CELEST Study Research Articles

Upadacitinib Was Efficacious and Well-tolerated Over 30 Months in Patients With Crohn’s Disease in the CELEST Extension Study

The long-term efficacy and safety of upadacitinib was evaluated in an open-label extension (OLE) of a phase II, double-blind, randomized trial of patients with Crohn's disease. Patients who completed the 52-week study (CELEST) received upadacitinib in the CELEST OLE as follows: those who had received immediate-release upadacitinib 3, 6, or 12 mg twice daily or 24 mg once daily (QD) received extended-release upadacitinib 15 mg QD and those who had received immediate-release upadacitinib 12 or 24 mg twice daily as rescue therapy received extended-release upadacitinib 30 mg QD. If any patient initiating upadacitinib 15 mg QD in CELEST OLE lost response at or after week 4, the dose was escalated to upadacitinib 30 mg QD (dose-escalated group). Clinical, endoscopic, inflammatory and quality-of-life measures were assessed. A total of 107 CELEST study completers entered CELEST OLE. The proportion of patients with clinical remission 2.8/1.0 was maintained between week 0 and month 30 in all groups (month 30: 15 mg, 61%; 30 mg, 54%; dose-escalation, 55%). Endoscopic response was maintained in all groups (month 24: 68%, 67%, and 40%, respectively). The rates of adverse events (AEs), serious AEs, AEs leading to discontinuation, infections, serious infections, herpes zoster, and creatine phosphokinase elevation were higher with upadacitinib 30 mg vs 15 mg. Sustained long-term benefit at 30 months and further endoscopic improvements to month 24 were observed in patients with Crohn's disease receiving upadacitinib. Safety over 30 months was consistent with the known safety profile of upadacitinib. gov ID no: NCT02782663.

Randomized Controlled Trial Substudy of Cell-specific Mechanisms of Janus Kinase 1 Inhibition With Upadacitinib in the Crohn's Disease Intestinal Mucosa: Analysis From the CELEST Study.

BackgroundJanus kinase (JAK) inhibition shows promise for treatment of patients with moderate to severe Crohn’s disease. We aimed to provide mechanistic insights into the JAK1-selective inhibitor upadacitinib through a transcriptomics substudy on biopsies from patients with Crohn's disease from CELEST.MethodsSeventy-four patients consented to this optional substudy. Ileal and colonic biopsies were collected during endoscopy at screening and week 12 or 16. RNA isolated from 226 samples was analyzed by RNAseq, with additional qPCR analysis. Additional biopsies from patients with Crohn's disease receiving anti-tumor necrosis factor (anti-TNF; n = 34) and healthy controls (n = 10) were used for qPCR. Single-cell RNAseq public profiles were used to evaluate treatment effects on specific cellular subsets, associations with endoscopic improvement, and indirect comparisons with the anti-TNF-treated cohort.ResultsIn involved areas of mucosa with endoscopic remission after upadacitinib treatment, 1156 and 76 protein-coding genes were significantly regulated (false discovery rate < 0.05) at week 12/16 in colonic and ileal biopsies, respectively (60 overlapped), compared with baseline. Upadacitinib did not significantly affect transcriptomes of noninvolved intestinal areas. CELEST patients (mostly anti-TNF-refractory) showed baseline differences in gene expression compared with a separate cohort of biologic-naïve patients. Notably, upadacitinib reversed overexpression of inflammatory fibroblast and interferon-γ effector signature markers.ConclusionsUpadacitinib modulates inflammatory pathways in mucosal lesions of patients with anti-TNF-refractory Crohn's disease, including inflammatory fibroblast and interferon-γ-expressing cytotoxic T cell compartments. This substudy is the first to describe the molecular response to JAK1 inhibition in inflammatory bowel disease and differential effects relative to anti-TNF treatment. (Clinical trial identifier: NCT02365649)

Quality of Life and Work Productivity Improvements with Upadacitinib: Phase 2b Evidence from Patients with Moderate to Severe Crohn's Disease.

