Will the recent FDA decision to expand the boxed warning for JAK inhibitors—citing risk for heart-related issues, cancer, and death—dampen some of this enthusiasm for this emerging class of medicines?

By Denise Mann, Editor at Large

Lots of hope is pinned on Janus kinase (JAK) inhibitors for the treatment of atopic dermatitis (AD), alopecia areata, vitiligo, plus other skin diseases, and the pipeline is full.

Will the recent FDA decision to expand the boxed warning for JAK inhibitors—citing risk for heart-related issues, cancer, and death—dampen some of this enthusiasm for this emerging class of medicines?

The FDA based its warning—the strictest caution it can give—on results from ORAL Surveillance, a post-marketing safety trial that was required to demonstrate non-inferiority of tofacitinib compared to TNF inhibitors in patients with rheumatoid arthritis (RA) when it comes to risk for cardiovascular events and malignancies. This trial also investigated thrombosis and mortality.

As a result of this trial, “we are requiring revisions to the Boxed Warning … for Xeljanz/Xeljanz XR, Olumiant, and Rinvoq to include information about the risks of serious heart-related events, cancer, blood clots, and death," the FDA says in a statement. 

The FDA also recommends that doctors consider the benefits and risks for individual patients before initiating or continuing treatment with JAK inhibitors, particularly among current or past smokers, patients with other cardiovascular risk factors, and those who develop a malignancy, and those with a known malignancy other than a successfully treated non-melanoma skin cancer.

Two other JAK inhibitors, Jakafi (ruxolitinib) and Inrebic (fedratinib) are not indicated for the treatment of arthritis and other inflammatory conditions and so are not required to update their labels. 

All Eyes on the FDA

No JAK inhibitors are currently FDA approved in the US for skin disease. Randomized clinical trials, however, have shown efficacy in alopecia areata, AD, psoriasis, and vitiligo, and off-label use has shown efficacy in dermatomyositis, granuloma annulare and sarcoidosis, lichen planus, morphea, and pruritus.

The stakes are high for dermatologists and the patients they treat, says Brett King, MD, PhD, a dermatologist and associate professor of dermatology at Yale School of Medicine in New Haven, CT. Dr. King pioneered the use of JAK inhibitors in dermatology. 

“These drugs are effective and really needed but they have risk, no matter how small, and so we need to be thoughtful regarding their use. The FDA guidance will help us to do that,” he says.

JAK inhibitors will have an important role in AD, but they will usually be employed when dupilumab hasn’t worked well enough, he says. Because dupilumab is a very effective medicine with an outstanding safety profile—a safety profile that has been consistently reinforced since FDA approval more than four years ago—it makes sense that it would be first-line therapy, at least in most cases, Dr. King says.“It is awesome that we are going to have JAK inhibitors for our patients with AD because, as good as dupilumab is, it doesn’t work for everybody,” he says.

Even in psoriasis, for which there are numerous highly effective treatments, an effective oral agent such as deucravacitinib (a JAK inhibitor), will be welcome by dermatologists and their patients, he says, even if there is a boxed warning.The FDA may not approve higher doses of JAK inhibitors for skin disease or if they do, they may state that the highest doses need to be limited to a short period of use, he suggests.

There’s also the question about whether topical JAK inhibitors will get a boxed warning, he says. The Prescription Drug User Fee Act (PDUFA) action date for Incyte's ruxolitinib cream is set for September 21, 2021. “I will not be surprised if it gets approved with a boxed warning as we are going to smear this stuff all over the skin, so there will be some systemic absorption," Dr. King says.

Jonathan Silverberg, MD, PhD, MPH, an associate professor of dermatology at The George Washington University School of Medicine and Health Sciences in Washington DC, agrees that the more tools dermatologists have to treat AD, the better off that patients will be.

“Not everyone wants a shot, so we need good oral options in AD,” he says.

"Other oral agents used in immune-mediated skin diseases, such as methotrexate, cyclosporine, mycophenolate, or azathioprine, have variable efficacy and pronounced safety risks," he says. "JAK inhibitors have been extensively studied across numerous trials within AD and we have clear cut evidence that they work, how well they work, and in which subsets tend to do better than others."

There is no one-size-fits-all option for AD. "We have to take patient preferences and disease severity into account and come to shared decisions about what works best,” Dr. Silverberg says.

Some questions remain, adds Victor Huang, MD, an assistant professor of clinical dermatology at UC Davis Health. “The mechanisms by which these medicines might be causing increased clots and heart attacks are still unclear, and time will tell whether these findings represent a peculiarity with tofacitinib or whether the risk is built into the biology of JAK inhibitors.”

Naples, FL-based dermatologist Brandon Kirsch, MD says there may well be a chilling effect in the meantime. “I suspect that a boxed warning will lead to a sharply focused and critical reexamination of the risk-benefit profile of JAKs for a large majority of my peers, particularly given that the skin conditions of concern are not life-threatening,” he says. “This reexamination will be a direct reflection of the dramatic change in posture exhibited by the FDA. Patient attitudes will also undoubtedly manifest greater concern and reluctance, further dampening enthusiasm for the future writing of prescriptions.”

Jeffrey M. Cohen, MD, an assistant professor of dermatology at Yale School of Medicine, agrees. “Any boxed warning from the FDA is significant, and these new warnings for cardiovascular events, malignancy, blood clots, and death will almost certainly impact utilization of these agents,” he says. “These new warnings will likely introduce pause in prescribing for dermatologists and will almost certainly create hesitation from patients.”

JAK Inhibitors and Unmet Needs

The paradigm will be different in diseases like alopecia areata, where there isn’t an effective therapy.

“Regarding the potential impact of the FDA-required boxed warning for certain JAK inhibitors on treatments for vitiligo and hair disorders (in which these drugs are being studied), it's essential to fully consider each patient's profile and history with a careful risk-benefit analysis,” says Pearl E. Grimes, MD, director of the Vitiligo and Pigmentation Institute of Southern California, and a Clinical Professor of Dermatology at UCLA. “In our practice, when appropriate, we have effectively and safely used other medications with boxed warnings, when the patient scenario warrants it,” she says.

“In the case of JAK inhibitors, we welcome these medications on the horizon to augment our treatment options for our dermatology patients suffering from life-altering diseases."