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AbbVie’s Rinvoq, Pfizer’s Xeljanz and Lilly’s Olumiant slapped with new FDA warnings amid JAK safety crackdown

The second regulatory shoe has finally dropped for AbbVie, Pfizer and Eli Lilly amid the safety review of JAK inhibitors for inflammatory diseases. But confirmed labels for their existing indications have yet to answer all questions.

The FDA has finally updated the labels for AbbVie’s Rinvoq, Pfizer’s Xeljanz and Eli Lilly’s Olumiant with new safety warnings and restrictions. The move comes three months after the agency said it would tweak the JAK inhibitors’ labels to include new information about serious heart-related side effects and cancer risks.

Importantly, the safety red flags come with a requirement that the drugs only be used in patients who can’t tolerate or don’t respond well to old-school TNF inhibitors such as AbbVie’s Humira. Thanks to the usage limitation, SVB Leerink analyst Geoffrey Porges has lowered his 2025 sales estimate for Rinvoq by about $900 million to $6.1 billion.

Together with fellow anti-inflammation drug Skyrizi, Rinvoq is a key part of AbbVie’s plan to grow revenues beyond Humira’s U.S. patent cliff in 2023. The Illinois pharma has pegged Rinvoq’s risk-adjusted sales potential in 2025 at more than $8 billion. During a conference call in October, AbbVie CEO Rick Gonzalez stopped short of confirming that projection, asking to wait until after the release of the final FDA label. The company hadn’t replied to a Fierce Pharma request for comment by publication time.

The JAK safety mess stemmed from concerning findings in a post-marketing study of Xeljanz in rheumatoid arthritis patients who already had cardiovascular risk factors. Investigators noticed an increased risk of blood clots, major heart-related event death, death and cancer in patients taking the Pfizer drug compared with those on TNF inhibitors.

The updated Xeljanz label (PDF) now has all those findings in the boxed warning section. The drug’s existing approvals for rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and juvenile idiopathic arthritis are now all pushed behind first-line treatment with TNF blockers.

Although the red flags came from the Xeljanz study, the FDA clearly showed it considers the risks a classwide problem for oral JAK inhibitors by requiring similar updates to the Rinvoq and Olumiant labels. Even before the latest amendments, the three JAK inhibitors already carried boxed warnings about similar risk factors, just not in comparison with fellow TNF drugs.

Rinvoq appears to have got what Porges called “milder language” on the risks. The new Rinvoq boxed warning specifies that the higher rates of the safety problems over TNF blockers are observed in another JAK inhibitor. What’s more, there were no restrictions on how long a patient can take Rinvoq.

The somewhat better-than-expected wording will “make a modest difference” only to new physicians or those who aren’t familiar with JAKs, he said in a Monday note.

Nevertheless, Porges believes Rinvoq is in a better position than the other two JAK inhibitors “given the strength of the data and AbbVie’s well-entrenched position in immunology.” Plus, no other drug regulators outside the U.S. have posted similar restrictions, he noted.

A Lilly spokesperson confirmed to Fierce Pharma that the company has also got an updated label for Olumiant. The company recently reported pooled safety data from nine clinical trials and a long-term extension trial for Olumiant, which appeared to show a slightly better heart safety and cancer risk profile than Xeljanz.

While the FDA has finalized the label for Xeljanz and Rinvoq, major uncertainties remain. All three JAK inhibitors still await outcomes from prolonged FDA reviews in the large atopic dermatitis indication. In addition, Pfizer’s new JAK drug Cibinqo—which was already approved in the U.K.—and Bristol Myers Squibb’s TYK2 inhibitor deucravacitinib are looking to get their entry into the U.S. market with pending FDA decisions. TYK2 is a member of the JAK family.