Ford, Sharanya

Abstract Background and Aims Upadacitinib (UPA)—an oral, reversible selective Janus kinase inhibitor—has a favorable benefit–risk profile for patients with Crohn’s disease (CD) and ulcerative colitis (UC). We evaluated the benefit–risk of UPA in select subgroups with CD or UC. Methods Patients were randomized to UPA 45 mg (UPA45) once daily (QD) or placebo (PBO) induction for 12 (CD: U-EXCEED, U-EXCEL) or 8 weeks (UC: U-ACHIEVE, U-ACCOMPLISH). Clinical responders were re-randomized to QD UPA 15 mg (UPA15), UPA 30 mg (UPA30), or PBO for 52-week maintenance (CD: U-ENDURE; UC: U-ACHIEVE). This exploratory post hoc analysis assessed efficacy and safety outcomes (adverse events of special interest [AESIs]: serious infections, major adverse cardiovascular [CV] events, malignancies, and venous thromboembolic events) by CV risk, prior treatment failure, and age. Results This analysis included 1021 patients with CD and 1097 with UC during induction, and 673 with CD and 746 with UC during maintenance. Improved efficacy outcomes comparable to the overall study populations were observed with UPA versus PBO across subgroups. Patients receiving UPA30 generally showed numerically higher rates of improvements versus UPA15. AESI rates were generally comparable between UPA and PBO across subgroups except for numerically higher rates of herpes zoster and serious infections in CD with UPA. Conclusions UPA resulted in consistent benefit versus placebo across CV risk, prior treatment failure, and age subgroups. No treatment differences were seen in AESIs across subgroups except herpes zoster and serious infections, reinforcing the favorable benefit–risk profile for UPA in CD and UC seen in the overall study populations. Clinical trial numbers NCT02819635, NCT03653026, NCT03345836, NCT03345849, NCT03345823

Abstract Importance and Objective Upadacitinib, an oral, reversible Janus kinase inhibitor, is approved for the treatment of moderate-to-severe Crohn’s disease (CD). Limiting corticosteroid exposure is an important goal in treating CD. This posthoc analysis evaluated the corticosteroid-sparing effects of upadacitinib in patients with CD. Design and Setting This study included pooled data from two phase 3, multicenter, double-blind induction trials and one maintenance trial. Randomization was stratified by corticosteroid use at induction baseline, with a mandatory corticosteroid taper starting at induction week 4. Efficacy was evaluated by baseline corticosteroid use and by achieving corticosteroid-free outcomes through year 2 of maintenance therapy. Safety was also assessed. Results At baseline, 34.7% (234/674) and 35.7% (124/347) of upadacitinib 45 mg and placebo-treated patients were taking corticosteroids, respectively. At induction week 12 and maintenance week 52, higher rates of upadacitinib-treated patients were corticosteroid-free among all patients and among patients with baseline corticosteroid use compared with placebo; upadacitinib-treated patients achieved higher rates of corticosteroid-free outcomes, compared with placebo, including corticosteroid-free clinical remission (stool frequency/abdominal pain score [SF/APS]: 42.7% vs 16.1%; CD activity index [CDAI]: 41.2% vs 23.4%) and corticosteroid-free endoscopic response (37.0% vs 8.1%), with similar results observed among responders to upadacitinib induction therapy at maintenance week 52. Corticosteroid-free outcomes were sustained through year 2 of maintenance therapy. The safety profile was similar to the overall population, with no new safety risks identified. Conclusions and Relevance The results from pivotal studies demonstrated that upadacitinib effectively induced early and sustainable corticosteroid-free clinical remission with a manageable safety profile in patients with moderate-to-severe CD. Clinical trial identifiers U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.

