Death in Phase 3 Study Dampens Positive Top-Line Data for Upadacitinib

AbbVie reported on Wednesday that a phase 3 trial of its upadacitinib as monotherapy for rheumatoid arthritis (RA) met all of its primary and key secondary endpoints, giving more momentum to the drug that appears poised to help AbbVie retain its share of the RA market after adalimumab biosimilars launch in the United States. However, a death reported during the trial raises renewed concerns about the safety of the Janus kinase (JAK) inhibitor.

The SELECT-MONOTHERAPY clinical trial followed patients with moderate to severe RA who had not responded adequately to treatment with methotrexate. Results at 14 weeks of treatment with once-daily doses of either 15 mg or 30 mg met the study’s primary endpoints of producing a response of ACR20—a 20% improvement by American College of Rheumatology criteria—or low disease activity versus methotrexate therapy. The study found the following at week 14 for patients receiving 15 mg and 30 mg doses of the investigational drug, respectively:

• 68% and 71% reached ACR20
• 42% and 52% reached ACR50
• 23% and 33% reached ACR70
• 45% and 53% reached low disease activity
• 28% and 41% reached clinical remission.

"The positive results from the SELECT-MONOTHERAPY study are encouraging, as they are the first evidence to support the potential of upadacitinib as a therapy without the need for background methotrexate," said Michael Severino, MD.

Serious adverse events (AEs) occurred in 5% and 3% of patients receiving upadacitinib, and AbbVie says that no new safety signals were detected.

However, these positive top-line results are dampened by 1 patient death during the study; a patient had a fatal hemorrhagic stroke, caused by a ruptured aneurysm, while taking the 15-mg dose of the drug. There was also 1 event of pulmonary embolism in the study, occurring in the 15-mg dose group, in a patient with preexisting risk factors for embolism. These results follow a September 2017 report that 2 patients had died in a late-stage trial of upadacitinib, although AbbVie told Reuters at the time that neither death was considered to be related to the investigational drug.

Despite that assurance, JAK inhibitors as a class have come under increased scrutiny; a recent systematic review of the FDA’s Adverse Event Reporting System found elevated reporting for thromboembolic AEs for 2 approved JAK inhibitors, tofacitinib (Xeljanz) and ruxolitinib (Jakafi), and suggested that a class-wide safety issue might exist for JAK inhibitors.