Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

BACKGROUND Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P = 0.005 and P = 0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS Among patients with moderately to severely active Crohn’s disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.

Evolving concepts in phases I and II drug development for Crohn's Disease

The highest attrition rates during drug development programmes occur at the proof of concept stage. Given the large number of molecules under development for Crohn’s disease, a need exists to improve the efficiency of early drug development by fast-tracking promising agents and terminating ineffective ones. Multiple opportunities are available to achieve these goals, including the use of more responsive outcome measures, and the incorporation of sophisticated pharmacokinetic modelling and/or highly specific pharmacodynamic markers into exposure-based dosing regimens and novel trial designs. In this article we review these strategies and propose an integrated paradigm of early drug development in Crohn’s disease

Carbon footprint of common procedures in inflammatory bowel disease

Background: The aim of this study was to assess the environmental impact, primarily the carbon footprint of the most common procedures in inflammatory bowel disease (IBD). Methods: In this study, all processes and products used during a total of eight laparoscopic ileocecal resections (ICRs) in patients with Crohn’s disease (CD), eight laparoscopic subtotal colectomies (STCs) for ulcerative colitis (UC), and eight ligation of the intersphincteric fistula tract (LIFT) procedures in patients with Crohn’s perianal fistula (PAF) (all in adults ≥ 16 years) between March 2023 and May 2024 were collected. A life cycle assessment (LCA) was conducted, mean CO 2 emission rates were calculated, the major contributors (“hotspots”) were determined, and midpoint/endpoint analysis was performed. Results: The mean total carbon footprints of laparoscopic ICR, STC, and LIFT were, respectively, 104 kg, 116 kg, and 43.6 kg CO 2eq, equaling one-way trips by airplane from Amsterdam to Paris, to Manchester, and to Düsseldorf, respectively. The main contributors in laparoscopic ICR and STC were transport of employees and patients (48% and 49%, respectively), energy use in the theater (21% and 27%, respectively), and the use of surgical equipment (14% and 17%, respectively). In LIFT procedures, transport of employees/patients accounted for 47% of total emission rates, followed by the use of surgical equipment (28%), and electricity use in the theater (13%). Besides the impact on global warming, significant impact on fine particulate matter formation, land use, terrestrial acidification, and fossil resource scarcity was identified. Endpoint analysis showed an amount of disability-adjusted life years (DALYs) of approximately 2 h of health damage per laparoscopic ICR/STC and 47 min per LIFT. Conclusions: The carbon footprint of three commonly performed IBD surgeries is mainly determined by transportation of patients/healthcare personnel, followed by electricity and material use. The latter two vary with the complexity of the surgeries. IBD surgeons should focus on minimizing energy resources and using standard surgical materials. Also, employees should be encouraged to travel by foot/bicycle/public transport/carpooling/electric car.</p

Tight control for Crohn's disease with adalimumab-based treatment is cost-effective: an economic assessment of the CALM trial

Objective To evaluate the cost-effectiveness of an inflammatory biomarker and clinical symptom directed tight control strategy (TC) compared with symptom-based clinical management (CM) in patients with Crohn’s disease (CD) naïve to immunosuppressants and biologics using a UK public payer perspective. Design A regression model estimated weekly CD Activity Index (CDAI)-based transition matrices (remission: CDAI <150, moderate: CDAI ≥150 to <300, severe: CDAI ≥300 to <450, very severe: CDAI ≥450) based on the Effect of Tight Control Management on Crohn’s Disease (CALM) trial. A regression predicted hospitalisations. Health utilities and costs were applied to health states. Work productivity was monetised and included in sensitivity analyses. Remission rate, CD-related hospitalisations, adalimumab injections, other direct medical costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER) were calculated. Results Over 48 weeks, TC was associated with a higher clinical remission (CDAI <150) rate (58.2% vs 46.8%), fewer CD-related hospitalisations (0.124 vs 0.297 events per patient) and more injections of adalimumab (40 mg sc) (mean 31.0 vs 24.7) than CM. TC was associated with 0.032 higher QALYs and £593 higher total medical costs. The ICER was £18 656 per QALY. The ICER was cost-effective in 57.9% of simulations. TC became dominant, meaning less costly but more effective, when work productivity was included. Conclusion A TC strategy as used in the CALM trial is cost-effective compared with CM. Incorporating costs related to work productivity increases the economic value of TC. Cross-national inferences from this analysis should be made with caution given differences in healthcare systems. Trial registration number NCT01235689

Dynamic prediction of bleeding risk in thrombocytopenic preterm neonates

Clinical epidemiolog

Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis

;irikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial. Methods: We conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed. Results: A total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer. Conclusions: Mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizuma

Extended Risankizumab Treatment in Patients With Crohn's Disease Who Did Not Achieve Clinical Response to Induction Treatment.

BACKGROUND AND AIMS: The efficacy and safety of extended treatment with risankizumab (RZB), an anti-interleukin-23 p19 monoclonal antibody, were evaluated in patients with moderate to severe Crohn's disease (CD) who did not achieve clinical response to 12 weeks (W) RZB induction treatment ('initial nonresponders'). METHODS: Initial nonresponders to intravenous (IV) RZB induction (600mg or 1200mg at W0, W4, and W8) were rerandomized 1:1:1 to receive extended blinded RZB treatment (1200mg IV at W12, W16, and W20, or subcutaneous [SC] 180mg or 360mg at W12 and W20). Patients with clinical response to SC RZB at W24 ('delayed responders') continued their dose in FORTIFY. Clinical, endoscopic, and safety outcomes were evaluated. RESULTS: Most initial nonresponders achieved SF/APS clinical response by W24 (76.2% [180mg SC], 63.7% [360mg SC], 62.3% [1200mg IV]), while a subset also achieved W24 SF/APS clinical remission (43.0%, 45.1%, 22.1%), endoscopic response (32.4%, 32.5%, 40.5%), and endoscopic remission (25.1%, 18.0%, 23.5%). Most delayed responders to SC RZB continued to demonstrate clinical response at FORTIFY W52 (56.7% [180mg SC], 69.7% [360mg SC]), along with SF/APS clinical remission (43.3%, 54.5%), endoscopic response (36.7%, 45.5%), and endoscopic remission (40.0%, 42.4%). Numerically greater efficacy was generally observed with 360mg SC vs 180mg SC. The safety profile of extended treatment was consistent with previously reported trials. CONCLUSION: Most initial nonresponders to IV RZB induction who received 12W of extended RZB treatment demonstrated improved clinical and endoscopic outcomes at W24. Improvements in patients who received SC RZB extended treatment were maintained during FORTIFY. Extended treatment was well tolerated with no new safety risks identified