IntroductionIn the phase 2 CELEST study, positive efficacy results were obtained with the Janus kinase 1 inhibitor upadacitinib for adult patients with moderate to severe Crohn’s disease. We present the health-related quality of life and work productivity improvement results with upadacitinib from CELEST.MethodsCELEST (NCT02365649) was a double-blind study where patients were randomized 1:1:1:1:1:1 in the 16-week induction period to placebo or upadacitinib 3 mg twice daily (BID), 6 mg BID, 12 mg BID, 24 mg BID, or 24 mg once daily (QD). Patients completing the induction period were re-randomized 1:1:1 to receive upadacitinib 3 mg BID, 12 mg BID, or 24 mg QD for 36 weeks or 3 mg BID, 6 mg BID, or 12 mg BID (after amendment). Inflammatory Bowel Disease Questionnaire (IBDQ), European Quality of Life-5 Dimensions visual analog scale (EQ-5D VAS), and Work Productivity and Activity Impairment (WPAI) questionnaire outcomes were assessed at baseline and Weeks 8, 16, and 52.ResultsAt Week 16, a significant percentage (P ≤ 0.05) of patients receiving upadacitinib 6-mg BID dose or higher achieved IBDQ response (IBDQ score change ≥ 16 points; 49%–57% for upadacitinib vs. 24% for placebo) and IBDQ remission, except 24 mg QD (IBDQ score ≥ 170; 26%–39% for upadacitinib vs. 11% for placebo). Greater improvements in IBDQ total score, EQ-5D VAS, and activity impairment from baseline (P ≤ 0.1) versus placebo were also observed. Larger improvements (P ≤ 0.1) in IBDQ response and total score and EQ-5D VAS were observed at Week 8 with 6 and 24 mg BID versus placebo, with improvements for all dosages maintained or greater at Week 52 for IBDQ, EQ-5D VAS, and WPAI endpoints, in particular for the 12-mg BID group.ConclusionImprovements in health-related quality of life and work productivity were achieved and sustained with upadacitinib in patients with moderate to severe Crohn’s disease.Trial RegistrationClinicalTrials.gov identifier, NCT02365649.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01660-7.

DOP79 Dose escalation of upadacitinib in Crohn’s disease patients with an inadequate response: Data from the randomised CELEST study

Abstract Background Patients with Crohn’s disease (CD) may lose response to treatment, requiring dose adjustments. This analysis from the CELEST study evaluated efficacy and safety in patients with CD who required an escalated dose of upadacitinib (UPA), an oral selective JAK1 inhibitor. Methods CELEST (NCT02365649) was a placebo-controlled phase 2 study of adults with moderate-to-severe CD refractory to immunosuppressants/biologics. Patients were randomised to placebo or UPA 3, 6, 12, or 24 mg twice daily (BID) or 24mg once daily (QD) for 16 weeks (weeks), followed by a 36-week double-blind maintenance period to receive 3, 6 or 12mg BID or 24mg QD (Figure 1). Patients who met criteria for inadequate response (average daily liquid/soft stool frequency [SF] &amp;gt;2.2 or average daily abdominal pain score &amp;gt;1.8, and increase in hs-CRP &amp;gt;1 mg/l from baseline [BL] or hs-CRP ≥5 mg/l at previous or current visit) at or after week 20 were eligible to receive open-label (OL) therapy with UPA 12mg BID. Patients with inadequate response at or after 4 weeks of OL 12 mg BID could further escalate to OL 24 mg BID. Data were analysed using descriptive statistics of clinical/endoscopic improvement, change from BL in hs-CRP and faecal calprotectin (FC), and AEs at week 52. Results Among 220 randomised patients, 180 were re-randomised into the maintenance period; 60 had inadequate response and received OL 12 mg BID. Of the 60 patients, 25 (42%) were in clinical response at week 16. After receiving OL 12 mg, 27 patients (45%) required escalation to OL 24 mg BID. A higher proportion of patients who received OL 24 mg received 2 or more prior TNF antagonists, and had higher BL FC, SF, and Simplified Endoscopic Score for CD (SES-CD) compared with patients who remained on OL 12 mg BID (Table 1). At week 52, 15% of patients who received OL 12 mg achieved clinical remission and 10% achieved endoscopic response. Of the patients who escalated to OL 24 mg, 39% achieved clinical remission and 41% were in endoscopic response at week 52 (Table 2). At week 52, change from BL in FC and hs-CRP was −2123 ± 2475 µg/g and −5.1 mg/l, respectively, for patients who received OL 24 mg vs. −423 ± 2953 and −6.4 mg/l for OL 12 mg. Serious infection was reported in 3 patients (2 receiving OL 12 mg and 1 receiving OL 24 mg). Two nonserious herpes zoster events were reported (1 on each dose), but neither event led to discontinuation of UPA. No malignancies, cardiovascular events, thromboembolic events, intestinal perforations, tuberculosis, or deaths were reported for patients who dose-escalated. Conclusion Patients with non-response or loss of response during CELEST gained clinical remission and endoscopic response with UPA 12 mg BID or further escalation to 24 mg BID. No new safety risks were observed for either dose of UPA, consistent with double-blind CELEST results.

