Subcutaneous infliximab for inflammatory bowel disease: The subcutaneous infliximab biosimilar CT-P13 was non-inferior to intravenous application during maintenance therapy with regard to efficacy, safety and immunogenicity.
Schreiber S, Ben-Horin S, Leszczyszyn J, Dudkowiak R, Lahat A, Gawdis-Wojnarska B, Pukitis A, Horynski M, Farkas K, Kierkus J, Kowalski M, Lee SJ, Kim SH, Suh JH, Kim MR, Lee SG, Ye BD, Reinisch W
Randomized controlled trial: Subcutaneous vs. intravenous infliximab CT-P13 maintenance in inflammatory bowel disease
Background and aims: This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) versus intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD).
Methods: This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor-naive patients with active ulcerative colitis (total Mayo score 6–12 points with endoscopic subscore ≥ 2) or Crohn's disease (Crohn's Disease Activity Index 220–450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary end point was non-inferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%.
Results: Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary end point of non-inferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI: 786.37–1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching.
Conclusions: The pharmacokinetic non-inferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in inflammatory bowel disease.
Dr. Dr. B.D. Ye, Department of Gastroenterology and Inflammatory Bowel Disease Center, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea
Prof. Dr. W. Reinisch, Klinische Abteilung für Gastroenterologie und Hepatologie, Universitätsklinik für Innere Medizin III, Medizinische Universität Wien, Währinger Gürtel 18–20, 1090 Wien, Austria
Filgotinib as induction and maintenance therapy for ulcerative colitis: Filgotinib (200 mg/day) was well tolerated and efficacious in inducing and maintaining remission compared with placebo in a phase 2b/3 trial program (SELECTION).
Feagan BG, Danese S, Loftus EV Jr, Vermeire S, Schreiber S, Ritter T, Fogel R, Mehta R, Nijhawan S, Kempiński R, Filip R, Hospodarskyy I, Seidler U, Seibold F, Beales ILP, Kim HJ, McNally J, Yun C, Zhao S, Liu X, Hsueh CH, Tasset C, Besuyen R, Watanabe M, Sandborn WJ, Rogler G, Hibi T, Peyrin-Biroulet L
Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): A phase 2b/3 double-blind, randomized, placebo-controlled trial
Background: The global prevalence of ulcerative colitis is increasing, and induction and maintenance of remission is a crucial therapeutic goal. The authors assessed the efficacy and safety of filgotinib, a once-daily, oral Janus kinase 1 preferential inhibitor, for treatment of ulcerative colitis.
Methods: This phase 2b/3, double-blind, randomized, placebo-controlled trial including 2 induction studies and 1 maintenance study was done in 341 study centers in 40 countries. Eligible patients were aged 18–75 years with moderately to severely active ulcerative colitis for at least 6 months before enrolment (induction study A: inadequate clinical response, loss of response to or intolerance to corticosteroids or immunosuppressants, naive to tumor necrosis factor [TNF] antagonists and vedolizumab [biologic-naive]; induction study B: inadequate clinical response, loss of response to or intolerance to any TNF antagonist or vedolizumab, no TNF antagonist or vedolizumab use within 8 weeks before screening [biologic-experienced]). Patients were randomly assigned 2:2:1 to receive oral filgotinib 200 mg, filgotinib 100 mg, or placebo once per day for 11 weeks. Patients who had either clinical remission or a Mayo Clinic Score response at week 10 in either induction study entered the maintenance study. Patients who received induction filgotinib were re-randomized 2:1 to continue their induction filgotinib regimen or to placebo. Patients who received induction placebo continued receiving placebo. The primary end point was clinical remission by Mayo endoscopic, rectal bleeding, and stool frequency subscores at weeks 10 and 58. For the induction studies, efficacy was assessed in all randomized patients who received at least 1 dose of study drug or placebo within that study. For the maintenance study, efficacy was assessed in all patients randomized to any filgotinib treatment group in the induction studies who received at least 1 dose of study drug or placebo in the maintenance study. Patients who received placebo throughout the induction and maintenance study were not included in the full analysis set for the maintenance study. Safety was assessed in all patients who received at least 1 dose of the study drug or placebo within each study.
