To evaluate the long-term safety of adalimumab (ADA), up to 5 years (yrs), as it is used in routine clinical practice in patients (pts) with moderately to severely active Crohn’s disease (CD) from the observational registry PYRAMID. All pts entering the multicenter, non-interventional registry PYRAMID were to be followed for up to 6 yrs. Adverse events (AEs) were collected from the first dose up to 70 days after the last dose of ADA or through the 01 Dec 2012 cut-off. Rates of AEs were assessed per 100 patient-yrs (PY). A total of 5061 pts (57% female, mean age 37.8 yrs, median duration of CD 8.2 yrs) have enrolled in PYRAMID, totaling 13,914.2 PY of exposure, including prior exposure in CD ADA clinical trials. As of 01 December 2012, 3197 pts (63.2%) were still participating and 397 pts (7.8%) had up to 5 years of ADA exposure. Of the 2600 pts (51%) who received biologic therapy prior to enrollment, 98% were infliximab-experienced. Concomitant corticosteroids (CS), immunosuppressants (IMM) and IMM + CS were used by 30%, 36%, and 12% of pts, respectively. More pts receiving ADA combination therapy with IMM and/or CS experienced serious infections than pts receiving ADA monotherapy (10.7%/10.2% versus 7.3%, P < 0.02). Standardized mortality ratios, calculated using the most recent country-specific mortality rates in a general population through 2006, were 0.90 (95% confidence interval [CI] 0.64–1.24) overall, 1.10 (95% CI 0.65–1.74) for females, and 0.77 (95% CI 0.46–1.20) for males. There were 37 treatment-emergent deaths reported; 6 of the 37 were considered possibly related to ADA. The table shows an overview of exposure-adjusted registry treatment-emergent AEs for years 3 and 5. At the 5-year timepoint, long-term ADA exposure continues to be well-tolerated in pts with moderately to severely active CD. No new safety signals have been identified. AE rates have remained stable over time.
The management of patients with IBD requires evaluation with objective tools, both at the time of diagnosis and throughout the course of the disease, to determine the location, extension, activity and severity of inflammatory lesions, as well as, the potential existence of complications. Whereas endoscopy is a well-established and uniformly performed diagnostic examination, the implementation of radiologic techniques for assessment of IBD is still heterogeneous; variations in technical aspects and the degrees of experience and preferences exist across countries in Europe. ECCO and ESGAR scientific societies jointly elaborated a consensus to establish standards for imaging in IBD using magnetic resonance imaging, computed tomography, ultrasonography, and including also other radiologic procedures such as conventional radiology or nuclear medicine examinations for different clinical situations that include general principles, upper GI tract, colon and rectum, perineum, liver and biliary tract, emergency situation, and the postoperative setting. The statements and general recommendations of this consensus are based on the highest level of evidence available, but significant gaps remain in certain areas such as the comparison of diagnostic accuracy between different techniques, the value for therapeutic monitoring, and the prognostic implications of particular findings.
Introduction: GALAXI 1 is a ph 2, double-blind, PBO-controlled study of guselkumab (GUS), an IL-23 antagonist, for the treatment of pts with moderately to severely active CD who had inadequate response or intolerance to conventional therapies (corticosteroid, immunosuppressant) and/or biologics (TNF antagonist, vedolizumab). PRO-2 symptom remission is a measurement of efficacy based on mean daily patient reported symptoms of abdominal pain (none, mild, moderate and severe) and the number of liquid or very soft stools (stool frequency). Here we report change from baseline in abdominal pain (AP), stool frequency (SF) and PRO-2 remission following induction with GUS vs PBO in an interim analysis cohort. Methods: Pts with moderate to severe CD (CDAI score 220-450) were randomized 1:1:1:1:1 to GUS 200, 600, or 1200mg IV at Wks 0, 4, 8; ustekinumab (UST) ∼6mg/kg IV at Wk 0 and 90mg SC at Wk 8; or PBO IV. AP, SF, and PRO-2 symptom remission (AP mean daily score at or below 1 and mean daily SF score at or below 3 and no worsening of AP or SF from baseline) were evaluated from Wk4 through Wk12 for pooled GUS arms vs PBO. UST was a reference arm. Results: Two hundred fifty pts were evaluated with ∼50% having failed previous biologic therapy (mean CD duration, 8.8yr; mean CDAI, 306.2; median CRP, 5.4mg/L; median FeCal, 594.0mg/kg). Mean baseline AP for PBO and GUS combined was 2.04 and 2.02, respectively; mean baseline SF for PBO and GUS combined was 5.51 and 5.27, respectively. Other baseline demographics and disease characteristics were generally similar among treatment groups. Pts treated with GUS had greater reductions in AP and SF through Wk12 compared with PBO (Fig 1). At Wks 4, 8, and 12, higher proportions of GUS-treated pts achieved PRO-2 remission compared with PBO (Table 1). Similarly, within each subgroup of pts who failed biologic therapy (BIO-failure) or conventional therapy (CON-failure), GUS-treated pts achieved a higher rate of PRO-2 remission at Wks 4, 8, and 12 compared with PBO. Conclusion: In moderately to severely active CD, pts treated with GUS had greater reductions in AP and SF at all post-baseline visits. Furthermore, a higher proportion of pts achieved PRO-2 remission during induction dosing compared with PBO. For the overall population, as well as for BIO- and CON-failure subgroups, the differences between GUS and PBO-treated pts increased over time with a greater proportion of GUS-treated pts achieving early PRO-2 remission. Small sample sizes limit conclusions for subgroups.Figure 1.: Relationship between Anxiety, Depression and Fatigue PROMIS raw score and Perceived vulnerability to illness.Table 1.: Descriptive Characteristics of Subject Demographics.