817 Identification of Biomarkers and Mechanistic Insight for Upadacitinib in Crohn’s Disease: Serum Inflammatory Mediator Analysis From the Phase 2b CELEST Study

INTRODUCTION: We report pharmacodynamic profiling of serum inflammatory mediators in CELEST (patients) pts with the aim of understanding UPA mechanism of action in CD and linking biomarkers to intestinal inflammation, abdominal pain (AP), and stool frequency (SF). METHODS: The CELEST Ph2 study evaluated the efficacy/ safety of multiple dosing regimens of UPA vs PBO in adults with moderately to severely active CD and inadequate response or intolerance to immunomodulators and/or TNF inhibitors.1,2 Serum samples from baseline (BL) visit and end of induction period (Wk16) were analyzed by OLINK® inflammation panel (92 proteins) and Singulex immunoassay for interleukin-17A(IL-17A), IL-17F, IL-22, and IL-23p19. Protein level changes (BL–Wk16) were analyzed by an ANCOVA model where BL protein level was adjusted as a covariate and treatment effect was considered significant when a false discovery rate &lt; 0.10 was observed after multiplicity adjustment on F-test P-values. Spearman rank correlation coefficients(rs) determined relationships between BL levels or BL–Wk16 level changes of serum biomarkers (also including serum C-reactive protein and fecal calprotectin) and improvements in Simple Endoscopic Score for CD (SES-CD), AP, and SF. RESULTS: Paired BL and Wk16 serum samples were available from 104 pts (UPA 3 mg twice daily [BID], n = 18; 6 mg BID, n = 19; 12 mg BID, n = 13; 24 mg BID, n = 18; 24 mg once daily, n = 18; and PBO, n = 18). UPA treatment significantly reduced expression of serum pro-inflammatory mediators (Table). that are associated with immune cell migration, type I/II interferon (IFN) responses, T cell activation, T helper cell-1 (Th1) responses, and CD8+ T cell responses. UPA treatment did not significantly modulate expression of IL-23/Th17-related serum cytokines in CD. Correlations were observed for BL–Wk16 changes in serum proteins and SES-CD, AP, or SF. Importantly, oncostatin-M reductions correlated with SES-CD (rs = 0.35, P = 0.02) and SF improvement (rs = 0.33, P = 0.04), suggesting similar drivers of these aspects of disease. AP improvement correlated with reductions in CSF-1 (rs = 0.37, P = 0.01), TNFRSF9 (rs = 0.34, P = 0.03), IL-12B (rs = 0.31, P = 0.07), CXCL9 (rs = 0.31, P = 0.07), and CD8A (rs = 0.31, P = 0.09), which are all associated with the Th1/CD8/IFN-γ pathway. CONCLUSION: This analysis of inflammatory mediators in serum of CD pts from CELEST identifies potential pharmacodynamic biomarkers and mechanistic insights for the JAK-1 inhibitor, UPA.

