Introduction

Eosinophilic esophagitis (EoE) is a chronic, progressive, type 2 inflammatory disease with substantial impact on quality of life, and increasing incidence and prevalence. Dupilumab, a fully human monoclonal antibody, blocks IL-4 and IL-13, central drivers of type 2 inflammation, and is approved in the US and EU for the treatment of EoE.

Aims & Methods

We aimed to assess the effect of dupilumab on EoE outcomes in subgroups of patients from the Phase 3 LIBERTY EoE TREET (NCT03633617) study categorized by weight or body mass index (BMI).
Data were pooled from patients in Parts A and B who received dupilumab 300 mg or placebo qw (weekly) for 24 weeks (W24). The proportion of patients achieving ≤6 or <15 eosinophils per high-power field (eos/hpf), absolute change in Dysphagia Symptom Questionnaire (DSQ) score, mean change in Endoscopic Reference Score (EREFS), and Histologic Scoring System (HSS) grade/stage scores were assessed. Outcomes were compared between pre-specified weight (<60kg and ≥60kg) and BMI groups (<25kg/m², ≥25–<30kg/m², and ≥30kg/m²). As this is a post hoc analysis, all p-values are nominal.

Results

122 patients received dupilumab and 118 placebo. At baseline, subgroups comprised: Weight <60kg (N=51) and ≥60kg (N=189); BMI <25kg/m² (N=121), ≥25–<30kg/m² (N=73), and ≥30kg/m² (N=46). Baseline demographics and disease characteristics were generally similar across subgroups. Dupilumab was efficacious regardless of baseline weight. At W24 dupilumab treatment resulted in a greater proportion of patients achieving ≤6 eos/hpf compared with placebo (weight <60kg 47% vs 5%, p=0.0031, ≥60kg 63% vs 6%, p<0.0001), and improved DSQ score (LS mean difference [LSMD] [95% CI]: weight <60kg –8.74 [–18.77, 1.30], p=0.0878, ≥60kg –10.36 [–14.57, –6.15], p<0.0001). Dupilumab-treated patients improved at W24 vs placebo in EREFS total score (LSMD [95% CI]: –2.47 [–3.89, –1.06], p=0.0006, –3.66 [–4.50, –2.81], p<0.0001), and HSS mean grade (–0.608 [–0.837, –0.380], p<0.0001, –0.737 [–0.839, –0.636], p<0.0001) and stage scores (–0.588 [–0.811, –0.365], p<0.0001, –0.730 [–0.826, –0.633], p<0.0001). Furthermore, dupilumab treatment resulted in a greater proportion of patients achieving <15 eos/hpf compared with placebo (weight <60kg 70% vs 10%, p=0.0006, ≥60kg 78% vs 7%, p<0.0001). Similar results were observed across BMI subgroups (Table).

Table: EoE endpoints in patients categorized by weight or BMI at Week 24

Conclusion

Patients with EoE improved in measures of histology, symptoms, and endoscopy, including an increased proportion achieving peak esophageal intraepithelial eosinophil count ≤6 and <15, along with reductions in DSQ score, HSS grade and stage scores, and EREFS total score at W24 with dupilumab 300 mg qw vs placebo regardless of baseline weight or BMI. Dupilumab was well tolerated, and the safety profile was similar to the overall treatment population.

Disclosure

Hirano I: Allakos, Pfizer/Arena Pharmaceuticals, Aslan, AstraZeneca, Calyx/Parexel, Ellodi/Adare Pharma Solutions, EsoCap, Gossamer Bio, Phathom, Nexstone Immunology, Receptos/BMS, Sanofi/Regeneron Pharmaceuticals Inc., Shire/Takeda – consultant; Adare Pharma Solution, Allakos, AstraZeneca, Pfizer/Arena, Meritage Pharma, Receptos/BMS, Regeneron Pharmaceuticals Inc., Shire/Takeda – research funding; Sanofi/Regeneron Pharmaceuticals Inc. – speaking.
Chehade M: Adare Pharma Solutions, Allakos, AstraZeneca, BMS, Phathom, Recludix Pharma, Regeneron Pharmaceuticals Inc., Sanofi, Shire/Takeda – consultant; Adare Pharma Solutions/Ellodi Pharmaceuticals, Allakos, AstraZeneca, Danone, Regeneron Pharmaceuticals Inc., Shire/Takeda – research funding.
Dellon ES: Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Landos, LucidDx, Morphic, Nexstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron Pharmaceuticals Inc., Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio– consultant; Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron Pharmaceuticals Inc., Revolo, Shire/Takeda – research funding; Allakos, Holoclara, Invea– educational grant.
Schoepfer AM: Adare Pharma Solutions, Aptalis, Dr. Falk – consultant; AstraZeneca, Aptalis, Dr. Falk, GSK, Nestlé, Novartis, Receptos/BMS, Regeneron Pharmaceuticals Inc. – research funding.
Xia C, Shabbir A: Regeneron Pharmaceuticals Inc. – employees and shareholders.
Glotfelty L: Sanofi – employees, may hold stock and/or stock options in the company.

