In February, the FDA issued a drug safety communication on tofacitinib (Xeljanz), an oral, small-molecule Janus kinase (JAK) inhibitor. According to the FDA communication, a clinical trial in patients with rheumatoid arthritis who were taking an as-yet unapproved 10-mg dose of tofacitinib twice each day found an increased risk of blood clots and death.
In February, the FDA issued a drug safety communication on tofacitinib (Xeljanz), an oral, small-molecule Janus kinase (JAK) inhibitor. According to the FDA communication, a clinical trial in patients with rheumatoid arthritis (RA) who were taking an as-yet unapproved 10-mg dose of tofacitinib twice each day found an increased risk of blood clots and death.
Pfizer, maker of tofacitinib, announced that it has taken steps to transition the patients involved in the study—an ongoing, open-label study evaluating the safety of tofacitinib at 2 doses versus a control group of patients receiving an anti—tumor necrosis factor (anti-TNF)—to the approved 5-mg twice-daily dose. Pfizer noted that similar safety signals were not identified in other clinical trials in RA or in routine monitoring of safety data.
Tofacitinib, which is approved to treat RA, psoriatic arthritis, and ulcerative colitis, has been widely expected to compete with innovator anti-TNF therapies and their emerging biosimilars. Studies have demonstrated that the JAK inhibitor could result in a lower cost to treat RA than cycling anti-TNF drugs in the case of nonresponse, and for many patients, an oral therapy is preferable to either infusion of products like infliximab and its biosimilars or self-administration of injectable biologics like adalimumab (Humira) or etanercept (Enbrel). Additionally, in cases in which ensuring a cold chain for the storage of biologics is difficult, oral small-molecule drugs may be advantageous.
However, JAK inhibitors as a class have come under increased scrutiny in recent months; in April 2018, the FDA’s Arthritis Advisory Committee voted to recommend a low dose of Eli Lilly’s JAK inhibitor, baricitinib, but voted against recommending approval of a higher dose given concerns about the potential for dose-dependent adverse events such as thrombosis.
The drug was later approved by the FDA at the lower dose, under the name Olumiant, with a black box warning that includes a caution related to deep venous thrombosis, pulmonary embolism, and arterial thrombosis, among other warnings.
AbbVie’s proposed JAK inhibitor, upadacitinib, which the company hopes to launch in 6 US indications by 2022 (ahead of biosimilar competition for the company’s flagship RA drug, Humira), could see increased scrutiny from regulators during its priority review. In a phase 3 trial, 1 patient taking a 15-mg dose of the drug had a fatal hemorrhagic stroke caused by a ruptured aneurysm, and there was also 1 event of pulmonary embolism in the study, also in a patient taking a 15-mg dose of the drug.
Ongoing concerns about JAK inhibitors with respect to safety could potentially be a boon for biosimilars of anti-TNF drugs. Biosimilars may allow for substantial cost savings versus their reference products, especially once biosimilars of adalimumab and etanercept reach US patients, and with established safety profiles, anti-TNFs could continue to lead in the inflammatory disease space.