Mo1837 – Effect of Upadacitinib on Extra-Intestinal Manifestations in Patients with Moderate to Severe Crohn’s Disease: Data from the Celest Study

Mo1837 – Effect of Upadacitinib on Extra-Intestinal Manifestations in Patients with Moderate to Severe Crohn’s Disease: Data from the Celest Study

Tu1732 – Changes in Simplified Endoscopic Score for Crohn's Disease (SES-CD) During a 16-Week Induction Treatment with Upadacitinib: Analysis of the Randomised Controlled Celest Study

Tu1732 – Changes in Simplified Endoscopic Score for Crohn's Disease (SES-CD) During a 16-Week Induction Treatment with Upadacitinib: Analysis of the Randomised Controlled Celest Study

Tu1714 – Impact of Upadacitinib on the General Clinical Condition of Patients with Crohn's Disease (CD): Data from the Randomised Celest Study

Tu1714 – Impact of Upadacitinib on the General Clinical Condition of Patients with Crohn's Disease (CD): Data from the Randomised Celest Study

DOP50 Effect of upadacitinib on extra-intestinal manifestations in patients with moderate to severe Crohn’s disease: data from the CELEST study

DOP50 Effect of upadacitinib on extra-intestinal manifestations in patients with moderate to severe Crohn’s disease: data from the CELEST study

P313 Impact of upadacitinib on the general clinical condition of patients with Crohn’s disease (CD): data from the randomised CELEST study

P313 Impact of upadacitinib on the general clinical condition of patients with Crohn’s disease (CD): data from the randomised CELEST study

P378 Changes in Simplified Endoscopic Score for Crohn’s disease (SES-CD) during a 16-week induction treatment with upadacitinib: analysis of the randomised controlled CELEST study

P378 Changes in Simplified Endoscopic Score for Crohn’s disease (SES-CD) during a 16-week induction treatment with upadacitinib: analysis of the randomised controlled CELEST study

906 - Efficacy and Safety of Upadacitinib Maintenance Treatment for Moderate to Severe Crohn's Disease: Results from the Celest Study

906 - Efficacy and Safety of Upadacitinib Maintenance Treatment for Moderate to Severe Crohn's Disease: Results from the Celest Study

Su1803 - Correlation of Endoscopic and Clinical Endpoints During Induction Therapy in Patients with Moderate to Severe Crohn's Disease: Analysis from Celest Study

Su1803 - Correlation of Endoscopic and Clinical Endpoints During Induction Therapy in Patients with Moderate to Severe Crohn's Disease: Analysis from Celest Study

Sa1758 - Upadacitinib Improves Steroid-Free Clinical and Endoscopic Endpoints in Patients with Crohn's Disease: Data from the Celest Study

Sa1758 - Upadacitinib Improves Steroid-Free Clinical and Endoscopic Endpoints in Patients with Crohn's Disease: Data from the Celest Study

Sa1755 - Rapidity of Clinical and Laboratory Improvements Following Upadacitinib Induction Treatment: Data from the Celest Study

Sa1755 - Rapidity of Clinical and Laboratory Improvements Following Upadacitinib Induction Treatment: Data from the Celest Study

Sa1764 - Upadacitinib Exposure-Response Relationships for Efficacy in Subjects with Moderately to Severely Active Crohn's Disease - Analysis of Celest Study

Sa1764 - Upadacitinib Exposure-Response Relationships for Efficacy in Subjects with Moderately to Severely Active Crohn's Disease - Analysis of Celest Study

OP022 Rapidity of clinical and laboratory improvements following upadacitinib induction treatment: data from the CELEST study

OP022 Rapidity of clinical and laboratory improvements following upadacitinib induction treatment: data from the CELEST study

P273 Efficacy and safety of upadacitinib maintenance treatment for moderate to severe Crohn’s disease: Results from the CELEST study

P273 Efficacy and safety of upadacitinib maintenance treatment for moderate to severe Crohn’s disease: Results from the CELEST study

P533 Correlation of endoscopic and clinical endpoints during induction therapy in patients with moderate-to-severe Crohn’s disease: Analysis from CELEST study

P533 Correlation of endoscopic and clinical endpoints during induction therapy in patients with moderate-to-severe Crohn’s disease: Analysis from CELEST study

P601 Upadacitinib improves steroid-free clinical and endoscopic endpoints in patients with Crohn’s disease: Data from the CELEST study

P601 Upadacitinib improves steroid-free clinical and endoscopic endpoints in patients with Crohn’s disease: Data from the CELEST study