JAK inhibitors: fate in doubt for rheumatoid arthritis?

Abstract

In a landmark decision, the UK's National Institute for Health and Care Excellence (NICE) have approved the use of the Janus kinase (JAK) inhibitor filgotinib in patients with moderate-to-severe rheumatoid arthritis. This the first targeted drug recommended in the UK for patients with moderate disease, and the approval notably diverges from the US FDA's decision in August 2020 to reject filgitonib on concerns over testicular toxicity. With two opposing verdicts and a long history of safety concerns with JAK inhibitors, does the NICE decision reflect a lack of caution? Approximately 1% of the UK population have rheumatoid arthritis, and with up to half of patients failing to achieve remission with prior DMARD treatment, there is huge demand for new therapies. JAK inhibitors have been at the forefront of the race for new drugs, with Gilead's filgotinib and Abbvie's upadacitinib among the top competitors. The FDA approved upadacitinib for rheumatoid arthritis in 2019, but this came along with a black box warning about increased risk of serious infection, malignancy, and thrombosis—a feature also shared by other approved JAK inhibitors including Pfizer's tofacitinib. Indeed, Gilead had emphasised filgotinib's relative safety as a positive distinguisher. However, the drugs' effect on sperm is a long-standing concern; one that may have influenced AbbVie's decision to drop filgotinib in 2015 and focus on upadacitinib. NICE's approval of filgotinib—for patients with moderate-to-severe rheumatoid arthritis who have responded inadequately to previous therapy with two or more DMARDs—was based in part on the results of the FINCH 3 trial, which showed superiority of filgotinib (200 mg) plus methotrexate versus methotrexate alone. Despite this, the FDA chose to reject filgotinib due to concerns over the benefit-risk profile—in particular, increased risk of testicular damage and reduced sperm count—a decision expected to cost Gilead up to US$3 billion in annual sales for rheumatoid arthritis alone. Gilead is already conducting two safety trials looking at male reproductive safety: the MANTA study in men with inflammatory bowel disease, and the MANTA-RAy study in men with active rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and nonradiographic axial spondyloarthritis. But rather than wait for these results, the company curtailed plans to pursue the drug in the US and cancelled its rheumatoid arthritis trials programme completely, citing a competitive US market. The FDA's concern over testicular toxicity draws an important focus on the often-overlooked topic of male infertility for many rheumatological drugs. Much of the available data on the effects of DMARDs on reproductive function are based on maternal exposures, and women are often counselled on the potential for adverse reproductive effects of these medications. Male infertility, by contrast, is often overlooked both when developing drugs and when prescribing them. A retrospective analysis of men receiving an anti-TNF agent found that only 10% received counselling and even fewer had discussions on sperm cryopreservation, despite some evidence that TNF is critical for optimal sperm production. Indeed, the FDA's rejection of filgotinib can be seen as an important step in recognising fertility as an important issue for both men and women. Gilead is still pursuing filgotinib trials in other conditions, such as inflammatory bowel disease, largely because the US market is less competitive than it is with rheumatoid arthritis drugs. But safety concerns are still an issue. Pfizer recently announced the results of their FDA-mandated ORAL Surveillance safety study of tofacitinib compared with TNF inhibitors in patients with rheumatoid arthritis and cardiovascular risk factors, which revealed significantly higher rates of adjudicated malignancies and major cardiovascular events with tofacitinib. A postmarketing safety study of baricitinib is expected to be completed in 2025; however, the ORAL Surveillance results will surely put pressure on the FDA to restrict tofactinib use and to be more cautious with future approval of JAK inhibitors for any indication. NICE's approval of filgotinib on the backdrop of the long-standing safety concerns around this class of drug raises questions over its future use in patients with rheumatoid arthritis. Once regarded as the next generation of management, there is now growing concern over the suitability of these drugs. Gilead's cancellation of its rheumatoid arthritis clinical trial programme means that questions over the benefit-risk profile of filgotinib for the patients will remain unanswered for now; but this case has added additional concerns for the rheumatology community.