Xeljanz Safety Data Could Mean Headache for JAK Inhibitor Class

 Pfizer announced the co-primary endpoint results of the ORAL Surveillance (NCT02092467) post-marketing safety study of Xeljanz (tofacitinib), a Janus kinase (JAK) inhibitor, in RA patients with cardiovascular (CV) risk factors. According to the findings of the study, Xeljanz failed to demonstrate non-inferiority to treatment with a tumor necrosis factor inhibitor in terms of the risk of major adverse cardiovascular events (MACE) and cancer (excluding non-melanoma skin cancer) at doses of 5 mg and 10 mg twice daily, respectively. These results suggest that Xeljanz and possibly other JAK inhibitor products will face difficulties in the future.

Janus Kinase Drugs Development market Surveillance trial in the middle of the study in early 2019 because of links between the 10 mg twice daily dose of Xeljanz and a higher risk of thrombosis and overall mortality. Despite the fact that there were no safety warnings for the 5mg twice-daily dose at the time, some important opinion leaders who were surveyed by GlobalData in 2020 cautiously decided to limit the use of Xeljanz in RA patients who had CV risk factors. According to the most recent data from Pfizer, this appears to have been a wise decision because the worrying MACE and cancer outcomes were similar at the 5mg and 10mg doses.

Pfizer's next step is damage control, which it collaborates with the FDA and other regulatory agencies on. In order to reassure patients, physicians, and regulators that all other patient groups can continue to receive the drug safely, the company needs to make an effort to determine the precise level of CV risk that is associated with these adverse safety outcomes. This evaluation is likely to result in a longer boxed warning that goes into greater detail about the risks of MACE and cancer in the United States. GlobalData predicted, prior to the release of these new data, that competition from new JAK inhibitors like AbbVie's Rinvoq would cause global Xeljanz sales ($1.5 billion at peak) RA to decrease by approximately 13% between 2020 and 2024. In the years leading up to the expiration of the drug's patent, this recent attack on Xeljanz's safety will probably reduce the product's market share even further.

Even though problems for Xeljanz could mean less competition for other JAK inhibitors, the entire class of drugs will probably now be scrutinized more closely. JAK inhibitors, for instance, received a class-wide boxed warning in the US in response to the 2019 announcement of Xeljanz's elevated thrombosis risk. Physicians may become more wary of the JAK inhibitor class as a whole as a result of these new data, which may prompt the FDA and other regulatory authorities to request that JAK inhibitor manufacturers carry out comparable cardiovascular safety studies. However, there is some hope in the field that JAK1-specific inhibitors like Rinvoq from AbbVie and Jyseleca from Gilead/Galapagos might have lower safety risks than multi-JAK inhibitors like Xeljanz. They would definitely gain a significant competitive advantage if either of these products can demonstrate improved safety in this vulnerable population.