Panaccione, Remo

Abstract Background Upadacitinib (UPA) is a selective and reversible Janus kinase inhibitor.U-ACCOMPLISH is one of two phase 3 induction trials that evaluated the safety and efficacy of UPA 45 mg once daily (QD) in adults with ulcerative colitis (UC). Methods U-ACCOMPLISH was a multicentre, randomized, double-blind, placebo-controlled trial (NCT03653026) that enrolled patients with moderate-to-severe UC (defined as adapted Mayo score 5–9 with centrally read endoscopic score 2–3) who had inadequate response, loss of response, or intolerance to aminosalicylates, immunosuppressants, corticosteroids and/or biologics. Patients were randomized 2:1 to UPA 45 mg QD or placebo (PBO) for 8 weeks. At week 8, responders entered the maintenance phase and non-responders entered the extended treatment period to receive open-label UPA 45 mg QD for additional 8 weeks.The primary endpoint (clinical remission per adapted Mayo Score) and ranked secondary endpoints including symptomatic, endoscopic– histologic evaluations from the 8-week PBO-controlled period are reported here. Non-responder imputation incorporating multiple imputation for missing data due to COVID-19 are reported. Results 522 patients were randomized (UPA, n=345; PBO, n=177); the intent-to-treat population included 341 patients in UPA and 174 patients in PBO group. Baseline demographics and disease characteristics were similar between groups; 50.7% and 51.1% were biologic inadequate responders in UPA and PBO groups, respectively (Table 1). A significantly higher proportion of patients receiving UPA 45 mg QD (33.5%) versus PBO (4.1%) achieved the primary endpoint (adjusted treatment difference: 29.0% [23.2, 34.7]; P<0.001). A significantly higher proportion of patients receiving UPA versus PBO also achieved all ranked secondary endpoints (all P<0.001; Figure 1).Serious adverse events were reported by 3.2% and 4.5% of patients in UPA and PBO groups, respectively (Table 2). Similar rates of serious infection were observed in both groups (0.6%); 2 events each of herpes zoster and opportunistic infection were reported in UPA group. No active tuberculosis, malignancy, adjudicated major adverse cardiovascular events, or deaths were reported in the study. One patient with venous thromboembolism (deep vein thrombosis and pulmonary embolism) and 1 patient with gastrointestinal perforation were reported in the placebo group. Conclusion In U-ACCOMPLISH, 8-week UPA 45 mg QD induction treatment led to statistically significant improvements in clinical, endoscopic, and combined endoscopic-histologic endpoints. The treatment was well tolerated, and the safety profile and AE prevalence was comparable with previous studies of UPA with no new safety signals identified.

Abstract Background Endoscopic healing has become a critical treatment target in Crohn’s disease (CD). Risankizumab (RZB), a humanized immunoglobulin G1 monoclonal antibody against the p19 subunit of interleukin 23, is being investigated as a treatment for moderate-to-severe CD. This analysis assessed different endoscopic endpoints in patients treated with RZB induction therapy in two double-blind, randomised, placebo (PBO)-controlled studies (ADVANCE [NCT03104413] and MOTIVATE [NCT03105128]). Methods Patients with moderate-to-severe CD (CD Activity Index [CDAI] of 220–450, Simple Endoscopic Score for CD [SES-CD] ≥ 6 [≥ 4 for isolated ileal disease] excluding the narrowing component, and average daily [liquid/very soft] stool frequency [SF] ≥ 4 and/or average daily abdominal pain [AP] score ≥ 2) who had demonstrated prior inadequate response or intolerance to conventional and/or biologic treatment (ADVANCE) or to biologic treatment (MOTIVATE) were randomised 2:2:1 (ADVANCE) or 1:1:1 (MOTIVATE) to receive intravenous (IV) RZB 600 mg, RZB 1200 mg, or PBO at weeks 0, 4, and 8. This analysis evaluated the proportion of patients who achieved endoscopic remission ulcer-free endoscopy (ie, absence of ulcers), and composite endpoints of CDAI clinical response and endoscopic response, and enhanced clinical response and endoscopic response at week 12 (endpoints defined in Figure 1 footnotes). All endoscopies were centrally read by a blinded reviewer. Safety was assessed throughout the studies. Results In ADVANCE and MOTIVATE, 850 and 569 patients, respectively, were randomised and included in the intent-to-treat population for this analysis. At week 12 greater proportions of RZB- vs PBO-treated patients in both studies achieved endoscopic remission (P ≤ .001), ulcer-free endoscopy (P ≤ .01), CDAI clinical response and endoscopic response (P ≤ .001), and enhanced clinical response and endoscopic response (P ≤ .001; Figure 1). Treatment with RZB 600 mg or 1200 mg was well tolerated, and no new safety risks were identified.1,2 Conclusion Induction therapy with IV RZB 600 mg or 1200 mg resulted in improved outcomes at week 12 compared with PBO as assessed by endoscopy and by composite endoscopic-clinical endpoints in patients with moderate-to-severe CD. References

