On January 27, Pfizer announced co-primary endpoint results from ORAL Surveillance (NCT02092467), a required post-marketing safety study of the Janus kinase (JAK) inhibitor Xeljanz (tofacitinib) in rheumatoid arthritis (RA) patients with cardiovascular (CV) risk factors. Study results show that Xeljanz, at both 5mg and 10mg twice-daily dosing, failed to demonstrate non-inferiority to tumor necrosis factor inhibitor treatment in regard to the risk of major adverse cardiovascular events (MACE) and malignancies (excluding non-melanoma skin cancer). These results signal troubles ahead for Xeljanz and potentially other JAK inhibitor products.

The ORAL Surveillance trial first came under scrutiny in early 2019, when Pfizer had to modify the protocol mid-study due to associations between the 10mg twice-daily dose of Xeljanz and higher risk of thrombosis and overall mortality. Although there were no safety signals with the 5mg twice-daily dose at the time, some key opinion leaders interviewed by GlobalData in 2020 cautiously chose to limit the use of Xeljanz in RA patients with CV risk factors. This appears to have been a good judgement call as the latest data from Pfizer suggest that worrying MACE and malignancy outcomes were similar at the 5mg and 10mg doses.

Working with the FDA and other regulatory agencies, Pfizer’s next step is damage control. The company needs to try to pinpoint the specific level of CV risk associated with these negative safety outcomes and reassure patients, physicians, and regulators that all other groups of patients can continue to receive the drug safely. In the US, this evaluation will likely lead to an even lengthier boxed warning that elaborates on malignancy and MACE risks. Prior to the release of these new data, GlobalData forecast that global Xeljanz sales ($1.5B at peak) RA would fall approximately 13% between 2020 and 2024, due to competition from new JAK inhibitors like AbbVie’s Rinvoq. This recent strike against Xeljanz’s safety will likely further diminish the drug’s market share in the years leading up to patent expiry.

While trouble for Xeljanz could mean less competition for other JAK inhibitors, it is more likely that the entire drug class will now be subject to added scrutiny. For example, in the US, following the 2019 announcement of Xeljanz’s elevated thrombosis risk, JAK inhibitors received a class-wide boxed warning highlighting this potential risk. These new data may push the FDA and other regulatory authorities to request JAK inhibitor developers to perform similar cardiovascular safety studies, an inquiry that might make physicians more wary of the drug class in general. However, there is some hope in the field that JAK1-specific inhibitors, such as AbbVie’s Rinvoq and Gilead/Galapagos’ Jyseleca, may have lower safety risks compared to multi-JAK inhibitors, such as Xeljanz. If either of these products can demonstrate improved safety in this vulnerable population, it would certainly provide them with a strong competitive edge.

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By GlobalData