LINKED CONTENT
This article is linked to Kim et al papers. To view these articles, visit https://doi.org/10.1111/apt.17989 and https://doi.org/10.1111/apt.18023.
IntroductionSB17 is a proposed biosimilar to ustekinumab reference product (UST-RP), which is a fully human IgG1/kappa monoclonal antibody to interleukin (IL)-12/23. In accordance with FDA and EMA ...guidelines, ‘totality-of-the-evidence’ proves similarity between a proposed biosimilar and its reference product and includes analytical, non-clinical and clinical data. The justification for extrapolation of SB17 was based on ‘totality-of-the-evidence’ (i) MoA of ustekinumab binding to p40 subunit of IL-12/23, which has been associated with immune-mediated diseases, including approved indications of UST-RP (ii) overall data from the comparability comparison to UST-RP using analytical methods showing similar molecular structure and in vitro function (iii) PK studies showing similar exposure, and PD studies in healthy subject and (iv) efficacy and safety based on clinical studies. The phase III study was conducted in ustekinumab-naïve patients with moderate-to-severe psoriasis (PsO) as the most sensitive design to assess potential differences in efficacy and the risk of immunogenicity. The objective is to describe the biosimilarity of SB17 to UST-RP for potential extrapolation from PsO to other indications.MethodsAnalytical comparability of SB17 to UST-RP was assessed in ELISA binding assays. PK equivalence, efficacy, safety, tolerability, and immunogenicity similarity were assessed in clinical trials of healthy subjects and PsO patients.ResultsIn the analytical assessment (Yang, et al., ECCO 2024. P134), SB17 showed similarity to EU- and US-UST-RP in overall critical and non-critical quality attributes.In a phase I study (Jeong, et al., AAD 2023. 41531), SB17 and EU- and US-UST-RP had similar PK and comparable safety, tolerability, and immunogenicity. In a phase III study of patients with moderate-to-severe PsO (Feldman, et al., EADV 2023. P0720), SB17 had equivalent efficacy, comparable safety and immunogenicity to UST-RP up to Week 28.ConclusionWith similar target binding and PK and confirmed similarity in efficacy and safety for PsO patients, SB17 is proposed to be highly similar to UST-RP in physicochemical, non-clinical, and clinical studies and data supports its extrapolation to UST-RP indications.
The infliximab biosimilar CT-P13 was approved for use in Crohn's disease after clinical comparison with originator infliximab in ankylosing spondylitis and rheumatoid arthritis; however, concerns ...about such indication extrapolation have been expressed. This study investigated whether CT-P13 is non-inferior to infliximab in patients with Crohn's disease who were naive to biological therapy.
In this randomised, multicentre, double-blind, phase 3 non-inferiority study, we enrolled patients with active Crohn's disease who had not responded to, or were intolerant to, non-biological treatments. Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. Patients received 5 mg/kg CT-P13 or infliximab at weeks 0, 2, 6, and then every 8 weeks up to week 54. The primary endpoint was the proportion of patients with a decrease of 70 points or more in Crohn's Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of −20% was set (CT-P13 was non-inferior to infliximab if the lower limit of the two-sided 95% CI for the treatment difference was greater than −20). This trial is registered with ClinicalTrials.gov, number NCT02096861, and is completed.
Between Aug 20, 2014, and Feb 15, 2017, 308 patients were assessed for eligibility, and 220 patients were enrolled: 111 were randomly assigned to initiate CT-P13 (56 to the CT-P13–CT-P13 group and 55 to the CT-P13–infliximab group) and 109 to initiate infliximab (54 to the infliximab–infliximab group and 55 to the infliximab–CT-P13 group). CDAI-70 response rates at week 6 were similar for CT-P13 (77 69·4%, 95% CI 59·9 to 77·8 of 111) and infliximab (81 74·3%, 95% CI 65·1 to 82·2 of 109; difference −4·9% 95% CI −16·9 to 7·3), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 64% in the CT-P13–CT-P13 group, 34 62% in the CT-P13–infliximab group, 37 69% in the infliximab–infliximab group, and 40 73% in the infliximab–CT-P13 group).
This study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn's disease. Biosimilar CT-P13 could be a new option for the treatment of active Crohn's disease.
Celltrion, Pfizer.