Findings: Between November 14, 2016, and March 31, 2020, the authors screened 2040 patients for eligibility. 659 patients enrolled in induction study A were randomly assigned to receive filgotinib 100 mg (n = 277), filgotinib 200 mg (n = 245), or placebo (n = 137). 689 patients enrolled into induction study B were randomly assigned to receive filgotinib 100 mg (n = 285), filgotinib 200 mg (n = 262), or placebo (n = 142). 34 patients in induction study A and 54 patients in induction study B discontinued the study drug before week 10. After efficacy assessment at week 10, 664 patients entered the maintenance study (391 from induction study A, 273 from induction study B). 93 patients continued to receive placebo. 270 patients who had received filgotinib 100 mg in the induction study were randomly assigned to receive filgotinib 100 mg (n = 179) or placebo (n = 91). 301 patients who had received filgotinib 200 mg in the induction study were randomly assigned to receive filgotinib 200 mg (n = 202) or placebo (n = 99). 263 patients discontinued treatment in the maintenance study. At week 10, a greater proportion of patients given filgotinib 200 mg had clinical remission than those given placebo (induction study A 26.1% vs. 15.3%, difference 10.8%; 95% CI: 2.1–19.5, p = 0.0157; induction study B 11.5% vs. 4.2%, difference 7.2%; 95% CI: 1.6–12.8, p = 0.0103). At week 58, 37.2% of patients given filgotinib 200 mg had clinical remission versus 11.2% in the respective placebo group (difference 26.0%, 95% CI: 16.0–35.9; p < 0.0001). Clinical remission was not significantly different between filgotinib 100 mg and placebo at week 10, but was significant by week 58 (23.8% vs. 13.5%, difference 10.4%; 95% CI: 0.0–20.7, p = 0.0420). The incidence of serious adverse events and adverse events of interest was similar between treatment groups. In the induction studies, serious adverse events occurred in 28 of 562 patients (5.0%) given filgotinib 100 mg, 22 of 507 patients (4.3%) given filgotinib 200 mg, and 13 of 279 patients (4.7%) given placebo. In the maintenance study, serious adverse events were reported in 8 of 179 patients (4.5%) given filgotinib 100 mg, 7 of 91 patients (7.7%) in the respective placebo group, 9 of 202 patients (4.5%) in the filgotinib 200 mg group, and no patients in the respective placebo group. No deaths were reported during either induction study. Two patients died during the maintenance study; neither was related to treatment.
Interpretation: Filgotinib 200 mg was well tolerated, and efficacious in inducing and maintaining clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis.
Prof. Dr. B.G. Feagan, Division of Gastroenterology, London Health Sciences Centre, Western University, London, ON N6A 5A5, Canada
Prof. Dr. L. Peyrin-Biroulet, Department of Gastroenterology, Nancy University Hospital, University of Lorraine, 54 511 Vandœuvre-lès-Nancy, France
Immunogenicity of SARS-CoV2 vaccines in patients with inflammatory bowel diseases an infliximab therapy: In a British cohort, infliximab was associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 vaccines. Vaccination after SARS-CoV2 infection or a second dose of vaccine led to seroconversion in most patients. The second vaccine dose should therefore not be delayed.
Gut. 2021; in press
Kennedy NA, Lin S, Goodhand JR, Chanchlani N, Hamilton B, Bewshea C, Nice R, Chee D, Fraser Cummings JR, Fraser A, Irving PM, Kamperidis N, Kok KB, Lamb CA, Macdonald J, Mehta S, Pollok RCG, Raine T, Smith PJ, Verma AM, Jochum S, McDonald TJ, Sebastian S, Lees CW, Powell N, Ahmad T; CLARITY IBD study
Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD
Objective: Delayed second dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. The authors investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single dose of a SARS-CoV-2 vaccine.