Abstract Background Guselkumab (GUS) is a selective dual-acting IL-23p19 subunit inhibitor that potently blocks IL-23 and binds to CD64 demonstrated efficacy with intravenous (IV) induction in patients with moderately to severely active Crohn’s disease (CD) in the GALAXI trials.1 Subcutaneous (SC) induction with GUS evaluated in the Ph3 GRAVITI trial was also efficacious in treating patients with CD.2 Here we present a comparison of the pharmacodynamic and mechanistic response of GUS SC and GUS IV induction therapy in CD. Methods Serum proteins were evaluated from 290 GRAVITI patients randomised to PBO or GUS 400mg SC q4w, and a subset of 292 GALAXI patients randomised to PBO or GUS 200mg IV q4w at Weeks 0 and 12 using a 92-analyte inflammatory protein panel. Transcriptional profiling from each of the five anatomic segments in GRAVITI was conducted with samples from 277 patients at WK0 and WK12 using RNA sequencing. A tissue inflammation score (bMIS3) was used to assess segmental molecular inflammation which correlated with segmental histology scores defined by Global Histologic Activity Score (GHAS), endoscopic scores and subscores defined by Simple Endoscopic Score for CD (SES-CD).3 Analysis of treatment effect was performed using molecularly inflamed samples (defined as bMIS >0) from segments with SES-CD >0 at baseline. Transcriptional gene modules were evaluated for differential expression. Results In serum, protein changes observed with GUS 400mg SC q4w induction at WK12 were highly correlated with those observed with GUS 200mg IV q4w induction at WK12 (R=0.96, p<0.05), including similar reduction of IFNγ, IL-17A, CRP and fecal calprotectin (p<0.05; Figure 1). In tissue, segmental molecular inflammation assessed by bMIS correlated with segmental histological and endoscopic subscores (percent affected tissue and ulceration severity). In each anatomic segment, GUS SC induction reduced key cellular and inflammatory transcriptional modules at WK12 including plasma cell, inflammatory epithelial, neutrophil, and IL-23/Th17 biology consistent with molecular analysis from GUS IV induction in GALAXI Ph2b.4 The decrease in molecular inflammation in 5 anatomic segments corresponded to the segmental endoscopic improvement observed in isolated ileal, ileocolonic and colonic patient subgroups. Conclusion Following SC induction, the protein changes observed in serum at WK12 in GRAVITI were highly correlated with those seen with GUS IV induction from GALAXI Ph3. These data demonstrate similar molecular effects of GUS SC and IV induction doses and are aligned with previously reported similar efficacy results, supporting the flexible choice for patients and healthcare professionals between GUS SC and IV to treat patients with CD. References 1.Panaccione R, Danese S, Feagan BE, et al. Efficacy and safety of guselkumab therapy in patients with moderately to severely active Crohn’s disease: results of the GALAXI 2 & 3 phase 3 studies. Gastroenterology. 2024; 5 (Supplement): p1057b. 2.Panaccione R, Hart A, Steinwurz F et al. Efficacy and Safety of Subcutaneous Guselkumab Induction Therapy in Patients with Moderately to Severely Active Crohn’s Disease: Results Through Week 48 From the Phase 3 GRAVITI Study. ACG 2024. 3.C Argmann, et al. Biopsy and blood-based molecular biomarker of inflammation in IBD. Gut. 2022; 0:1-17. 4.Richards D, Venkat S, Ruane D, et al. Guselkumab Decreases Key Cellular Inflammatory Processes Across Ileum and Colon Tissue in Crohn’s Disease. P0950 ACG 2024.
