheumatica/GCA, SLE, Sjorgen’s and idiopathic inflammatory myopathies/juvenile dermatomyositis, and tofacitinib in Phase II for Behets, Sjorgen’s, SLE, and TAK/large vessel vasculitis, he told delegates.

Safety in the spotlight

The recent ORAL Surveillance trial comparing tofacitinib to TNF inhibitors revealed new signals in older patients with one CV risk factor, prompting a class-wide warning from the US FDA, and an ongoing assessment of the data by the EMEA.

However, Professor Keily reassured delegates that, overall, there were actually very few CV events in the trial, and that the numbers needed to harm were very high.

The data showed a MACE incidence rate of 0.91 per 100 patient years in the tofacitinib 5mg twice daily group, and 0.71 for the comparative TNFi, while the number of CV events were 47 versus 37, respectively.

However, it must also be taken into account that TNF inhibitors “do a really good job at reducing CV risk”, which tofacitinib didn’t quite match up to, and that it is also unknown how other drugs, such as rituximab, would compare, he pointed out.

This is also the case with regard to malignancies; TNF inhibitors are very good at suppressing inflammation, a key driver of cancers (and CV risk), and again tofacitinib didn’t quite match up in the patients studied, Professor Kiely said.

So, “in high risk patients we have a signal, but that’s relative to TNFi which are the best that you could possibly do to reduce CV events and malignancy,” he noted.

As such, rheumatologists, he advised, should be mindful of the other factors and co-morbidities that increase the risk of MACE and malignancy and address these where possible, but “suppressing inflammation is the key priority, however you get there”.

Also in favour of JAK inhibitors, in ORAL’s high-risk cohort, rates of serious infection and DVT/PE were reassuringly similar between the group treated with 5mg twice daily tofacitinib and those given the comparative TNF inhibitor.

There was clearly a higher risk of herpes zoster in the tofacitinib group, but symptoms were generally mono-dermatome and non-serious. Furthermore, this adverse event will become even more manageable with the wider roll-out of the Shingrix vaccine, Prof Kiely said.

Looking forward, post-marketing surveillance will remain crucial to providing an accurate, real-world picture of the safety and efficacy of JAK inhibitors, and the picture could well change.

But for now, “for rheumatic and musculoskeletal disease, where pathogenesis is driven by type 1 cytokines utilising JAK signalling, the future of [JAK inhibitors] is exciting,” he concluded.

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