Design: Antibody responses and seroconversion rates in infliximab-treated patients (n = 865) were compared with a cohort treated with vedolizumab (n = 428), a gut-selective anti-integrin α4β7 monoclonal antibody. The primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations, measured using the Elecsys anti-SARS-CoV-2 spike (S) antibody assay 3–10 weeks after vaccination, in patients without evidence of prior infection. Secondary outcomes were seroconversion rates (defined by a cut-off of 15 U/ml), and antibody responses following past infection or a second dose of the BNT162b2 vaccine.
Results: Geometric mean (SD) anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/ml [5.9] vs. 28.8 U/ml [5.4], p < 0.0001) and ChAdOx1 nCoV-19 (4.7 U/ml [4.9]) vs. 13.8 U/ml [5.9], p < 0.0001) vaccines. In this multivariable models, antibody concentrations were lower in infliximab-treated compared with vedolizumab-treated patients who received the BNT162b2 (fold change [FC] 0.29 [95% CI: 0.21–0.40], p < 0.0001) and ChAdOx1 nCoV-19 (FC 0.39 [95% CI: 0.30–0.51], p < 0.0001) vaccines. In both models, age ≥ 60 years, immunomodulator use, Crohn's disease and smoking were associated with lower, while non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after 2 doses of BNT162b2 vaccine.
Conclusion: Infliximab is associated with attenuated immunogenicity to a single dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab.
Dr. T. Ahmad, Gastroenterology, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter, UK
Chronic hepatitis B virus (HBV) infection: A recent South Korean study reveals that risks of hepatocellular carcinoma (HCC) and clinical events do not differ significantly between spontaneous and therapy-induced HBsAg seroclearance. However, the annual HCC risk exceeds the recommended cut-off for HCC surveillance even after HBsAg seroclearance, suggesting that continued HCC surveillance is required. Future studies need to clarify whether these Asian study results also apply to e.g. European cohorts.
Choi J, Yoo S, Lim YS
Comparison of long-term clinical outcomes between spontaneous and therapy-induced HBsAg seroclearance
Background and aims: Hepatitis B surface antigen (HBsAg) seroclearance is considered a realistic goal in patients with chronic hepatitis B (CHB), known as "functional cure." However, it remains elusive whether nucleos(t)ide analogue (NA)-induced HBsAg seroclearance, compared with spontaneous HBsAg seroclearance, differs in its association with favorable long-term clinical outcomes.
Approach and results: A total of 1972 CHB patients with confirmed HBsAg seroclearance at least 2 consecutive times, 6 months apart, were retrospectively analyzed. Risks of hepatocellular carcinoma (HCC) development and composite clinical events, including HCC, liver-related death, and liver transplantation, were compared between spontaneous and NA-induced HBsAg seroclearance. Of 1972 patients, mean patient age was 53.7 years, and 64.4% were men. Cirrhosis was present in 297 patients (15.1%). HBsAg seroclearance was achieved spontaneously in 1624 patients (82.4%) and by NA treatment in 348 patients (17.6%). HCC developed in 49 patients, with an annual incidence of 0.38 of 100 person-years during a median follow-up of 5.6 years. With 336 propensity score-matched pairs, risks of HCC (p = 0.52) and clinical events (p = 0.14) were not significantly different between NA-induced and spontaneous HBsAg seroclearance. By multivariable analysis, NA-induced HBsAg seroclearance, compared with spontaneous HBsAg seroclearance, was not associated with the significantly higher risk of HCC (adjusted hazard ratio [aHR] = 1.49; p = 0.26) and clinical events (aHR = 1.78; p = 0.06).
Conclusions: Risks of hepatocellular carinoma (HCC) and clinical events were not significantly different between spontaneous and nucleos(t)ide analogue-induced HBsAg seroclearance. Nonetheless, annual risk of HCC exceeds the recommended cut-off for HCC surveillance even after HBsAg seroclearance, suggesting that continued HCC surveillance is required.