Abstract Background We studied the efficacy and safety of ustekinumab (UST) vs adalimumab (ADA) through 1 year in biologic-naïve patients (pts) with moderate-to-severe Crohn’s disease. Methods SEAVUE was a multicenter, randomized, blinded, parallel-group, active-controlled study in adults with CD Activity Index (CDAI) scores ≥220/≤450. Biologic-naïve pts failing/intolerant to conventional therapy with any size ulcer on baseline (BL) ileocolonoscopy were eligible. Pts were randomized 1:1 to UST (⁓6mg/kg IV at BL then 90mg SC every 8 weeks [Ws]) or ADA (160/80mg SC at BL/W2, then 40mg SC every 2 Ws) per US-approved regimens (no dose modifications). Primary endpoint was clinical remission at W52 (CDAI <150). Major secondary endpoints were corticosteroid-free remission, clinical response (≥100-point CDAI decrease from BL), remission in pt-reported CDAI components (PRO-2 symptom remission: abdominal pain mean daily score ≤1 and stool frequency mean daily score ≤3), and endoscopic remission (SES-CD score ≤3/0 for pts with BL score=3) at W52 and clinical remission at W16. Results 386 pts were randomized to UST or ADA. BL demographics and disease characteristics were balanced between groups and indicative of pts with early, moderate-to-severe CD (median CD duration, 2.58 years; CDAI, 289.5; SES-CD, 8.0). At W52, 65% of UST-treated and 61% of ADA-treated pts achieved clinical remission (Δ=4.0%; 95% CI, -5.5%, 13.5%; p=0.417). Major secondary endpoints, including endoscopic remission, were similar between groups (Table 1), as were remission rates at assessment points through W52. Some other secondary endpoints showed numerical (not statistical) differences between UST and ADA (Table 1). Key safety events are summarized in Table 2. Among UST-treated and ADA-treated pts, 34.0% and 40.5% had infections, 2.6% and 7.2% had serious adverse events (AEs) of worsening CD, and 6.3% and 11.3% had AEs that led to discontinuation (DC) of study drug, respectively. One ADA-treated pt had active pulmonary TB. Injection-site reactions associated with active treatment occurred in 1.0% of UST-treated and 10.3% of ADA-treated pts. Overall, 15.2% of UST-treated and 23.6% of ADA-treated pts DC before W52. Reasons for DC were primarily lack of efficacy (UST, 2.1% vs ADA, 5.1%), AEs (UST, 5.7% vs ADA, 10.7%), and withdrawal of consent (UST, 5.8% vs ADA, 5.1%). Time to treatment DC was longer with UST vs ADA (post hoc analysis). Conclusion Both UST and ADA were highly effective in this population of biologic-naïve pts. Rates of clinical remission at W52 were not statistically significantly different between treatment groups. DC rates were numerically lower for UST. Safety results were consistent with prior experience for both treatments.