Background/Purpose: Upadacitinib, a selective inhibitor of Janus kinase 1 (JAK1), is currently being evaluated for the treatment of several autoimmune disorders, including axial spondyloarthritis (axial SpA).  In the SELECT-AXIS I study (NCT03178487), upadacitinib 15 mg once-daily (QD) demonstrated favorable efficacy in ankylosing spondylitis (AS) patients who had an inadequate response to non-steroidal anti-inflammatory drugs and who were naïve to biological disease modifying antirheumatic drugs. The purpose of this analysis was to a) explore the relationship between upadacitinib exposures and several AS efficacy endpoints and safety parameters to support dose selection for future studies and b) compare upadacitinib plasma exposures in subjects with AS to subjects with rheumatoid arthritis to assess disease-related differences in upadacitinib pharmacokinetics (PK).

Methods: The analyses included data from 187 subjects in the SELECT-AXIS I study. Subjects were randomized to receive upadacitinib 15 mg QD (n=93) or matching placebo (n=94). PK samples were taken at pre-defined visits and modeled using a population approach. Within the evaluated dose, exposure-response quartile plots were created to assess the relationship between upadacitinib average plasma concentrations and the probability of achieving Week 14 efficacy endpoints (ASAS 40, ASAS 20, ASAS partial remission [PR])  or experiencing adverse events/relevant changes in laboratory variables (lymphopenia [Grade 3 per CTCAE or higher], infection, decreases in hemoglobin).

Results: Upadacitinib plasma concentrations (Table 1) and PK parameters (drug clearance and volume of distribution) in subjects with AS were similar to those previously observed in subjects with RA in the SELECT-BEYOND and SELECT-NEXT studies.

Subjects in the active treatment arm had statistically significant higher response rates for ASAS 40, ASAS 20, and ASAS PR compared to those in the placebo arm. However, within the single active treatment arm there were no clear exposure-response relationships between increasing upadacitinib average concentrations and the probability of achieving the evaluated efficacy outcomes, suggesting achieving the plateau of response. With increasing upadacitinib exposure, there was an increase in the percentage of subjects experiencing decreases of hemoglobin of ≥ 1 g/dL from baseline; with no subjects having ≥ 2 g/dL decreases of hemoglobin from baseline. There were no upadacitinib exposure-dependent increases in percentage of subjects experiencing lymphopenia or infection. There was a single observed case of Grade 2 neutropenia in a subject receiving active treatment and no observed cases of serious infections.

Conclusion: Upadacitinib pharmacokinetics are similar in subjects with AS and RA. Upadacitinib 15 mg QD dose is predicted to maximize efficacy in subjects with AS. Overall, the results of this analysis support  selection of the upadacitinib 15 mg QD dose for further evaluation in future studies in AS/axial SpA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/exposure-response-analyses-for-upadacitinib-efficacy-and-safety-in-ankylosing-spondylitis-analyses-of-the-select-axis-i-study/