FDA Imposes New Safety Warnings on JAK Inhibitors: AbbVie’s Rinvoq, Pfizer’s Xeljanz, and Lilly’s Olumiant Restricted to Second-Line Use

Compiled by Aspirin

Three months ago, the FDA announced it would revise the labeling of JAK inhibitor drugs to include new information about serious heart-related side effects and cancer risks. On December 6, 2021, Eastern Time, the FDA finally decided to apply new safety warnings and restrictive labels to AbbVie’s Rinvoq, Pfizer’s Xeljanz, and Eli Lilly’s Olumiant.

These new safety warnings require that these three drugs be used only in patients who cannot tolerate or respond poorly to TNF inhibitors (such as AbbVie's Humira). Due to this safety warning and the update of the restricted label, Geoffrey Porges, an analyst at SVB Leerink, reduced the sales forecast for Rinvoq in 2025 by approximately $900 million to the current $6.1 billion.

Rinvoq, along with another anti-inflammatory drug Skyrizi, is one of AbbVie's two key future revenue growth drivers to offset the decline in sales due to the expiration of Humira's U.S. patent in 2023. AbbVie had projected that Rinvoq’s risk-adjusted sales would exceed $8 billion by 2025. However, during an October 2021 conference call, AbbVie CEO Rick Gonzalez did not confirm this earlier forecast amid potential adjustments to safety warning labels. He requested to wait for the FDA’s final label update before providing further comments.

Safety concerns about JAK inhibitors stem from findings related to the post-marketing study of Xeljanz. The study tracked data analysis of rheumatoid arthritis patients with cardiovascular risk factors taking Xeljanz. Researchers observed that patients taking Pfizer's Xeljanz had an increased risk of blood clots, major heart-related events, death, and cancer compared to those taking TNF inhibitors.

The updated Xeljanz label now includes all of the above findings in the black box warning section. The drug's existing approved treatments for rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and juvenile idiopathic arthritis have now been moved to follow first-line treatment with TNF inhibitors.

Despite safety concerns and warning signs from post-marketing surveillance studies of Xeljanz, the FDA has made it clear that it considers such safety risks a widespread issue among JAK inhibitor drugs, including oral medications in this class. As a result, it has mandated similar label updates for Rinvoq and Olumiant. In fact, prior to the latest label modifications, these three JAK inhibitors already carried black box warnings for similar risk factors, though without comparison to other TNF inhibitor drugs.

The black box safety warning for Rinvoq appears to be relatively mild. The new black box warning for Rinvoq indicates that the incidence of safety issues observed with another JAK inhibitor was higher than that of TNF inhibitors. Moreover, the FDA has not imposed any restrictions on the duration of Rinvoq treatment for patients.

Porges believes that Rinvoq is in a relatively better position compared to the other two JAK inhibitor drugs, "given the disclosed data of this drug and AbbVie's solid standing in the field of immunology." He also noted that other drug regulatory agencies outside the United States have not issued similar safety warnings or restrictions. Nevertheless, Geoffrey Porges pointed out that the slightly better-than-expected wording regarding Rinvoq would only "have a certain impact" on new doctors or those unfamiliar with JAK inhibitors.

Although the FDA has finalized the label updates for Xeljanz and Rinvoq, significant uncertainties remain. All three JAK inhibitor drugs are still awaiting the final FDA results of the long-term review for the atopic dermatitis indication. In addition, Pfizer's new JAK inhibitor Cibinqo has been approved in the UK, and Bristol-Myers Squibb’s TYK2 inhibitor deucravacitinib is seeking entry into the U.S. market, but the FDA has yet to make a decision. Since TYK2 is also a member of the JAK family, this label update casts an uncertain shadow over deucravacitinib.

Reference Source: AbbVie's Rinvoq, Pfizer's Xeljanz and Lilly's Olumiant Slapped with New FDA Warnings Amid JAK Safety Crackdown