Earlier this week, Pfizer said it had moved some rheumatoid arthritis patients taking Xeljanz to a lower dose, based on data from a postmarketing study designed to assess the drug’s CV risks. More patients taking the higher dose had suffered blood clots in the lungs than those on the lower dose—and more had died, too.
The thing is, Xeljanz isn’t the first drug in its class to run into dose-related safety issues. In April 2017, the FDA rejected Eli Lilly’s Olumiant, citing a need for more data “to determine the most appropriate doses” and to “further characterize safety concerns across treatment arms.” When Olumiant came back up for review last year, an FDA advisory panel highlighted safety questions around the higher-dose option Lilly had proposed. When the agency eventually did approve the therapy last summer, it only OK’d the lower dose. And the approved dose came with a black-box warning about the risk of serious blood clots.
As for AbbVie’s JAK candidate upadacitinib, a hemorrhagic stroke death and a pulmonary embolism—both in patients the pharma says had “pre-existing cardiovascular risk factors”—marred phase 3 results for the low-dose group.
Still, it’s unclear whether the FDA is looking into the possibility of trouble within the class. A spokeswoman for the agency said via email that “additional recommendations may be made based on our ongoing review,” but it declined to say whether that review began before or after Pfizer unveiled its trial results and exactly which drugs the review covered.
“FDA is working with Pfizer to evaluate currently available safety information for tofacitinib,” she added. The drug already bears a black-box warning, but it only mentions infection and cancer risks.
And not all of the JAK class’ members have turned up red flags. Filgotinib, a candidate from Gilead and Galapagos, didn’t surface any reports of deep vein thrombosis or pulmonary embolism in its first round of phase 3 data, which rolled out last September.
Potential classwide safety issues could throw a wrench in the plans for Pfizer, Lilly, AbbVie and Gilead. JAK inhibitor side effects—which can include infections and elevated cholesterol—have until now been considered “more acceptable” in rheumatoid arthritis than those of its rival TNF-alpha drugs, Bernstein analyst Ronny Gal has written. He’s predicted JAKs could go on to snap up 24% of the RA market, threatening second-line choices such as Amgen’s Enbrel.