Xeljanz’s worrisome safety signal has been picked up across the pond. After the FDA issued an alert on the Pfizer blockbuster early this week, the European Medicines Agency said it's kicking off a review of its own.

The FDA is sifting through data from a postmarketing study in rheumatoid arthritis, which flagged serious blood clots in the lungs and deaths among patients taking the 10-mg dose. Pfizer said last week it had moved the 10-mg patients to the 5-mg dose and shared the data with the FDA.

Now, European regulators are digging in. "EMA is assessing the results of the study and will consider what regulatory action is needed," an EMA spokesperson told FiercePharma in a statement.

As is the case in the U.S., the 10-mg Xeljanz dose is only approved in Europe in ulcerative colitis. Xeljanz's approval in patients with RA and psoriatic arthritis specifies the 5-mg dose.

Xeljanz’s journey to EMA approval wasn’t smooth. In April 2013, the agency’s Committee for Medicinal Products for Human Use (CHMP) refused to approve the Pfizer drug out of "major concerns about the overall safety profile of Xeljanz." The regulator at that time was mainly worried about serious infections in Xeljanz patients but also noted side effects that included increased fat levels in the blood and cardiovascular risks.

Back then, Pfizer submitted to the EMA the same data it had used to win FDA approval. The FDA endorsed the drug in 2012 but asked Pfizer to run the postmarketing study that's now at issue.

In its positive opinion in 2017 after reviewing additional data provided by Pfizer, CHMP noted that the overall incidence of major CV events was low at 0.39 per 100 person-years. But it acknowledged the drug's safety profile remained "complex and clinically challenging," and said long-latency risks such as heart attacks and strokes would be examined in the postmarketing safety study.

The study, which focuses on patients with at least one CV risk factor, is evaluating the risk of cardiovascular events, opportunistic infections and cancer for Xeljanz at both doses—5 mg and 10 mg twice daily—versus a TNF inhibitor control group. When the increased rate of pulmonary embolism and death in the 10-mg group showed up, that prompted the FDA to send a public alert and start an investigation.

The postmarketing study will continue, with all patients taking the 5-mg dose; it’s expected to be completed by the end of 2019.

The Xeljanz episode represents a moment of déjà vu for the JAK inhibitor family, as Eli Lilly’s Olumiant was once rejected by the FDA for the exact same thromboembolic safety concerns. The difference is that the EMA didn’t take issue with Olumiant, approving it a month before Xeljanz for the European market, even though it noted increased blood cholesterol levels with the Lilly drug. When Lilly finally won its U.S. approval last year, the FDA rejected its 4-mg dose and only approved the lower 2-mg dose with a boxed warning. The EMA had greenlighted both.

The first oral JAK inhibitor on the market, Xeljanz pulled in $1.77 billion in global sales last year, up 32% from 2017. But both Xeljanz and Olumiant could face some in-class competition soon, as AbbVie’s application for upadacitinib in RA is under FDA priority review with a decision expected in the third quarter. And Gilead’s filgotinib is also wrapping up phase 3 in preparation for regulatory submissions.

In its 2018 in Review report released in February, EvaluatePharma predicted the AbbVie drug could generate $2.18 billion in 2024 sales, and the Gilead drug $1.49 billion.

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