Thiopurine therapy, commonly used in autoimmune conditions, can be complicated by life-threatening leukopenia. This leukopenia is associated with genetic variation in TPMT (encoding thiopurine ...S-methyltransferase). Despite a lower frequency of TPMT mutations in Asians, the incidence of thiopurine-induced leukopenia is higher in Asians than in individuals of European descent. Here we performed an Immunochip-based 2-stage association study in 978 Korean subjects with Crohn's disease treated with thiopurines. We identified a nonsynonymous SNP in NUDT15 (encoding p.Arg139Cys) that was strongly associated with thiopurine-induced early leukopenia (odds ratio (OR) = 35.6; P(combined) = 4.88 × 10(-94)). In Koreans, this variant demonstrated sensitivity and specificity of 89.4% and 93.2%, respectively, for thiopurine-induced early leukopenia (in comparison to 12.1% and 97.6% for TPMT variants). Although rare, this SNP was also strongly associated with thiopurine-induced leukopenia in subjects with inflammatory bowel disease of European descent (OR = 9.50; P = 4.64 × 10(-4)). Thus, NUDT15 is a pharmacogenetic determinant for thiopurine-induced leukopenia in diverse populations.
To determine whether magnetic resonance (MR) enterography performed with diffusion-weighted imaging (DWI) without intravenous contrast material is noninferior to contrast material-enhanced (CE) MR ...enterography for the evaluation of small-bowel inflammation in Crohn disease.
Institutional review board approval and informed consent were obtained for this prospective noninferiority study. Fifty consecutive adults suspected of having Crohn disease underwent clinical assessment, MR enterography, and ileocolonoscopy within 1 week. MR enterography included conventional imaging and DWI (b = 900 sec/mm(2)). In 44 patients with Crohn disease, 171 small-bowel segments that were generally well distended and showed a wide range of findings, from normalcy to severe inflammation (34 men, 10 women; mean age ± standard deviation, 26.9 years ± 6.1), were selected for analysis. Image sets consisting of (a) T2-weighted sequences with DWI and (b) T2-weighted sequences with CE T1-weighted sequences were reviewed by using a crossover design with blinding and randomization. Statistical analyses included noninferiority testing regarding proportional agreement between DWI and CE MR enterography for the identification of bowel inflammation with a noninferiority margin of 80%, correlation between DWI and CE MR enterography scores of bowel inflammation severity, and comparison of accuracy between DWI and CE MR enterography for the diagnosis of terminal ileal inflammation by using endoscopic findings as the reference standard.
The agreement between DWI and CE MR enterography for the identification of bowel inflammation was 91.8% (157 of 171 segments; one-sided 95% confidence interval: ≥88.4%). The correlation coefficient between DWI and CE MR enterography scores was 0.937 (P < .001). DWI and CE MR enterography did not differ significantly regarding the sensitivity and specificity for the diagnosis of terminal ileal inflammation (P > .999). DWI and CE MR enterography concurred in the diagnosis of penetrating complications in five of eight segments.
DWI MR enterography was noninferior to CE MR enterography for the evaluation of inflammation in Crohn disease in generally well-distended small bowel, except for the diagnosis of penetration.
Although the incidence of inflammatory bowel disease IBD is increasing in Asia, data on long-term epidemiological trends are limited. We performed a 30-year longitudinal study to investigate temporal ...trends in the epidemiology of Crohn's disease CD and ulcerative colitis UC in Seoul, Korea.
This population-based study included 1431 IBD patients 418 CD, 1013 UC diagnosed between 1986 and 2015 in the Songpa-Kangdong district of Seoul, Korea. Temporal trends in incidence, prevalence, and disease phenotype at diagnosis were analysed.
The adjusted mean annual incidence rates of CD and UC per 100 000 inhabitants increased from 0.06 (95% confidence interval CI, 0.05-0.07) and 0.29 95% CI, 0.27-0.31, respectively, in 1986-1990 to 2.44 95% CI, 2.38-2.50 and 5.82 95% CI, 5.73-5.92, respectively, in 2011-2015. Average annual percentage change in IBD incidence was 12.3% in 1986-1995, 12.3% in 1996-2005, and 3.3% in 2006-2015. The male-to-female ratio of the adjusted incidence rate was 3.3:1 for CD and 1.2:1 for UC. Perianal fistula/abscess was present in 43.3% of patients before or at CD diagnosis. At diagnosis, 54.3% of UC patients presented only with proctitis. The adjusted prevalence rate in 2015 was 31.59/100 000 95% CI, 31.10-32.07 for CD and 76.66/100 000 95% CI, 75.91-77.42 for UC.
The incidence and prevalence of IBD in Korea have continued to increase over the past three decades. Korean patients have distinct demographic and phenotypic characteristics, including a male predominance and high frequency of perianal fistula/abscess in CD and high proportion of proctitis in UC.
Summary
Background
The impact of continuing or stopping 5‐aminosalicylates (5‐ASA) after commencing anti‐tumour necrosis factor (anti‐TNF) therapy in patients with inflammatory bowel disease (IBD) ...remains unclear.
