Clinical remission after dose escalation of upadacitinib

Crohn’s disease (CD) patients with non-response or loss of response to upadacitinib during the CELEST study gained clinical remission and endoscopic response with upadacitinib 12 mg twice daily or further escalation to 24 mg twice daily. There were no new safety signals for either dose of this oral selective JAK1 inhibitor.

CELEST was a phase 2 study of adults with moderate-to-severe CD refractory to immunosuppressants/biologics [1]. Patients were randomised to placebo or upadacitinib 3, 6, 12, or 24 mg twice daily, or 24 mg once daily for 16 weeks (n=220), followed by 3, 6, or 12 mg twice daily, or 24 mg once daily in a double-blind maintenance period of 36 weeks (n=180). Patients with inadequate response (n=60) received open-label upadacitinib 12 mg twice daily, with further escalation to 24 mg twice daily possible if an adequate response was not achieved by at least 4 weeks of open-label treatment.

After 16 weeks of open-label treatment, 25 (42%) had clinical response; 27 patients (45%) required escalation to upadacitinib 24 mg twice daily. At week 52, 15% and 10% of patients in the 12 mg group achieved clinical remission and endoscopic response, respectively. In the 24 mg group, these percentages were 39% and 41%. Three patients had a serious infection (2 receiving 12 mg). There were no malignancies, cardiovascular events, thromboembolic events, intestinal perforations, tuberculosis, or deaths in the dose-escalated groups.

An analysis of the phase 2b U-ACHIEVE study found that upadacitinib modulates expression of serum pro-inflammatory mediators found in pathways associated with the pathogenesis of ulcerative colitis [2]. Upadacitinib increased expression of mediators that promoted haematopoiesis, neuroprotection, and mucosal repair. Clinical improvements in ulcerative colitis were found to correlate with changes in biomarkers associated with reduced inflammation and improved haematopoiesis, mucosal repair, and neuroprotection/neurodegeneration.

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      1. Sandborn W, et al. ECCO-IBD 2020, DOP79.
      2. Vermeire S, et al. ECCO-IBD 2020, DOP17.

Posted on 14 April, 20208 April, 2024