Prof. Dr. J. Choi or Prof. Dr. Y.-S. Lim, Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, South Korea
Wilson disease: Diagnosis of Wilson disease based on laboratory or genetic parameters is often difficult. A current study shows that the determination of ATP7B peptides is highly effective in the diagnosis of Wilson disease (sensitivity 91.2%, specificity 98.1%, positive predictive value 98%, negative predictive value 91.5%). This also applied to Wilson disease patients with normal ceruloplasmin levels or ambiguous genetic results.
Collins CJ, Yi F, Dayuha R, Duong P, Horslen S, Camarata M, Coskun AK, Houwen RHJ, Pop TL, Zoller H, Yoo HW, Jung SW, Weiss KH, Schilsky ML, Ferenci P, Hahn SH
Direct measurement of ATP7B peptides is highly effective in the diagnosis of Wilson disease
Background and aims: Both existing clinical criteria and genetic testing have significant limitations for the diagnosis of Wilson disease (WD), often creating ambiguities in patient identification and leading to delayed diagnosis and ineffective management. ATP7B protein concentration, indicated by direct measurement of surrogate peptides from patient dried blood spot samples, could provide primary evidence of WD. ATP7B concentrations were measured in patient samples from diverse backgrounds, diagnostic potential is determined, and results are compared with biochemical and genetic results from individual patients.
Methods: 264 samples from biorepositories at 3 international and 2 domestic academic centers and 150 normal controls were obtained after Institutional Review Board approval. Genetically or clinically confirmed WD patients with a Leipzig score > 3 and obligate heterozygote (carriers) from affected family members were included. ATP7B peptide measurements were made by immunoaffinity enrichment mass spectrometry.
Results: Two ATP7B peptides were used to measure ATP7B protein concentration. Receiver-operating characteristics curve analysis generates an area under the curve of 0.98. ATP7B peptide analysis of the sequence ATP7B 887 was found to have a sensitivity of 91.2%, specificity of 98.1%, positive predictive value of 98.0%, and a negative predictive value of 91.5%. In patients with normal ceruloplasmin concentrations (> 20 mg/dl), 14 of 16 (87.5%) were ATP7B-deficient. In patients without clear genetic results, 94% were ATP7B-deficient.
Conclusions: Quantification of ATP7B peptide effectively identified patients with Wilson disease in 92.1% of presented cases and reduced ambiguities resulting from ceruloplasmin and genetic analysis. Clarity is brought to patients with ambiguous genetic results, significantly aiding in non-invasive diagnosis. A proposed diagnostic score and algorithm incorporating ATP7B peptide concentrations can be rapidly diagnostic and supplemental to current Leipzig scoring systems.
Prof. Dr. P. Ferenci, Klinische Abteilung für Gastroenterologie und Hepatologie, Universitätsklinik für Innere Medizin III, Medizinische Universität Wien, Währinger Gürtel 18–20, 1090 Vienna, Austria
S.H. Hahn, M.D., Ph.D., Professor of Pediatrics, University of Washington School of Medicine/Seattle Children’s Hospital, 4800 Sand Point Way NE, Seattle, WA 98105, USA
Non-alcoholic fatty liver disease (NAFLD):A nationwide Swedish cohort study shows that all histological NAFLD stages are associated with significantly increased overall mortality with the risk increasing with stage (simple steatosis - steatohepatitis - fibrosis - cirrhosis). Most of this excess mortality was due to extrahepatic cancer and cirrhosis, while the contributions from cardiovascular disease and hepatocellular carcinoma were lower.
Simon TG, Roelstraete B, Khalili H, Hagström H, Ludvigsson JF
Mortality in biopsy-confirmed non-alcoholic fatty liver disease: Results from a nationwide cohort
Objective: Population-based data are lacking regarding the risk of overall and cause-specific mortality across the complete histological spectrum of non-alcoholic fatty liver disease (NAFLD).
Design: This nationwide, matched cohort study included all individuals in Sweden with biopsy-confirmed NAFLD (1966–2017; n = 10,568). NAFLD was confirmed histologically from all liver biopsies submitted to Sweden's 28 pathology departments, after excluding other etiologies of liver disease, and further categorized as, simple steatosis, non-fibrotic steatohepatitis (NASH), non-cirrhotic fibrosis and cirrhosis. NAFLD cases were matched to ≤ 5 general population comparators by age, sex, calendar year and county (n = 49,925). Using Cox regression, the authors estimated multivariable-adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs).
