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LONDON — The highly selective oral JAK1 inhibitor zemprocitinib met its primary and key secondary endpoints in patients with moderate to severe active rheumatoid arthritis (RA) who had an inadequate response to prior biologic therapy, according to data from the phase 3 COURAGE-RA trial presented at the European Alliance of Associations for Rheumatology (EULAR) 2026 Annual Meeting.

Despite a widening advanced therapeutic landscape, a substantial subset of patients fail to achieve durable responses or eventually lose efficacy, Xiaofeng Zeng, MD, PhD, professor in the Department of Rheumatology and Immunology at Peking Union Medical College Hospital, Beijing, China, said at the meeting. This creates a clinical gap for effective oral options with favorable benefit-risk profiles, particularly for a difficult-to-treat patient population that has already cycled through advanced therapies.

“We have many drugs for rheumatoid arthritis, and yet some patients complain about symptoms after going through many of them,” Roberta Priori, MD, PhD, a rheumatologist at the Sapienza University of Rome, Italy, told Medscape Medical News. 

Zemprocitinib preferentially targets JAK1 over JAK2 and JAK3 signaling pathways, maximizing anti-inflammatory efficacy while minimizing cytopenias, lipid alterations, and other off-target toxicities historically associated with less selective pan-JAK inhibition.

Rapid Symptom Relief and Sustained Remission

In the randomized, double-blind, placebo-controlled phase 3 trial, 429 adults were enrolled with active moderate to severe RA and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARDs). Patients were randomized 1:1 to receive zemprocitinib 12 mg twice daily or placebo on top of a stable background regimen of conventional synthetic DMARDs (csDMARDs).

Baseline characteristics were well balanced between the active and control arms. The mean age was 51.6 years in the zemprocitinib group and 53.4 years in the placebo group, with females accounting for 81.4% and 87.4% of the respective cohorts. The population represented a highly refractory group with long-standing disease; mean disease duration spanned 6.7 years for the zemprocitinib arm and 8.6 years for the placebo arm.

Most participants had high baseline disease activity, and more than 55% of patients in both groups exhibited a Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) of > 5.1. Mean baseline DAS28-CRP scores in the zemprocitinib and placebo groups were 5.35 and 5.31, respectively, and mean Health Assessment Questionnaire-Disability Index (HAQ-DI) scores were 1.18 and 1.11, respectively. Nearly all patients (99.1%) had an inadequate response to one prior bDMARD, and approximately 22% had prior exposure to a JAK inhibitor. Background use of csDMARDs, primarily methotrexate, was comparable in both arms (about 74%), as was baseline corticosteroid use (34.0% vs 41.1%).

Efficacy data, analyzed using nonresponder imputation for missing values, demonstrated a rapid onset of action. Significant differences in the proportion of patients reaching a 20% improvement in American College of Rheumatology (ACR20) response criteria and ACR50 criteria compared with placebo emerged as early as week 2, followed by significant separation in ACR70 rates by week 4.

By week 12, the therapeutic benefit was highly pronounced across all primary and secondary metrics. These clinical responses were not only sustained but showed progressive improvement in rates of patients reaching the primary endpoint of ACR20 at week 24 with zemprocitinib vs placebo (79.1% vs 39.7%) and also in secondary endpoints of ACR50 at week 24 (55.8% vs 22.0%) and ACR70 at week 24 (34.4% vs 7.5%). Low disease activity at week 24, defined as DAS28-CRP ≤ 3.2, increased to 67.0% in patients treated with zemprocitinib compared with 23.4% in the placebo group. Zemprocitinib maintained its significant lead across all top-tier goals, including 70% symptom relief, full remission, and low-activity indexes.

Favorable Safety Profile

Through 24 weeks of treatment, zemprocitinib was generally well tolerated, with no new or unexpected safety signals identified. Most adverse events were mild or moderate.

The investigators noted that the overall safety profile of zemprocitinib appeared to be more favorable than historical data reported for less selective oral JAK inhibitors in this patient population.

“For newly diagnosed patients, this can be one more option,” Priori said. She added that the oral administration of zemprocitinib is especially advantageous for younger patients, who are more inclined than older patients to avoid going to the clinic for monthly IV infusions. 

Zeng and Priori have reported no relevant financial relationships.

Manuela Callari is a freelance science journalist specializing in human and planetary health. Her work has been published in The Medical Republic, Rare Disease Advisor, New Scientist, The Guardian, MIT Technology Review, and others.