FDA Issues Heart Safety and Cancer Warnings for JAK Inhibitors from Pfizer, AbbVie, and Lilly

Compiled and translated by | Fan Dongdong

This Wednesday, the U.S. Food and Drug Administration (FDA) required Pfizer's Xeljanz, AbbVie's Rinvoq, and Eli Lilly's Olumiant to carry explicit labeling warnings regarding cardiovascular safety and cancer risks for patients receiving treatment.

All three drugs belong to the JAK inhibitor class and already carry a black box warning for the risk of thrombosis and lymphoma. In light of this newly added safety warning, the FDA has relegated these drugs to a later position in the treatment sequence for their indications and restricted their use across all approved indications to patients who have failed or are unsuitable for TNF blocker therapy. This news has also prompted analysts to significantly lower their long-term sales forecasts for Rinvoq, AbbVie’s flagship immunology drug.

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Currently, safety concerns associated with Pfizer’s arthritis drug Xeljanz have led to increasingly stringent regulatory restrictions on other JAK inhibitors in the same class. Xeljanz received FDA approval in 2012, becoming the first JAK inhibitor to reach the market. The drug was approved in the European Union at a later date, in early 2017. Today, Xeljanz has become a blockbuster drug for Pfizer, with sales reaching $1.774 billion in 2018. However, safety concerns have cast a shadow over the commercial prospects of Xeljanz and the broader class of JAK inhibitors.

The FDA decided to add a black box warning after reviewing a large post-marketing study of Xeljanz. The study compared Pfizer’s JAK inhibitor with conventional TNF inhibitors, and trial results indicated that in patients aged 50 years or older with at least one pre-existing cardiovascular risk factor, treatment with JAK inhibitors significantly increases the risk of cardiovascular-related adverse events. Additionally, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) previously issued a safety warning imposing prescribing restrictions on Pfizer’s oral JAK inhibitor Xeljanz, stipulating that physicians must not prescribe the 10 mg twice-daily dosage to patients at high risk of pulmonary embolism.

Following the regulatory impact on Xeljanz, Olumiant and Rinvoq, as JAK inhibitors of the same class, have also been subject to corresponding regulatory measures. Prior to this FDA ruling, industry experts largely anticipated that the agency would ultimately impose stricter restrictions solely on Xeljanz, as other JAK inhibitors had not demonstrated cardiac safety and carcinogenic risks of a comparable magnitude in clinical trials. Some market observers even noted that the European Medicines Agency’s recent approval of Rinvoq for the treatment of atopic dermatitis could be viewed as a positive signal for JAK inhibitors.

In this regard, the FDA stated that Olumiant and Rinvoq lack large-scale safety trials comparable to those for Xeljanz, "and therefore their risks have not been adequately assessed." The agency noted that because Olumiant and Rinvoq "share a similar mechanism of action with Xeljanz," the FDA believes these drugs may carry risks similar to those observed in the Xeljanz safety trials. During the FDA's intensified safety review of JAK inhibitors, in addition to safety warnings issued for already marketed drugs, the agency also delayed the review of label expansions for several other drugs in this class, including Rinvoq’s applications for atopic dermatitis, psoriatic arthritis, and ankylosing spondylitis, as well as the applications for Olumiant and Pfizer’s abrocitinib for atopic dermatitis.

However, analysts remain divided in their interpretation of the regulatory guidance. In a client report on Wednesday, Bernstein analyst Ronny Gal stated that his team is lowering the peak sales forecast for Rinvoq from $17.2 billion to $11.2 billion. Conversely, Piper Sandler analysts do not view the news as detrimental to AbbVie. They expect the FDA's move to have only a "limited" short-term impact, noting that they "do not believe all JAK inhibitors will be permanently impacted by Xeljanz."

As one of AbbVie’s two key immunology drugs, Rinvoq carries high expectations, with the company hoping its sales growth will help bridge the massive revenue gap following Humira’s loss of U.S. market exclusivity. For Rinvoq’s approved atopic dermatitis indication alone, AbbVie has projected peak sales potential of $2 billion. Following Wednesday’s FDA regulatory update, market sentiment turned distinctly pessimistic, causing AbbVie’s stock to plummet and briefly drop nearly 8%.

Source: JAK inhibitors from Pfizer, AbbVie and Lilly hit with dreaded FDA heart safety, cancer warnings