Aims
To compare the outcomes of patients with IBD who stopped or continued 5‐ASA after starting anti‐TNF therapy.
Methods
We analysed data from the Korean National Health Insurance claims database between 2007 and 2020. We compared the clinical outcomes of patients who stopped or continued 5‐ASA within 90 days of anti‐TNF initiation. The primary outcome was any adverse clinical event defined as a composite of new corticosteroid use, IBD‐related hospitalisation, or intestinal surgery.
Results
Among 7442 patients included for analysis (4479 60.2% with Crohn's disease CD and 2963 39.8% with ulcerative colitis UC), 1037 (13.9%) discontinued 5‐ASA within 90 days of starting anti‐TNF therapy. During a median 4.3‐year follow‐up, discontinuation of 5‐ASA was not associated with an increased risk of adverse clinical events (adjusted hazard ratio 1.01, 95% confidence interval 0.93–1.10). The cumulative incidence of each adverse clinical event and the composite outcome were not significantly different between groups (all, p > 0.05). Additionally, separate analyses in CD and UC cohorts revealed no differences in adverse clinical outcomes between the 5‐ASA continuation and discontinuation groups. Subgroup analyses by presumed risk factors for disease relapse showed no significant differences in the risk of adverse events between groups.
Conclusions
In this nationwide population‐based study, discontinuing 5‐ASA after starting anti‐TNF therapy was not associated with an increased risk of adverse events in patients with IBD.
Background/Aims: The endoscopic step-up approach is accepted as the preferred treatment for complicated or symptomatic walled-off necrosis (WON). Direct endoscopic necrosectomy (DEN) is an effective ...therapeutic option, but few reports describe long-term follow-up in this patient population. Thus, we aim to assess the long-term outcomes of DEN following severe necrotizing pancreatitis. Methods: The data of all acute pancreatitis patients who underwent DEN following endoscopic transmural drainage from six referral centers between 2007 and 2017 were retrospectively collected. Results: Sixty patients (76.7% male, mean age 48.3 years) underwent a median of 4 sessions of DEN starting at a median of 45.5 days after the onset of acute pancreatitis. Clinical success was achieved in 51 patients (85%), with a 35% complication rate and a 5% mortality rate. Using multivariate analysis, the risk factor associated with DEN failure or major DEN complications requiring intervention or surgery was an identified bacterial/fungal WON infection (odds ratio, 19.3; 95% confidence interval, 1.5 to 261.7). During the median follow-up period of 27 months, complicated WON recurrence was observed in 5.3% of patients, and long-term complications occurred in 24.6% of patients (four exocrine insufficiency, nine newly developed diabetes mellitus, one recurrent small bowel obstruction, one chylous ascites). Conclusions: Considering that long-term complications are similar to those observed after pancreatectomy, DEN should be performed meticulously while minimizing damage to the viable pancreatic parenchyma with adequate antibiotic escalation.
Background and Aim
The anti‐interleukin‐23 antibody risankizumab is being investigated as a treatment for moderate‐to‐severe Crohn's disease. This post hoc subanalysis evaluates the efficacy and ...safety of risankizumab therapy in Asian patients.
Methods
ADVANCE (NCT03105128) and MOTIVATE (NCT03104413) were randomized, double‐blind, placebo‐controlled, phase 3 induction studies. Patients with intolerance/inadequate response to biologic (MOTIVATE) and/or conventional therapy (ADVANCE) were randomized to receive intravenous risankizumab (600 or 1200 mg) or placebo at weeks 0, 4, and 8. Clinical responders to risankizumab could enter the phase 3, randomized, double‐blind, placebo‐controlled maintenance withdrawal study (FORTIFY; NCT03105102). Patients were rerandomized to receive subcutaneous risankizumab (180 or 360 mg) or placebo (withdrawal) every 8 weeks for 52 weeks.
Results
Among 198 Asian patients in the induction studies, clinical remission and endoscopic response at week 12 were achieved by 61.4% and 40.0%, 59.5% and 35.8%, and 27.3% and 9.1% of patients in the risankizumab 600 mg, risankizumab 1200 mg, and placebo groups, respectively. Among 67 patients who entered the maintenance study, clinical remission and endoscopic response at week 52 were achieved by 57.1% and 52.4%, 75.0% and 40.0%, and 53.8% and 34.6% of patients in the risankizumab 180 mg, risankizumab 360 mg, and placebo (withdrawal) groups, respectively. Fistula closure was observed with risankizumab treatment in 28.6% (induction) and 57.1% (maintenance) of patients. Efficacy trends and safety profile were similar to those in non‐Asian patients.
Conclusion
Consistent with non‐Asian and global population results, risankizumab was effective and well tolerated in Asian patients with Crohn's disease.
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