Head-to-head studies ‘would be nice’: More data needed to ascertain JAK inhibitor risks
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More trials are needed to fully elucidate the cardiovascular, infection and malignancy risks linked to Janus kinase inhibitors in rheumatoid arthritis, said a presenter at the 2022 Association of Women in Rheumatology annual conference.
According to Kevin Winthrop, MD, MPH, director of the Center for Infectious Disease Studies at Oregon Health & Science University, cardiovascular disease, malignancy and serious infections are the main issues associated with not just tofacitinib (Xeljanz, Pfizer), but all JAK inhibitors — including baricitinib (Olumiant, Eli Lilly & Co.), upadacitinib (Rinvoq, Abbvie) and filgotinib (Jyseleca, Galapagos NV) — thanks to a class-wide black box warning issued by the FDA in 2021.
“These are the things that kill people with RA,” Winthrop told attendees at the hybrid meeting.
However, he argued that understanding the role of JAK inhibitors in these adverse events is imperfect and evolving. According to Winthrop, much of the safety data associated with JAK inhibitors has come in studies comparing these drugs with other biologics, rather than head-to-head trials comparing risks between JAK inhibitors.
As such, it is difficult to ascertain the true risk for any individual JAK inhibitor, he said.
“A lot of our safety with JAK inhibitors is relative to TNF blockers,” Winthrop said.
Regarding specific adverse outcomes, Winthrop stated that tofacitinib has been associated with malignancy. However, again, much of the data have only compared the drug with a TNF inhibitor, he noted. Additionally, the data suggest smokers and individuals aged 65 years or older are also at increased risk for malignancy with JAK inhibitors. However, Winthrop pointed out that these populations are generally at increased risk for malignancy regardless.
There is a similar phenomenon for other infections, according to Winthrop. Specifically, he noted that patients aged 65 years and older are at increased risk for fatal infection when being treated with tofacitinib. However, he stressed that individuals in this age demographic are at risk for infections almost universally.
“Most biologics and JAK inhibitors carry similar serious infection risks,” he said, adding that the range is between three and five infections per 100 patient-years. “Filgotinib at both dosing levels may carry similar infection risks, which is why I was perplexed with the FDA’s decision to not move this forward.”
Meanwhile, the risk for herpes zoster with tofacitinib is “concerning,” not yet fully understood, according to Winthrop. In the general population, about 0.4% of individuals develop herpes zoster a second time, while data suggest that 3% to 5% of patients treated with JAK inhibitors will contract the disease during trials, he reported.
“We need to do studies to figure out how to prevent zoster in the JAK setting,” Winthrop said.
The risk for major adverse cardiovascular events (MACE) is another puzzling association, according to Winthrop.
“Tofacitinib is not noninferior to TNF inhibitors in MACE risk,” he said, adding that parsing out that association has proven challenging. “The jury is out. Those are studies that need to be done.”
Regarding other cardiovascular outcomes, Winthrop noted that both the 2.4 mg and 4 mg doses of baricitinib have been associated with similar risks for venous thromboembolism (VTE). Moreover, findings from the ORAL Surveillance study showed that JAK inhibitors carried a lower risk for VTE than TNF inhibitors.
However, the data on this topic for all drugs in the JAK class are not complete.
“Whether there is a risk for VTE with filgotinib or upadacitinib is an open question,” he said.
According to Winthrop, it may be useful to look to Europe for a signal on how to approach all of this inconclusive safety data for JAK inhibitors. He noted that the European Medicines Agency issued a warning only for tofacitinib in smokers aged 65 years and older, but that there are not warnings for other drugs in the class.
“The FDA took a better-safe-than-sorry approach,” he said, and stressed that many of the aforementioned risks are included in FDA warnings. “They basically lumped all the JAK inhibitors together.”
Winthrop acknowledged that because the data are, in fact, inconclusive, that this may ultimately be the better approach.
“But I do not see the data to support that yet,” he said. “It would be nice to see some head-to-head studies.”
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Winthrop K. JAK Safety update. Presented at: AWIR Annual Conference; August 18-21, 2022; Hilton Head Island, South Carolina (hybrid meeting).
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