Results: Over a median of 14.2 years, 4338 NAFLD patients died. Compared with controls, NAFLD patients had significantly increased overall mortality (16.9 vs. 28.6/1000 person-years [PY], difference = 11.7/1000 PY, aHR = 1.93, 95% CI: 1.86–2.00). Compared with controls, significant excess mortality risk was observed with simple steatosis (8.3/1000 PY, aHR = 1.71, 95% CI: 1.64–1.79), non-fibrotic NASH (13.4/1000 PY, aHR = 2.14, 95% CI: 1.93–2.38), non-cirrhotic fibrosis (18.4/1000 PY, aHR = 2.44, 95% CI: 2.22–2.69) and cirrhosis (53.6/1000 PY, aHR = 3.79, 95% CI: 3.34–4.30; ptrend < 0.01). This dose-dependent gradient was similar when simple steatosis was the reference (ptrend < 0.01). The excess mortality associated with NAFLD was primarily from extrahepatic cancer (4.5/1000 PY, aHR = 2.16, 95% CI: 2.03–2.30), followed by cirrhosis (2.7/1000 PY, aHR = 18.15, 95% CI: 14.78–22.30), cardiovascular disease (1.4/1000 PY, aHR = 1.35, 95% CI: 1.26–1.44) and hepatocellular carcinoma (1.2/1000 PY, aHR = 11.12, 95% CI: 8.65–14.30).
Conclusion: All non-alcoholic fatty liver disease (NAFLD) histological stages were associated with significantly increased overall mortality, and this risk increased progressively with worsening NAFLD histology. Most of this excess mortality was from extrahepatic cancer and cirrhosis, while in contrast, the contributions of cardiovascular disease and hepatocellular carinoma were modest.
Prof. Dr. J.F. Ludvigsson, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 76 Stockholm, Sweden
Checkpoint inhibition as first-line therapy for advanced gastric, gastroesophageal junction and esophageal adenocarcinoma: Nivolumab plus chemotherapy resulted in superior overall survival as well as progression-free survival as compared to chemotherapy alone in a phase 3 trial and represents a new standard of first-line treatment for these patients.
Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, Wyrwicz L, Yamaguchi K, Skoczylas T, Campos Bragagnoli A, Liu T, Schenker M, Yanez P, Tehfe M, Kowalyszyn R, Karamouzis MV, Bruges R, Zander T, Pazo-Cid R, Hitre E, Feeney K, Cleary JM, Poulart V, Cullen D, Lei M, Xiao H, Kondo K, Li M, Ajani JA
First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma (CheckMate 649): A randomized, open-label, phase 3 trial
Background: First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. The authors aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastroesophageal junction, and esophageal adenocarcinoma. They report the first results for nivolumab plus chemotherapy versus chemotherapy alone.
Methods: In this multicenter, randomized, open-label, phase 3 trial (CheckMate 649), they enrolled adults (≥ 18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastroesophageal junction, or esophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centers in 29 countries. Patients were randomly assigned (1:1:1 while all 3 groups were open) via interactive web response technology (block sizes of 6) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary end points for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumors had a PD-L1 combined positive score (CPS) of 5 or more. Safety was assessed in all patients who received at least one dose of the assigned treatment.
Findings: From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, the authors concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n = 789, 50%] or chemotherapy alone [n = 792, 50%]). The median follow-up for OS was 13.1 months (interquartile range [IQR], 6.7–19.1) for nivolumab plus chemotherapy and 11.1 months (5.8–16.1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] = 0.71; 98.4% CI: 0.59–0.86; p < 0.0001) and PFS (HR = 0.68; 98% CI: 0.56–0.81; p < 0.0001) versus chemotherapy alone in patients with a PD-L1 CPS of 5 or more (minimum follow-up 12.1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of 1 or more and all randomly assigned patients. Among all treated patients, 462 of 782 patients (59%) in the nivolumab plus chemotherapy group and 341 of 767 patients (44%) in the chemotherapy alone group had grade 3–4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥ 25%) were nausea, diarrhea, and peripheral neuropathy across both groups. 16 deaths (2%) in the nivolumab plus chemotherapy group and 4 deaths (1%) in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.
