FDA's new JAK safety restrictions spell trouble for AbbVie's Rinvoq, but to what extent?

AbbVie’s megablockbuster Rinvoq ambition suffered a blow thanks to an updated safety warning and treatment restriction from the FDA. But pharma watchers have different opinions on just how significant the impact will be on AbbVie's JAK inhibitor.

In an announcement Wednesday, the FDA is revising Rinvoq’s boxed warning to include information about increased risks of serious heart-related events, cancer, blood clots and death. The agency is also limiting the drug’s use to patients who’ve tried but failed on at least one TNF inhibitor. Pfizer's Xeljanz and Eli Lilly's Olumiant, both also JAK inhibitors, were hit with the same limitations.

If Rinvoq is only used in second or later lines, it could mean a $1 billion to $3 billion reduction from AbbVie’s $8 billion 2025 sales estimate for the drug, SVB Leerink Geoffrey Porges wrote in a Wednesday note to investors. For his part, Bernstein analyst Ronny Gal reined in his 2030 sales projection for Rinvoq to $11.2 billion from the previous $17.2 billion.

To Porges, the updated safety language, which stemmed from findings from a postmarketing study by Pfizer’s fellow JAK inhibitor Xeljanz, wasn’t too surprising. But he didn’t foresee the post-TNF restriction.

Still, as Porges, Evercore ISI analyst Josh Schimmer and Piper Sandler analyst Christopher Raymond noted in their separate analyses, doctors are already reserving JAK inhibitors for arthritis patients who failed on TNF inhibitor out of a sense of abundant caution for safety and also due to payer restrictions.

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As Schimmer pointed out, “the majority of current and projected Rinvoq use” is indeed in the post-TNF inhibitor treatment setting. A recent survey of 100 high-volume U.S. rheumatologists that Piper Sandler conducted with Spherix Global Insights showed that only 14% of patients are getting Rinvoq as prior to TNF inhibitors. And a large number of physicians are avoiding JAKs for patients with high or moderate blood clot risks.

Rinvoq is currently approved to treat moderate to severe rheumatoid arthritis after failure on methotrexate. Its label before the FDA update already included a boxed warning on blood clots, lymphoma and other malignancies and serious infections.

While Porges said Rinvoq’s U.S. potential is “almost certainly reduced,” he still thinks it’s feasible that the drug can get to the $3.5 billion to $4.5 billion U.S. sales required for AbbVie to hit its $8 billion worldwide goal. If the U.S. market turns out to be more challenging, AbbVie could turn to Europe, where Rinvoq just won a go-ahead in atopic dermatitis without safety pushback from the European Medicines Agency, Porges suggested.

For its part, AbbVie is seeking FDA's blessing to expand Rinvoq into atopic dermatitis, psoriatic arthritis and ankylosing spondylitis plus expects a potential filing in ulcerative colitis. But because the FDA is now pushing Rinvoq’s use behind TNF in all approved indications, earlier use for those diseases are off the table, Porges said.

“AbbVie believes in the benefit-risk profile of Rinvoq. We continue to work with the FDA to bring Rinvoq to patients living with immune-mediated diseases,” the company said in a statement.

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But Gal is less optimistic. The Bernstein analyst now sees higher risks that the JAK inhibitor class may not win FDA approvals in less severe dermatological diseases such as atopic dermatitis and psoriasis. Besides Rinvoq, Xeljanz and Olumiant are also awaiting FDA decisions on their atopic dermatitis filings.

He sees a bigger problem than just the anti-TNFs. In other indications that Rinvoq’s eyeing, Gal suspected that the FDA will likely also sequence it behind other classes of drugs such as Johnson & Johnson’s IL-23 inhibitor Stelara, Sanofi’s IL-4/13 inhibitor Dupixent and even S1P modulators such as Bristol Myers Squibb’s Zeposia.  

“It may also be that FDA will choose to prevent or further curtail use of the JAK inhibitors in disease conditions where the risk-reward is lower,” Gal wrote in a note Wednesday.

By comparison, Piper Sandler’s Raymond maintained his 2025 sales estimate for Rinvoq at $8.13 billion. In rheumatoid arthritis, Raymond viewed the label revisions as affecting Rinvoq “on the margin.” As for eczema, he has long been putting Rinvoq’s future use to be after Dupixent.

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AbbVie has an option to dig itself out of the safety mess. As the FDA acknowledged, Rinvoq and Olumiant were dragged into the same safety warning and use limitation because they share similar mechanisms as Xeljanz. AbbVie could therefore conduct a large postmarketing study for Rinvoq, similar to the Pfizer trial, to prove its case to the FDA.

While the Xeljanz trial took seven years to complete, Gal suggested five years would be a reasonable estimate for a similar Rinvoq trial. Porges pointed out the study needs to show “definite proof of the absence of harm” to be able to reverse the troublesome labeling. Porges expects AbbVie won’t decide on whether to run such a trial until early 2022.

Editor's Note: The story has been updated with a statement from AbbVie.