Armuzzi, Alessandro

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 Adalimumab (ADA) is efficacious and well tolerated in adult patients with ulcerative colitis (UC).1,2 SERENE-UC (NCT02065622) is a study evaluating higher ADA dosing regimens from which induction study results have previously been reported3; here, we report data from the maintenance study. Methods This Phase 3, double-blind, randomised, multicentre study evaluated higher vs. standard ADA dosing regimens for induction and maintenance therapy in adult patients with moderately to severely active UC. Following completion of the induction study at Week 8, all patients were re-randomised 2:2:1 to ADA 40 mg every week (40 EW), ADA 40 mg every other week (40 EOW), or exploratory ADA 40 mg with therapeutic drug monitoring (TDM) regimens, stratified by induction treatment regimen, clinical response status at Week 8, and clinical remission (CRem) status at Week 8 among Week 8 responders. Efficacy endpoints were evaluated in Week 8 responders (ITT-RP) unless indicated differently. The primary efficacy endpoint was proportion of patients achieving CRem (full Mayo Score ≤2 with no subscore >1) at Week 52. The endoscopic component of the Mayo Score was scored via central reading. Non-responder imputation was used for missing values. Comparisons between 40 EW and 40 EOW dosing regimens used the Cochran–Mantel–Haenszel test adjusted for stratification. Safety assessment included a collection of adverse events (AEs), vital signs, and laboratory data. Results Of 852 patients in the Global (ex-Japan) induction study, 757 were re-randomised at Week 8 and 371 were included in the ITT-RP. In the ITT-RP, induction baseline demographics and disease characteristics were generally balanced across the 3 treatment arms; range across arms for mean UC disease duration was 6.2–7.8 years, 6.8–11.7% had prior infliximab use, and 62.5–63.5% were receiving corticosteroids. The overall mean ADA exposure was 252.2 days. The table displays results for efficacy endpoints. The observed safety profile was similar between maintenance treatment arms, including AEs of special interest (generally <1% across arms). Conclusion In the Global (ex-Japan) study of SERENE-UC, CRem at Week 52 was numerically higher among Week 8 responders in patients receiving ADA 40 EW compared with 40 EOW maintenance regimens (∆ = 10.5%), but not statistically significant. Higher maintenance treatment with 40 EW was generally safe and well tolerated with a similar safety profile to 40 EOW. No new long-term safety concerns were observed. References

BACKGROUND: Patients with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC), have a higher risk of Clostridium difficile infection (CDI) than the general population (1). The incidence of CDI is increasing among patients with IBD, and certain UC treatments may be associated with greater risk (1). We report CDI events in the tofacitinib UC clinical program, and the incidence of CDI among patients receiving other treatments for UC. METHODS: For the tofacitinib UC program, rates of CDI (patients with an adverse event [AE] of CDI, Clostridium difficile colitis, or Clostridium test-positive, plus concomitant oral metronidazole or vancomycin, counted once per cohort) are reported for Induction Cohort (patients from an 8-week Phase [P]2 and two 8-week P3 induction studies; placebo or tofacitinib 10 mg twice daily [BID; NCT00787202; NCT01465763; NCT01458951]); Maintenance Cohort (patients from a 52-week maintenance study; placebo or tofacitinib 5 or 10 mg BID [NCT01458574]); and Overall Cohort (all tofacitinib-treated patients in P2/3 induction and maintenance studies and an ongoing, open-label, long-term extension study [as of December 2016; NCT01470612]). Positive Clostridium difficile test at screening was an exclusion criterion for program entry. Overall Cohort incidence rate (IR) was calculated as number of unique patients with events per 100 patient-years (PY). For contextualization, CDI rates among patients receiving other UC medications were obtained from a retrospective cohort study utilizing data from the Truven MarketScan ® Database, an administrative healthcare claims database in the US. Patients with moderately to severely active UC, with either an inpatient or outpatient diagnosis code of CDI, plus a prescription for oral therapy (including metronidazole, vancomycin, and fidaxomicin) within 14 days of CDI diagnosis (observation period: October 1, 2010–September 30, 2015), were included. Truven cohort IRs were calculated as number of patients with events per 100 PY. RESULTS: In the tofacitinib Induction Cohort, CDI occurred in 3 patients (placebo, 1/282 [0.4%]; tofacitinib 10 mg BID, 2/938 [0.2%]). In the Maintenance Cohort, CDI occurred in 3 patients (placebo, 3/198 [1.5%]; tofacitinib 5 or 10 mg BID, 0/394 [0.0%]). In the Overall Cohort of all tofacitinib-treated patients (1,664 PY of follow-up), CDI occurred in 8/1,157 patients (0.7%), with an IR (95% confidence interval [CI]) of 0.48 (0.21, 0.95). Two cases were reported as serious AEs. All were mild (n = 4) or moderate (n = 4) in severity; 6 continued with study treatment, one temporarily discontinued, one permanently discontinued. All CDI cases resolved with treatment. In the Truven Cohort, 160 CDI events occurred during 4,918 PY of follow-up, with an overall CDI IR (95% CI) of 3.25 (2.77, 3.80); of which 116 were CDI-associated hospitalizations (4,936 PY of follow-up). Among patients receiving azathioprine, 6-mercaptopurine, or tumor necrosis factor inhibitors, CDI IRs were 3.23 (2.18, 4.62), 2.31 (1.26, 3.87), and 3.58 (2.95, 4.29), respectively. CONCLUSION(S): In the tofacitinib UC program, CDI rates among patients receiving tofacitinib were similar to or lower than those observed with placebo. The IR among patients receiving tofacitinib was numerically lower than those observed for immunomodulators and tumor necrosis factor inhibitors in the Truven Cohort.