Interpretation: Nivolumab is the first programmed cell death-1 inhibitor to show superior overall survival, along with progression-free survival benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastroesophageal junction, or esophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.
Dr. K. Shitara, Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, 277-8577, Japan
Novel therapy for celiac disease (1): In a proof-of-concept study, immune modulating gliadin nanoparticles (TAK-101) were well tolerated and prevented gluten-induced immune activation in patients with celiac disease. These findings suggest that antigen-specific tolerance was induced indicating that TAK-101 may represent a promising approach to treat celiac disease.
Kelly CP, Murray JA, Leffler DA, Getts DR, Bledsoe AC, Smithson G, First MR, Morris A, Boyne M, Elhofy A, Wu TT, Podojil JR, Miller SD; TAK-101 Study Group
TAK-101 nanoparticles induce gluten-specific tolerance in celiac disease: A randomized, double-blind, placebo-controlled study
Background and aims: In celiac disease, gluten induces immune activation, leading to enteropathy. TAK-101, gluten protein (gliadin) encapsulated in negatively charged poly(DL-lactide-co-glycolic acid) nanoparticles, is designed to induce gluten-specific tolerance.
Methods: TAK-101 was evaluated in phase 1 dose escalation safety and phase 2a double-blind, randomized, placebo-controlled studies. Primary end points included pharmacokinetics, safety, and tolerability of TAK-101 (phase 1) and change from baseline in circulating gliadin-specific interferon-γ-producing cells at day 6 of gluten challenge, in patients with celiac disease (phase 2a). Secondary end points in the phase 2a study included changes from baseline in enteropathy (villus height to crypt depth ratio [Vh:Cd]), and frequency of intestinal intraepithelial lymphocytes and peripheral gut-homing T cells.
Results: In phase 2a, 33 randomized patients completed the 14-day gluten challenge. TAK-101 induced an 88% reduction in change from baseline in interferon-γ spot-forming units versus placebo (2.01 vs. 17.58, p = 0.006). Vh:Cd deteriorated in the placebo group (-0.63, p = 0.002), but not in the TAK-101 group (-0.18, p = 0.110), although the intergroup change from baseline was not significant (p = 0.08). Intraepithelial lymphocyte numbers remained equal. TAK-101 reduced changes in circulating α4β7+CD4+ (0.26 vs. 1.05, p = 0.032), αEβ7+CD8+ (0.69 vs. 3.64, p = 0.003), and γδ (0.15 vs. 1.59, p = 0.010) effector memory T cells. TAK-101 (up to 8 mg/kg) induced no clinically meaningful changes in vital signs or routine clinical laboratory evaluations. No serious adverse events occurred.
Conclusions: TAK-101 was well tolerated and prevented gluten-induced immune activation in celiac disease. The findings from the present clinical trial suggest that antigen-specific tolerance was induced and represent a novel approach translatable to other immune-mediated diseases.
S.D. Miller, Ph.D., Professor of Microbiology and Immunology, Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, 420E Superior Street, Chicago, IL 60611, USA
Novel therapy for celiac disease (2): In a proof-of-concept study, therapy with ZED1227, an oral inhibitor of transglutaminase 2, attenuated gluten-induced duodenal mucosal damage in patients with celiac disease.
N Engl J Med. 2021;385(1):35–45
Schuppan D, Mäki M, Lundin KEA, Isola J, Friesing-Sosnik T, Taavela J, Popp A, Koskenpato J, Langhorst J, Hovde Ø, Lähdeaho ML, Fusco S, Schumann M, Török HP, Kupcinskas J, Zopf Y, Lohse AW, Scheinin M, Kull K, Biedermann L, Byrnes V, Stallmach A, Jahnsen J, Zeitz J, Mohrbacher R, Greinwald R; CEC-3 Trial Group
A randomized trial of a transglutaminase 2 inhibitor for celiac disease
Background: In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease.