Introduction

The efficacy of Helicobacter pylori (H. pylori) eradication regimens containing a proton pump inhibitor (PPI) plus antibiotics has gradually declined in recent years due to higher rates of antimicrobial resistance and insufficient acid inhibition. Vonoprazan (VPZ) is a novel potassium-competitive acid blocker which provides a stronger and longer-lasting effect on gastric acid suppression than PPIs. Our objective was to perform a systematic review and meta-analysis evaluating the efficacy and safety of VPZ for H. pylori eradication.

Aims & Methods

We conducted bibliographical searches in PubMed, Embase and the Cochrane Library up to April 2023. Selection: studies evaluating the use of VPZ in the eradication treatment. Outcomes: Efficacy was assessed by intention-to-treat analysis. Safety was also evaluated. Results were combined by meta-analysing risk differences (RD) and were stratified by dual, triple and quadruple therapy, first-line and rescue therapy, and by the presence of clarithromycin resistance.

Results

Overall, 75 studies were included, evaluating 44,992 patients, where 22,264 had received VPZ and 22,658 a PPI-based eradication therapy. The overall eradication rate with VPZ was 88% (95%CI=87-90%, 75 studies, I²=88%). When only RCTs were considered, similar results were obtained (87%, 95%CI=85-90%, 35 studies I²=84%).
When comparing dual, triple and quadruple VPZ-containing therapies, a tendency towards better efficacy with those regimens using a greater number of antibiotics was observed: 85%, 88% and 95%, respectively. However, when we compared the eradication rates between VPZ-based dual vs. triple regimens, no significant differences were reported, either in the overall analysis (P=0.17) or in the meta-analysis of studies directly comparing these regimens (P=0.21).
The eradication rate with VPZ-based therapy in first-line was 87% (95%CI=86-89%, 55 studies, I²=89%), and 90% (95%CI=87-93%, 37 studies, I²=84%) when used as rescue therapy. Among treatment-naïve patients, a significant superiority in the VPZ vs. PPI-based regimens was reported (87% vs. 70% respectively; RD=0.12, 95%CI=0.10-0.14, P<0.00001, I²=83%). However, no significant differences were shown between VPZ and PPIs when used in rescue therapy. When focusing on RCTs only, similar results were obtained.
Among those patients with clarithromycin-resistant strains, an overall efficacy of VPZ-based therapies was 81% (95%CI=75-85%, 18 studies, I²=60%), while in those with clarithromycin-susceptible strains it was 92% (95%CI=89-95%, 18 studies, I²=87%). We found a significant superiority of VPZ vs. PPIs (75% vs. 39%; RD=0.35, 95%CI=0.27-0.42, P<0.00001, 7 studies, 797 patients) in clarithromycin-resistant patients; whereas no significant differences were found in the clarithromycin-susceptible group. RCTs subgroup analysis showed similar results.
The overall incidence of adverse events with VPZ was 18% (95%CI=15-20%, 69 studies, I²=97%). No significant differences were found between VPZ and PPIs regimens tolerability.

Conclusion

The efficacy of VPZ-based regimens was over 85% in all treatments evaluated. The advantage of triple over dual VPZ could not be demonstrated in direct comparisons. In treatment-naïve patients as well as in those cases with clarithromycin-resistant strains, VPZ-based regimens performed better than PPIs-based ones; however, in rescue therapy and in clarithromycin-susceptible patients, this advantage was not confirmed. Tolerability was similar in both VPZ and PPIs regimens.

Disclosure

Dr. Gisbert has served as speaker, consultant, and advisory member for or has received research funding from Mayoly, Allergan, Diasorin, Gebro Pharma, and Richen. Dr. Nyssen has received research funding from Mayoly and Allergan.

Introduction

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, predominantly diagnosed in patients with chronic liver diseases. The absence of specific biomarkers and the typically asymptomatic progression of the disease lead to delayed diagnosis. Patients with liver disease, including HCC, exhibit alterations in the gut microbiome and increased bacterial permeability, factors that may influence disease progression and patient outcomes. In recent years, there has been a growing interest in exploring circulating microbiome signatures as potential indicators of liver disease stutus, providing a new avenue for understanding HCC.

