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An FDA safety review of an approved Pfizer anti-inflammatory medication is complete, and the conclusions are rippling across the entire drug class as the agency calls for additional warnings about the risk of serious adverse events, some of them potentially fatal.

The review focused on Xeljanz, a drug that was first approved as a treatment for rheumatoid arthritis (RA). The Pfizer drug is small molecule that blocks Janus kinase (JAK) enzymes, a family of enzymes that play a role in cell signaling in inflammatory diseases and cancer. Xeljanz’s blocking of  JAK enzymes can address an overactive immune system, but this approach can also spark other issues, such as blood clots, a diminished ability to fight infections, and even cancer. Those warnings are flagged on the drug’s label.

When the FDA initially approved Xeljanz in 2012, the regulator required Pfizer to conduct an additional study to further evaluate the risks of cardiovascular problems, cancer, and infections in rheumatoid arthritis patients age 50 and older who have at least one cardiovascular risk factor. The open-label study enrolled 4,362 volunteers who were randomly assigned to groups given one of two doses of Xeljanz or a tumor necrosis factor (TNF) blocker, an older medication used to treat arthritis. The two main goals of the study were to assess major adverse cardiovascular events and cancer.

According to the FDA’s report of the study results, both Xeljanz groups saw an increased risk of death, cardiovascular problems, cancer, and blood clots compared to the group of patients treated with TNF blockers. The cancer risk was also higher. The FDA said lymphomas and lung cancers were observed at higher rates in both Xeljanz groups compared to the TNF group. Those risks were particularly pronounced in current or past smokers.

Since Xeljanz’s initial approval, the drug has gone on to win additional regulatory nods for treating psoriatic arthritis, ulcerative colitis, and a type of arthritis that develops in kids and teens. Across all approved indications, the Pfizer drug produced generates more than $2.4 billion a year in sales last year, according to the company’s 2020 annual report. Other FDA-approved JAK inhibitors include Eli Lilly’s Olumiant and Rinvoq from AbbVie—both of them rheumatoid arthritis drugs. Like Xeljanz, the Lilly and AbbVie drugs carry black box warnings, the strictest and most prominent warnings that the FDA can place on a drug’s label. The FDA said Wednesday it is now requiring label revisions that further alert clinicians and patients to consider the risks of JAK inhibitors versus their benefits.

“Olumiant and Rinvoq have not been studied in trials similar to the large safety clinical trial with Xeljanz, so the risks have not been adequately evaluated,” the FDA said. “However, since they share mechanisms of action with Xeljanz, FDA considers that these medicines may have similar risks as seen in the Xeljanz safety trial.”

To ensure that the benefit of these drugs outweighs the risks to the patients who take them, the FDA is further limiting approved use of these drugs to patients who have not responded to or cannot tolerate treatment with TNF blockers.

Two other JAK inibitors, Jakafi from Incyte and Bristol Myers Squibb’s Inrebic, are treatments for blood disorders. Since they are not approved for arthritis and other inflammatory conditions, the FDA said that they are not included in the required prescribing information updates covering the JAK inhibitors from Pfizer, AbbVie, and Eli Lilly. But the FDA added that Jakafi and Inrebic will require different updates to their labels.

Still unclear is what the updates mean for JAK drug applications still under FDA review. A regulatory decision for Pfizer drug abrocitinib in atopic dermatitis has been postponed twice this year. Earlier this week, the pharmaceutical giant reported clinical data showing that the small molecule beat Regeneron Pharmaceuticals’ blockbuster drug Dupixent in a head-to-head study in atopic dermatitis. Pfizer is also waiting to see if the FDA will approve the expansion of Xeljanz’s approval to include ankylosing spondylitis, an inflammatory condition affecting the spine.

Rinvoq, first approved in 2019, accounted for $731 million in sales for AbbVie last year. The Illinois-based pharmaceutical giant awaits a regulatory decision on the expansion of Rinvoq’s approval to include moderate-to-severe atopic dermatitis. Olumiant, developed by partners Incyte and Lilly and marketed by Lilly, accounted for $639 million in sales last year. Lilly and Incyte also await a regulatory decision on their application to add moderate-to-severe atopic dermatitis to as an approved indication.

Photo by FDA

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