Abstract Background and Aims The long-term efficacy and safety of upadacitinib in patients with moderate to severe Crohn’s disease (CD) were evaluated in the U-ENDURE Long-Term Extension (LTE) study. Here we report the results after 2 years of total maintenance treatment. Methods U-ENDURE is an ongoing 240-week LTE study conducted at 243 sites across 43 countries (first patient enrolled in LTE 21 March 2019). Patients who completed the 52-week maintenance study continued their previously assigned treatment, once-daily upadacitinib 15 mg or upadacitinib 30 mg. Efficacy was analyzed at week 48 of the LTE; safety was analyzed in the cumulative study population (combined 52 week maintenance and 48 week LTE) and the LTE study population only (cutoff date: 19 December 2023). Results From LTE week 0 to week 48, as-observed efficacy rates for clinical remission (per stool frequency/abdominal pain score, upadacitinib 15 mg: 78.3% to 82.9%; upadacitinib 30 mg: 84.7% to 76.6%; per CD Activity Index, upadacitinib 15 mg: 81.3% to 83.1%; upadacitinib 30 mg: 86.1% to 86.8%), endoscopic response (upadacitinib 15 mg: 59.6% to 67.1%; upadacitinib 30 mg: 71.2% to 69.6%), inflammatory biomarkers, and quality-of-life outcomes remained stable. The safety profile of the cumulative maintenance population observed through LTE week 48 was consistent with previous trials in the upadacitinib CD program. Treatment-emergent adverse event rates for the cumulative maintenance population were 283.1 and 273.4 events/100 patient-years for upadacitinib 15 mg and upadacitinib 30 mg, respectively. Event rates of serious treatment-­emergent adverse events were 16.0 events/100 patient-years for upadacitinib 15 mg and 14.6 events/100 patient-years for upadacitinib 30 mg. The most common adverse events of special interest (≥ 5.0 events/100 patient-years) were hepatic disorder, lymphopenia, creatine phosphokinase elevation, herpes zoster, and anemia. There was 1 treatment-emergent adverse event of suicide leading to death. Conclusion Sustained clinical, endoscopic, quality-of-life, and biomarker outcomes were observed in patients who were initial responders to upadacitinib and completed 2 years of maintenance therapy, with no new safety signals identified. Clinical trial identifier U-ENDURE; ClinicalTrials.gov number, NCT03345823.

Abstract Background Long-term use of corticosteroids (CS) is a concern for patients with Crohn’s disease (CD), as prolonged use is associated with increased mortality and adverse outcomes. Upadacitinib (UPA), an oral, selective, reversible Janus kinase inhibitor, is approved for the treatment of moderate-to-severe CD and demonstrated CS-sparing efficacy, with a consistent safety profile through maintenance week (wk) 52.1-4 Here, we evaluated the long-term efficacy of UPA in achieving CS-free clinical and endoscopic outcomes in patients enrolled in the ongoing U-ENDURE long-term extension (LTE) study. Methods Patients who completed the U-ENDURE 52-wk maintenance study were eligible for the subsequent LTE study wherein they continued their previously assigned treatment (once daily UPA 15 mg [UPA15] or UPA 30 mg [UPA30]). Efficacy was assessed from LTE wk 0-wk48, among patients with 2 year (yr) (100 wk) of total maintenance therapy, within the overall population and in patients with baseline CS use (induction wk 0). CS-free endpoints (without CS use for ≥90 days before evaluation), included clinical remission (per stool frequency/abdominal pain score [SF/APS] and CD Activity Index [CDAI]), endoscopic response, and endoscopic remission, were evaluated using both as-observed and nonresponder imputation (NRI) methods, with NRI analysis presented in text. Safety was not evaluated here but was reported previously.3 Results Among patients with 2 yr of total maintenance therapy, 35.7% (87/244) received CS at baseline, with 13.1% (32/244) receiving CS at any time during the LTE study regardless of baseline CS use. Among patients taking baseline CS and those who received CS at any time during the LTE study (n=20), the median (range) time of CS use was 127.5 (2-1589) days. CS-free clinical remission was achieved at LTE wk 0 and wk 48 per SF/APS (overall population: UPA15, 71.7%, 58.9%; UPA30, 81.8%, 57.7%; patients with baseline CS use: UPA15, 71.8%, 53.8%; UPA30, 79.2%, 54.2%, NRI, Fig.1A-B) and CDAI criteria (overall population: UPA15, 74.8%, 60.7%; UPA30, 83.9%, 65.0%; patients with baseline CS use: UPA15, 74.4%, 56.4%; UPA30, 81.3%, 58.3%, NRI, Fig.1C-D). At LTE wk 48, a high fraction of UPA-treated patients achieved CS-free endoscopic response (overall population: UPA15, 48.6%; UPA30, 55.5%; patients with baseline CS use: UPA15, 38.5%; UPA30, 60.4%, NRI) and CS-free endoscopic remission (overall population: UPA15, 33.6%; UPA30, 46.0%; patients with baseline CS use: UPA15, 28.2%; UPA30, 54.2%, NRI, Fig.2). Conclusion Patients with moderate-to-severe CD who received long-term UPA maintenance treatment sustained high rates of CS-free clinical and endoscopic outcomes, suggesting that UPA may serve as an effective long-term CS-sparing therapy. References 1.RINVOQ [package insert], extended-release tablets, FDA Prescribing Information. AbbVie Inc; 2022. Accessed 1 June 2022.2. 2.RINVOQ [package insert], prolonged-release tablets. EMA Summary of Product Characteristics. AbbVie; 2022. Accessed 1 June 2022. 3.Loftus EV and Panes J et al. N Engl J Med 2023;388:1966-1980. J 4.M C Dubinsky, et al. JCC, 17; (Supp_1); 2023: i104–i106.