Aims & Methods

Aims: To identify the signatures of the circulating blood microbiome associated with hepatocellular carcinoma, response to treatment and disease prognosis.
Methods: This study conducted a post-hoc analysis of the SORAMIC clinical trial utilizing peripheral blood plasma samples. For this analysis, blood plasma samples from a cohort of 71 patients with HCC were examined (25 treated with Sorafenib and 46 with SIRT/Sorafenib). Peripheral blood samples were collected at two time points: baseline (prior to the initiation of anti-tumor therapy) with all 71 patients included, and post-therapy (7 to 9 weeks after treatment) with 39 patients included. Additionally, peripheral blood samples were obtained from 52 control subjects, who were endoscopically diagnosed with colonic diverticulosis, to compare against the patient group. The composition of the circulating blood microbiome was assessed through 16S rRNA gene sequencing, targeting the V1-V2 hypervariable regions. Subsequent analyses focused on identifying associations with potential novel biomarkers for diagnosis, prognosis, and response to treatment.

Results

Patients with HCC had significantly diminished α-diversity of the circulating blood microbiome as compared to controls. Significant differences were also observed in between microbial communities of these two cohorts based on Bray-Curtis dissimilarity index. Patients with HCC had significantly higher levels of Proteobacteria and Bacteroidetes and lower levels of Firmicutes and Campylobacterota. Differential abundance analysis revealed that families of Gordoniaceae, Cryomorphaceae, Burkholderiaceae, Comamonadaceae, Enterobacteriaceae were significantly enriched in patients with HCC. At the genus level, patients with HCC had higher levels of Gordonia, Fluviicola, Burholderia, Limnohabitans and Escherichia/Shigella and lower levels of Corynebacterium. HCC patients, who responded to treatment with SIRT/Sorafenib showed an increase in blood bacterial diversity, enrichment of families Burkholderiales incertae sedis, Arcobacteraceae, Peptostreptococcaceae, Moraxellaceae, genera Sphaerotilus, Aliacrobacter, Rhodoluna, Giesbergeria, Microbacterium, Romboutsia, Arcicella, Pseudorhodoferax and depletion in families Gordoniaceae, Cryomorphaceae and genera Cloacibacterium, Gordonia, Limnohabitans, Fluviicola after the treatment. Levels of Acinetobacter, Enhydrobacter and Micrococcus in the blood before the HCC treatment were associated with patient prognosis.

Conclusion

Patients with HCC exhibit a unique circulating blood microbiome profile characterized by reduced bacterial diversity. Response to treatment is linked to an increase in α-diversity and changes in the circulating microbiome profile. Specific members of the circulating microbiome show potential prognostic capabilities, suggesting their utility as biomarkers for predicting disease progression and treatment outcomes in HCC.

Introduction

Safety in endoscopy is of paramount importance with increasingly therapeutic and complex procedures. Despite safety initiatives, incidents still occur. In order to learn from these, we need to be able to better detect issues. The patient voice has been crucial in understanding healthcare from a different perspective. Specifically, patient reporting has been able to detect safety-related issues, which may not have been identified through other means [1, 2]. This is an area not previously explored in endoscopy.

Aims & Methods

Our aims were to develop a novel tool for patient reporting of safety incidents in endoscopy (PRISE), co-designed with patients. Secondary aims were to identify safety incidents, factors and perceptions.
This study was split into two phases. Phase one involved a literature review of articles related to patient reported incidents, followed by patient focus groups to identify key topic areas to address and survey design ideas. These findings informed development of the PRISE survey tool. A patient panel was created and, through regular refinement meetings with the research team, question items were created.
Phase two was a prospective pilot of the PRISE tool in a single academic centre. The survey was disseminated over an 8 month period through physical and electronic media. Patients were asked to complete this within 2 weeks of their procedure. Outcome measures included the percentage of positive responses (PPR) across question item domains, safety perception scores and number of safety incidents detected. Descriptive and comparative analyses were performed.

Results

In phase one, over 1600 articles were identified from search criteria. Following title, abstract and full text screens, 17 full text articles were included in the literature review. A total of 24 incident topic areas were identified. Three focus groups were conducted with 22 participants. Outcomes were focussed around five themes: question style, content, question items, timing, and dissemination. The PRISE co-design process was conducted over ten sessions. The final survey consists of the following sections: demographics, safety incidents and factors – 24 items, grouped into domains (pre-procedure, post-procedure, unit and staff), safety concerns – a qualitative section, and safety perceptions – a quantitative score.
In phase two, 596 patients responded to the survey. Perceptions of safety were overwhelmingly high (mean rating 9.7/10). The PPR for all domains was > 90%, with the staff domain (items on staff characteristics) rated significantly higher than all others (96.7% PPR; p < 0.001). Four clear PSIs were identified - three related to equipment failure and one regarding wrong bowel preparation. Six patients (1.0%) declared safety concerns. Two patients felt they suffered from a mistake. The five highest negatively rated question items were related to information handover, management of patient concerns during procedure, physical space in the unit, equipment faults during procedure, and unnecessary delays in care respectively. Thematic analysis of comments identified negative themes related to bowel preparation, care process issues, communication, constraints on service, environment, equipment, procedures, and staff.

