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Oral upadacitinib was superior to placebo and appeared non-inferior to subcutaneous adalimumab in treating symptoms of psoriatic arthritis.
The Janus kinase inhibitor upadacitinib improved symptoms of psoriatic arthritis in a 24-week, phase 3 placebo-controlled trial with active comparator adalimumab, a tumor necrosis factor α inhibitor approved for the indication.
Both 15 and 30mg oral daily doses of upadacitinib provided significantly greater relief than placebo, and the higher dose was superior to adalimumab 40mg subcutaneously every other week on the American College of Rheumatology 20 (ACR20) measure.
"Psoriatric arthritis is a chronic, painful autoimmune disease," said Iain McInnes, MD, PhD, Professor of Medicine and Versus Arthritis Professor of Rheumatology at University of Glasgow, UK and the lead study author, in an announcement of the study publication.
"I am encouraged by these results showing that upadacitinib can improve outcomes for people living with psoriatic arthritis who are facing the potentially debilitating impact of joint and skin symptoms, along with other debilitating challenges like fatigue," he stated.
McInnes and colleagues randomized 1,705 adult patients at 281 sites in 45 countries on a 1:1:1:1 ratio to receive either 15 or 30mg daily upadacitinib, placebo or adalimumab.Eachpatient had received a diagnosis of psoriatic arthritis, fulfilled the Classification Criteria for Psoriatic Arthritis, and had history of, or current plaque psoriasis.Demographic and clinical characteristics were similar across groups.
A total of 1704 patients received at least one dose of active drug or placebo, and so were included in the modified intention-to-treat analysis; and 548 patients completed the full 24-week study period.The primary end point was at least 20% improvement from baseline on the ACR20 measure of tender and swollen joints with upadacitinib as compared with placebo at week 12.
An additional primary target for the agent was improvement of at least 20% in at least 3 of 5 other domains, including assessment of disease activity on a numerical scale rated by both patient and physician, assessment of disability level based on a patient questionnaire, the patient's assessment of pain on a numerical rating scale, and high-sensitivity C-reactive protein level.
Although the trial design had included 14 multiplicity-controlled secondary end points, changes were made to the protocol and statistical analysis during the conduct of the trial to address regulatory-agency feedback on the method for testing noninferiority against adalimumab and for ordering of multiplicity-controlled end points on the basis of data from other trials.
Planned end points which could not be analyzed due to failure of the hierarchy at the point of ACR20 response with upadacitinib 15mg dose compared with adalimumab include resolution of dactylitis comparing upadacitinib with placebo, and comparing the change from baseline in the patient's assessment of pain with the adalimumab and upadacitinib.
"ACR50 and ACR70 responses are of special interest to the field of rheumatology, and comparisons of the 15mg and 30mg doses of upadacitinib with placebo and with adalimumab for these end points were prespecified," McInnes and colleagues indicated, "however, confidence intervals were not adjusted for multiple comparisons, and no conclusions can be drawn from the results."
The investigators were able to determine that the percentage of patients with psoriatic arthritis who had an ACR 20 response at week 12 was significantly higher with 15mg (70.6%) or 30mg (78.5%) upadacitinib than with placebo (36.2%).The 30mg dose, but not the 15mg dose was superior to adalimumab (13.5 percentage point difference between 30mg upadacitinib and adalimumab, and 5.6 point difference between the 15mg dose and the comparator).
In safety measures, serious infections were more frequent with the 30mg dose of upadacitinib than with placebo or adalimumab; but incidences of herpes zoster were similar (approximately 1%) for both doses of upadacitinib and placebo.Dose-dependent elevations in creatine kinase and adverse events involving hepatic disorders were reported with upadacitinib.
"There are limited data on which to base assumptions for comparisons of upadacitinib with adalimumab," McInnes and colleagues acknowledged.
"Longer and larger trials are required to determine the effect and risks of upadacitinib and its effects as compared with other drugs used to treat psoriatic arthritis," they concluded.
The study, "Trial of Upadacitinib and Adalimumab for Psoriatic Arthritis," was published online in The New England Journal of Medicine.