CHICAGO -- Treatment with the oral selective JAK1 inhibitor upadacitinib was superior to placebo and the active comparator adalimumab (Humira) for rheumatoid arthritis (RA) in a phase III study reported here at the .
In a with active RA despite treatment with methotrexate, a 20% response on the criteria of the ACR (ACR20) was achieved by 70.5% of those given upadacitinib, 15 mg/day, by 63% of those receiving adalimumab, 40 mg every other week, and by 36.4% of those given placebo (P<0.001 for upadacitinib versus placebo), according to Roy Fleischmann, MD, of the University of Texas Southwestern Medical Center in Dallas.
In addition, the proportions of patients at week 12 who were in remission, defined as a Disease Activity Score in 28 joints (DAS28) below 2.6, were 28.7%, 18%, and 6.1% in the upadacitinib, adalimumab, and placebo groups (P<0.001 for upadacitinib versus placebo).
"In this particular powered head-to-head study, upadacitinib plus methotrexate was superior to adalimumab plus methotrexate clinically and functionally, and was similar radiographically, and compared to placebo, it was superior clinically, functionally, and radiographically," Fleischmann said.
The study was sponsored by AbbVie, and was powered for noninferiority of upadacitinib versus adalimumab on background methotrexate.
In two other phase III trials, upadacitinib was found to be effective for patients with RA who had not responded adequately to (DMARDs) and .
The study participants were 80% female, and most were in their fifties. Disease duration was 8 years, and the baseline DAS28 was high, at 5.8. They had to have at least six swollen and tender joints.
All primary and key secondary endpoints were met, Fleischmann noted. ACR50 responses at week 12 were seen in 14.9% of patients receiving placebo, in 29.1% of those given adalimumab, and in 45.2% of those receiving upadacitinib (P<0.001 for upadacitinib versus both placebo and adalimumab), while ACR70 responses were achieved by 4.9%, 13.5%, and 24.9% (P<0.001 for upadacitinib versus both). "These are not small differences," he commented.
Low disease activity (DAS28 of 3.2 or lower) was achieved by 13.8% of the placebo group at week 12, by 28.7% of the adalimumab group, and by 45% of the upadacitinib group (P<0.001 for upadacitinib versus both).
Change from baseline in pain scores were -15.69, -25.61, and -32.10 in the placebo, adalimumab, and upadacitinib groups, respectively (P<0.001 for upadacitinib versus both).
A total of 91% of patients completed 26 weeks of treatment, and responses persisted throughout. By week 26, 35.6% of patients in the placebo group had ACR20 responses, compared with 57.2% of the adalimumab group and 67.4% of the upadacitinib group (P<0.001 for upadacitinib versus placebo, P<0.01 versus adalimumab).
By week 26, change from baseline on the modified total Sharp score, which measures radiographic progression, was 0.92 in the placebo group, 0.10 in the adalimumab group, and 0.24 in the upadacitinib group (P<0.001 for upadacitinib versus placebo). No radiographic progression by that time point was seen in 76%, 86.8%, and 83.5%, respectively.
Over the 26 weeks, rates of adverse events and serious infections were higher for upadacitinib than for placebo but were similar to adalimumab. Rates of discontinuation because of adverse events were 2.3% in the placebo group, 4.3 in the adalimumab group, and 3.5% in the upadacitinib group.
Herpes zoster was reported in 0.5%, 0.3%, and 0.8% in the placebo, adalimumab, and upadacitinib groups, respectively. There were three malignancies, five major adverse cardiovascular events, and four deaths, none of which were in the upadacitinib group.
Six venous thromboembolic events occurred, one in the placebo group, three in the adalimumab group, and two in the upadacitinib group. Thromboembolic events have been a concern with JAK inhibitors, and when baricitinib (Olumiant) was approved by the FDA earlier this year, the agency required a boxed warning expressing concerns about thrombosis, serious infections, and malignancies.
"I'm not going to say that upadacitinib is safer than adalimumab. The point here is that the VTEs occurred in all three groups," he said.
Upadacitinib remains investigational. In addition to rheumatoid arthritis, AbbVie is developing the drug for psoriatic arthritis, inflammatory bowel disease, atopic dermatitis, and axial spondyloarthritis.
Disclosures
The investigators reported financial relationships with multiple companies, including AbbVie, Eli Lilly, Pfizer, Gilead, Roche, Bristol-Myers Squibb, Sandoz, Amgen, UCB, Merck, Celgene, Spire, Crescendo, Flexion, Genentech, GlaxoSmithKline, Regeneron, Sanofi, and Novartis.
Primary Source
American College of Rheumatology annual meeting
Fleischmann R, et al “A phase 3, randomized, double-blind study comparing upadacitinib to placebo and to adalimumab, in patients with active rheumatoid arthritis with inadequate response to methotrexate” ACR 2018; Abstract 890.