Methods: In a proof-of-concept trial, the authors assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at 3 dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life).
Results: Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all 3 dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI]: 0.15–0.73) in the 10-mg group (p = 0.001), 0.49 (95% CI: 0.20–0.77) in the 50-mg group (p < 0.001), and 0.48 (95% CI: 0.20–0.77) in the 100-mg group (p < 0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI: -7.6–2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI: -8.9–0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI: -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group.
Conclusions: In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease.
Prof. Dr. D. Schuppan, Institut für Translationale Immunologie (TIM) and Ambulanz für Zöliakie und Darmerkrankungen, Forschungszentrum für Immuntherapie, Universitätsmedizin Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
Endoscopic therapy of benign biliary strictures secondary to chronic pancreatitis: Efficacy and safety of endotherapy using fully covered metal stents is non-inferior to repeated stenting with plastic. However, metal stents were associated with fewer interventions.
Ramchandani M, Lakhtakia S, Costamagna G, Tringali A, Püspöek A, Tribl B, Dolak W, Devière J, Arvanitakis M, van der Merwe S, Laleman W, Ponchon T, Lepilliez V, Gabbrielli A, Bernardoni L, Bruno MJ, Poley JW, Arnelo U, Lau J, Roy A, Bourke M, Kaffes A, Neuhaus H, Peetermans J, Rousseau M, Nageshwar Reddy D
Fully covered self-expanding metal stent vs. multiple plastic stents to treat benign biliary strictures secondary to chronic pancreatitis: A multicenter randomized trial
Background and aims: Benign biliary strictures (BBS) are complications of chronic pancreatitis (CP). Endotherapy using multiple plastic stents (MPS) or a fully covered self-expanding metal stent (FCSEMS) are acceptable treatment options for biliary obstructive symptoms in these patients.
Methods: Patients with symptomatic CP-associated BBS enrolled in a multicenter randomized non-inferiority trial comparing 12-month treatment with MPS versus FCSEMS. Primary outcome was stricture resolution status at 24 months, defined as absence of restenting and 24-month serum alkaline phosphatase not exceeding twice the level at stenting completion. Secondary outcomes included crossover rate, numbers of endoscopic retrograde cholangiopancreatography (ERCPs) and stents, and stent- or procedure-related serious adverse events.
Results: 84 patients were randomized to MPS and 80 to FCSEMS. Baseline technical success was 97.6% for MPS and 98.6% for FCSEMS. 11 patients crossed over from MPS to FCSEMS, and 10 from FCSEMS to MPS. For MPS versus FCSEMS, respectively, stricture resolution status at 24 months was 77.1% (54/70) versus 75.8% (47/62) (p = 0.008 for non-inferiority intention-to-treat analysis), mean number of ERCPs was 3.9 ± 1.3 versus 2.6 ± 1.3 (p < 0.001, intention-to-treat), and mean number of stents placed was 7.0 ± 4.4 versus 1.3 ± 0.6 (p < 0.001, as-treated). Serious adverse events occurred in 16 MPS (19.0%) and 19 FCSEMS (23.8%) patients (p = 0.568), including cholangitis/fever/jaundice (9 vs. 7 patients respectively), abdominal pain (5 vs. 5), cholecystitis (1 vs. 3) and post-ERCP pancreatitis (0 vs. 2). No stent- or procedure-related deaths occurred.
Conclusions: Endotherapy of chronic pancreatitis-associated benign biliary strictures has similar efficacy and safety for 12-month treatment using multiple plastic stents compared with a single fully covered self-expanding metal stent (FCSEMS) with FCSEMS requiring fewer endoscopic retrograde cholangiopancreatographies over 2 years.
Dr. D. Nageshwar Reddy, Gastroenterology, Asian Institute of Gastroenterology (AIG Hospitals), 6-3-661, Somajiguda, Hyderabad 500 082, India