The Food and Drug Administration is putting new restrictions in place for three similar, immune-regulating drugs after a large study of one of them raised further concerns about safety.
The study found that, when compared to another type of drug called a TNF inhibitor, patients given Pfizer's Xeljanz were at increased risk of blood clots, serious heart-related events like heart attack or stroke, as well as cancer and death. The FDA is therefore requiring that Xeljanz, Eli Lilly's Olumiant and AbbVie's Rinvoq only be given to patients who cannot take or do not respond to a TNF inhibitor. The rule applies to all the diseases those three drugs are approved to treat.
Xeljanz, Olumiant and Rinvoq each block Janus kinases, or JAKs, a family of proteins involved in immune system activities. Two other JAK drugs on the market, Incyte's Jakafi and Bristol Myers Squibb's Irebic, are excluded from the FDA's new mandate because they're used for blood disorders as opposed to inflammatory conditions, and as such need different updates to their prescribing information.
First approved in 2012, Xeljanz has proven an effective treatment for various kinds of arthritis and other inflammatory diseases like ulcerative colitis. Yet, the drug works by blocking immune-regulating proteins, meaning it can also impair how the body defends against harmful microbes or cancer. Over the years, the FDA has required the Xeljanz label to warn about the potential for serious infections, blood clots and malignancies.
Pfizer had hoped a large study pitting Xeljanz against TNF inhibitors — the class of drugs which includes blockbuster treatments like Humira and Enbrel — might ease some of these safety concerns. Instead, the results showed a higher incidence of health issues like major heart complications and cancer among those participants who were on Pfizer's drug.
Analysts have anticipated those results, despite being for Xeljanz alone, would lead to new prescribing rules across the approved JAK drugs. That appears to be the case, as the FDA is mandating the labels for Xeljanz, Olumiant and Rinvoq now include information about the risks of serious heart-related events, cancer, blood clots and death.
More surprising, though, were the new criteria specifying that patients must first go through a TNF inhibitor before being eligible for any of those three JAK drugs.
"The final language in the update is perhaps somewhat more worrisome than what we think most were expecting," wrote Vamil Divan, an analyst at Mizuho Securities, in a note to clients.
Some suspect that provision was particularly jarring for AbbVie and its investors, as the company's share price slid more than 7% in Wednesday afternoon trading. In contrast, Pfizer and Lilly shares were mostly unchanged.
"For AbbVie, Rinvoq’s potential is almost certainly reduced in the USA, by this labeling," Geoffrey Porges, an SVB Leerink analyst who covers the company, wrote in a note to clients. And "[s]ince AbbVie has more at stake with Rinvoq than other manufacturers it makes sense that their stock is most affected by this disclosure."
Still, many rheumatologists already use JAK drugs as a "second-line" or later option for after they've prescribed TNF inhibitors, and that hasn't stopped sales of the drugs from growing. Revenue from Xeljanz rose 9% last year to hit almost $2.5 billion, whereas Olumiant revenue shot up 50% to $639 million.
AbbVie, meanwhile, recorded $731 million in net Rinvoq revenue last year, and has forecasted $8 billion in sales by 2025. That forecast, though, hinges on the FDA clearing Rinvoq in diseases beyond rheumatoid arthritis, specifically eczema, psoriatic arthritis and a kind of spinal arthritis called ankylosing spondylitis. AbbVie had asked for approval in those indications, but the FDA delayed its decision while it finished investigating the safety concerns around Xeljanz.
On his end, Porges maintains that AbbVie could still meet its ambitious goal of $8 billion in Rinvoq sales by 2025 — supported by larger revenue outside the U.S., namely in Europe.
But whether the company follows in Pfizer's footsteps and conducts its own large safety trial remains to be seen. Pfizer's study enrolled 4,400 rheumatoid arthritis patients and took years to complete.
"We expect AbbVie to wait until the FDA decides what they are doing with [its other Rinvoq approval applications] and then to assess all of the safety data internally before making a decision on whether to roll the dice on being able to reverse the class labeling," Porges wrote.
"In our experience such labeling is very hard to reverse in the absence of definitive proof of the absence of harm."