Conclusion

A patient co-designed pilot prospective survey identified high perceived safety in the endoscopy unit. Staff characteristics were rated highly. Safety incidents were detected as well as areas to focus on for safety improvement.

References

1. Armitage, G., et al., Patient-reported safety incidents as a new source of patient safety data: an exploratory comparative study in an acute hospital in England. Journal of Health Services Research & Policy, 2017. 23(1): p. 36-43.
2. Weingart, S.N., et al., What can hospitalized patients tell us about adverse events? Learning from patient-reported incidents. Journal of general internal medicine, 2005. 20(9): p. 830-6.

Disclosure

HA is Chief Scientific Officer of Pre-emptive Medicine and Health Security at Flagship Pioneering. AD is Executive Chair of Pre-emptive Medicine and Health Security at Flagship Pioneering

Introduction

Helicobacter pylori treatment´s effectiveness decreases as treatment eradication attempts fail.

Aims & Methods

To evaluate the use and effectiveness of empirical rescue therapies on third and subsequent lines in Europe.
Sub-study of the the European Registry on H. pylori Management (Hp-EuReg), an international, multicenter, prospective, non-interventionist registry starting in 2013 aimed to evaluate the decisions and outcomes of H. pylori management by European gastroenterologists (32 countries, 300 researchers). All infected adult patients were systematically registered at AEG-REDCap e-CRF until January 2023, all cases with three or more eradication attempts were extracted. Only the empirically prescribed therapies were analyzed. Data were subject to quality review.

Results

In total, 2,254 rescue treatments were included: 1,624, 424, 150 and 56 in third-, fourth-, fifth- and sixth-line treatments, respectively. Mean age was 52 years, 67% of patients were women and 5% were allergic to penicillin. Sixty-three different therapy regimens were used, being three-in-one single-capsule bismuth quadruple therapy the most commonly prescribed, as shown in the table. Overall effectiveness was 73% by modified intention-to-treat (mITT), and 74% by per-protocol (PP) analyses. Bismuth quadruple therapy as single-capsule provided the highest mITT cure rate (86%).One regimen achieved an optimal eradication rate (≥90%, by mITT): quadruple PPI-bismuth-tetracycline-metronidazole, only when high-dose PPIs and 14 days’ prescriptions were used. The use of doxycycline instead of tetracycline was associated with lower eradication rates in classical bismuth quadruple therapies (p<0.05).

Conclusion

Empirical rescue treatments in third and subsequent lines obtain, in general, suboptimal eradication rates in Europe; however, bismuth quadruple therapy as single-capsule obtained encouraging results. Only the optimised bismuth quadruple therapy with tetracycline-metronidazole achieved ≥90% effectiveness.

Disclosure

Olga P. Nyssen received research funding from Mayoly and Allergan.
Javier P. Gisbert served as speaker, consultant, and advisory member for or received research funding from Mayoly, Allergan, Diasorin, Gebro Pharma, and Richen.

Introduction

Filgotinib (FIL) is a once-daily, oral, Janus 1 kinase preferential inhibitor approved for the treatment of ulcerative colitis (UC) in Europe and Japan. The efficacy and safety of FIL in patients with moderately to severely active UC was evaluated in the phase 2b/3 randomized, double-blind, placebo (PBO)-controlled SELECTION study (NCT02914522).¹

Aims & Methods

This post hoc analysis aimed to identify characteristics of FIL-treated patients that were associated with achieving corticosteroid (CS)-free remission. Adults aged 18–75 years were randomized 2:2:1 to induction FIL 100 mg, FIL 200 mg or PBO once daily for 11 weeks in induction study A (biologic-naive) and B (biologic-experienced). At week 10, patients in clinical remission or with a Mayo Clinic Score (MCS) response were re-randomized 2:1 to continue their FIL regimen or PBO for 47 weeks in the maintenance study. This analysis included only data from patients receiving CSs at baseline. Using univariate logistic regression, we analysed characteristics associated with achieving clinical remission at week 58 without using CSs for UC over a continuous period of ≥6 months (CS-free remission). P values <0.05 were considered statistically significant.