Abstract Background Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for the treatment of moderately to severely active Crohn’s disease (CD).1 The U-ENDURE (NCT03345823) maintenance study and long-term extension (LTE) evaluate the long-term efficacy and safety of UPA maintenance therapy. Here, we report the results of the U-ENDURE LTE. Methods Patients (pts) completing the U-ENDURE 52-week (wk) maintenance study were eligible to participate in the LTE and continue their previously assigned treatment (placebo [PBO], UPA 15 mg [UPA15] once daily [QD], or UPA 30 mg [UPA30] QD; blinded until the last pt completed maintenance wk52). Clinical response, clinical remission, endoscopic response, endoscopic remission, as well as high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP) were evaluated as-observed up to wk48 of the LTE among pts (PBO [N = 89], UPA15 [N = 107], UPA30 [N = 173]); excluding pts who received open-label UPA30 rescue therapy. Safety was assessed in all pts (PBO [N = 223], UPA15 [N = 221], UPA30 [N = 229]) from wk0 of the maintenance study up to LTE wk204 (cut-off date: 01 Aug 2023). Results At LTE wk0, the SF/APS clinical remission rates were 73.0%, 78.3%, and 80.3% for PBO, UPA15, and UPA30, respectively (Figure 1A). Similar rates were reported at LTE wk0 for CDAI clinical remission (PBO 75.3%, UPA15 81.3%, UPA30 80.9%; Figure 1B) and clinical response (CR-100: PBO 79.5%, UPA15 84.9%, UPA30 84.4%). Rates of clinical remission were stable through wk48 of the LTE. Endoscopic response (PBO 32.9%, UPA15 59.6%, UPA30 66.5%) and remission rates (PBO 27.8%, UPA15 42.4%, UPA30 47.3%) at LTE wk0 were sustained through wk48 with UPA while decreased with PBO (Figure 1C-D). At LTE wk0, the mean [95% CI] change from induction BL in hs-CRP was 1.8 [–0.4, 4.1], –13.2 [–17.9, –8.6], and –12.8 [–16.8, –8.9] for PBO, UPA15, and UPA30, respectively; sustained through wk48. Similar results were observed with FCP (mean [95% CI] change from induction BL: PBO 126 [–103, 356], UPA15 –2946 [–4121, –1772], UPA30 –1871 [–2577, –1165]). Severe adverse events (AEs) and serious AEs were lower with UPA treatment compared with PBO (Table 1). The rates of most AEs of special interest were similar between UPA and PBO; however, numerically higher rates of herpes zoster, adjudicated gastrointestinal perforations, neutropenia, lymphopenia, creatine phosphokinase elevation, and hepatic disorders were reported in pts treated with UPA vs PBO (Table 1). Conclusion In pts completing wk48 of the LTE, sustained efficacy was observed in clinical and endoscopic endpoints with over 2 years of UPA treatment, while maintaining an overall positive safety profile in pts with CD. Reference: 1. Loftus EV Jr, et al. N Engl J Med. 2023;388:1966–80