The FDA already has restrictions on the use ofPfizers JAK inhibitor Xeljanz at a higher dose because of safety concerns. Now, thanks to new red flags, the agency is weighing a move to tighten those restrictions.

In a post Thursday, the FDAalertedpatients and doctors that a postmarket study has linked Xeljanz to an increased risk of serious heart-related problems and cancer compared with TNF inhibitors, a group that includes such drugs as AbbVies Humira. The problems applied to both the 5-mg twice-daily dose and the higher 10-mg strength.

The agency said itll evaluate the clinical trial results and consider what moves to take. The last time it made that kind of comment, it wound up puttinga boxed warning on the high dose and strippingit of its use in previously untreated ulcerative colitis.

In the meantime, the FDA asks patients not to stop taking Xeljanz without first consulting with their doctors.

The FDAs announcement came days after Pfizer unveiled the data from the postmarket trial, which were required by the FDA in granting Xeljanz its first go-ahead in rheumatoid arthritis in 2012.

In the trial ofabout 4,400 rheumatoid arthritis patients who were at least 50 years old and had at least one cardiovascular risk factor, the rate of major cardiovascular events was higher for Xeljanz takers at 3.37%, versus 2.55% for the TNF group. Cancers developed in 4.19% of Xeljanz patients, also higher than the 2.89% among TNF receivers.

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Pfizer first warned of heart-related safety issues tied to the trials 10-mg Xeljanz dose in 2019. The FDA took note, slappinga warning label on the drugpointing to an increased risk of blood clots and death. The European Medicines Agency followed with a similar but slightly different restriction.

But the regulatory red alert doesnt affect Xeljanzs larger rheumatoid arthritis indication, because the high dosing regimen is only meant for ulcerative colitis patients. In fact, Xeljanz, as Pfizers cornerstone immunology product, managed to grow sales by 9% at constant currencies to $2.4 billion in 2020, with U.S. prescription volume rising 12% year over year, Pfizer CEO Albert Bourla, Ph.D., said on the companys fourth-quarter earnings call Tuesday.

But its different this time. As the trials raised red flags for both those doses, all three existing Xeljanz indicationswhich also include psoriatic arthritisas well as a potential nod in ankylosing spondylitis could be under threat.

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During the call, Pfizer management defended Xeljanzs place in those markets. Pfizer R&D chief Mikael Dolsten, M.D., Ph.D., said the postmarket trial participants belong to a unique population with increased severe risk, pointing to other clinical trial and real-world data it had accrued in larger patient groups.

As for the implications of the study on Xeljanz's label, Pfizer said its still too early to call. We still have a lot of work to do in terms of secondary endpoints, subpopulations and bringing all of this together to discuss this with regulators. So I think were still a ways off in terms of really understanding what impact it will be to our label, Angela Hwang, Pfizers biopharma president, said during the call.

Xeljanzs problems could hand fellow JAK inhibitors,such as AbbVies newly launched Rinvoq, an advantage. Although there are some concerns over potential scrutiny across the entire class, Rinvoq hasnt shown any imbalanced cardiovascular safety signals in the clinic. Pfizer also argued against reading Xeljanzs data into other JAK programs, mainly from the standpoint of its own follow-on programs such as abrocitinib, which is under FDA priority review in atopic dermatitis.

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FDA weighs tighter restrictions for Pfizer's Xeljanz on the heels of safety red flags - FiercePharma