Results

At baseline, 81, 37, 92 and 47 patients were receiving CSs in the maintenance FIL 100 mg (n=172), PBO-to-match (PTM) FIL 100 mg (n=89), FIL 200 mg (n=199) and PTM FIL 200 mg (n=98) groups, respectively. The rates of CS-free remission in the FIL 100 mg, PTM FIL 100 mg, FIL 200 mg and PTM FIL 200 mg groups were 13.6%, 5.4%, 27.2% and 6.4%, respectively. Age, body mass index, history of pancolitis, duration of UC, faecal calprotectin and C-reactive protein levels, MCS and concomitant use of systemic CSs, immunomodulators and aminosalicylates had no significant effect on CS-free remission in the FIL 200 mg group. Mean baseline Robarts Histopathology Index (RHI) (odds ratio [OR]=0.949, p=0.023) was significantly associated with 6-month CS-free remission in the FIL 200 mg group. A baseline Mayo endoscopic subscore (MES) of 2 (vs 3) was associated with significantly increased odds of 6-month CS-free remission in the FIL 200 mg and FIL 100 mg groups (Table). Being male, a former (vs current) smoker or biologic-experienced was associated with significantly reduced odds of 6-month CS-free remission in the FIL 200 mg group.

Table. Association between 6-month CS-free clinical remission (dependent variable) and baseline characteristics^a by treatment groups.

Conclusion

Most baseline characteristics analysed had no statistically significant effect on 6-month CS-free remission under FIL 200 mg treatment. Low baseline MES and RHI, female sex, being a current (vs former) smoker and biologic-naive may predict higher likelihood of sustained CS-free remission in patients receiving FIL 200 mg.

References

1. Feagan BG et al. Lancet 2021;397:2372–84.

Disclosure

TK has served as an advisory board member, consultant or speaker for AbbVie, Activaid, Ajinomoto Bio-Pharma, Alfresa Pharma, Astellas Pharma, Bristol Myers Squibb, Celltrion, Covidien, EA Pharma, Eisai, Eli Lilly, Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceuticals, JIMRO, JMDC, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, Thermo Fisher Scientific and Zeria Pharmaceutical, and has received research funding from AbbVie, Alfresa Pharma, EA Pharma, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Sekisui Medical, Takeda, Thermo Fisher Scientific and Zeria Pharmaceutical.
AD reports fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis and end point committees from Abivax, AbbVie, Arena Pharmaceuticals, Falk Foundation, Gilead/Galapagos, Janssen and Pfizer; consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Celltrion, Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Janssen, MSD, Pfizer, Pharmacosmos, Roche/Genentech, Sandoz/Hexal, Takeda, Tillotts, and Vifor Pharma; payment from lectures, including service on speakers bureaus from AbbVie, Biogen, Celltrion, the Falk Foundation, Ferring Pharmaceuticals, Gilead/Galapagos, High5ImmunoTV, Janssen Pharmaceuticals, MSD, Pfizer, Takeda, Tillotts Pharma and Vifor Pharma; and payment for manuscript preparation from the Falk Foundation, Takeda, Thieme Medical Publishers and UNI-MED Verlag.
XR has served as an advisory board member, consultant or speaker for AbbVie, Amgen, Biogen, Celltrion, Ferring Pharmaceuticals, Galapagos NV, Janssen Pharmaceuticals, MSD, Pfizer, Sandoz and Takeda.
YF is an employee of Gilead Sciences K.K.
AO is an employee and shareholder of Galapagos NV.
CJ is a contractor for Galapagos NV.
TH has received lecture fees from Aspen Japan K.K., Janssen Pharmaceuticals, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co., Ltd., Pfizer and Takeda; research grants from AbbVie GK, Activaid, Alfresa Pharma Corporation, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Inc., Janssen Pharmaceutical K.K., JMDC Inc., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc. and Takeda; scholarship contributions from Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd. and Zeria Pharmaceutical Co., Ltd.; and study group sponsorship from AbbVie GK, EA Pharma Co., Ltd., JIMRO Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Otsuka Holdings and Zeria Pharmaceutical Co., Ltd.
This study was funded by Gilead Sciences K.K.
The SELECTION trial was sponsored by Gilead Sciences Inc (Foster City, CA, USA). Galapagos NV (Mechelen, Belgium) was a collaborator for the SELECTION trial.
Writing support for the development of this abstract was provided by Tamsyn Stanborough, PhD, and Georgii Filatov of Oxford PharmaGenesis, Melbourne, Australia, and funded by Gilead Sciences K.K.