Healing Of Erosive Esophagitis Research Articles

Efficacy and safety of tegoprazan (LXI-15028) vs. esomeprazole in patients with erosive esophagitis: A multicenter, randomized, double-blind, non-inferiority phase Ⅲ trial.

An evidence gap still exists regarding the efficacy and safety of tegoprazan in Chinese patients with erosive esophagitis (EE) in China. This study aimed to verify the efficacy and safety of tegoprazan vs. esomeprazole in patients with EE in China. This study was a multicenter, randomized, double-blind, parallel, active-controlled, non-inferiority phase III trial of patients with EE randomized 1:1 to tegoprazan 50mg/day vs. esomeprazole 40mg/day. This study was conducted in 32sites between October 24, 2018 and October 18, 2019. The primary endpoint was the cumulative endoscopic healing rate at week 8. The secondary endpoint included endoscopic healing rate at week 4, changes in the reflux disease questionnaire (RDQ) and gastroesophageal reflux disease health-related quality of life (GERD-HRQL) scores, and symptom improvement. A total of 261 patients were randomized: 132 to the tegoprazan group and 129 to the esomeprazole group. The cumulative endoscopic healing rate at 8weeks in the tegoprazan group was non-inferior to that of the esomeprazole group (91.1% vs. 92.8%, difference: -1.7, 95% confidence interval [CI]: -8.5, 5.0, P=0.008). There were no statistically significant differences in the changes in RDQ (total, severity, and frequency) and GERD-HRQL scores between the two groups (all P>0.05). The percentages of days without symptoms, including daytime and nighttime symptoms based on patients' diaries, were similar between the two groups (all P>0.05). In the tegoprazan and esomeprazole groups, 71.5% (93/130) and 61.7% (79/128) of the participants reported adverse events (AEs), 2.3% and 0 experienced serious AEs, while 70.0% and 60.2% had treatment-emergent AEs, respectively. Tegoprazan 50mg/day demonstrated non-inferior efficacy in healing EE, symptom improvement, and quality of life, and it has similar tolerability compared with esomeprazole 40mg/day. ClinicalTrials.gov, NCT03615677.

Efficacy and Safety of Potassium-competitive Acid Blockers Versus Proton Pump Inhibitors in Treating Erosive Esophagitis: A Meta-analysis Based on Randomized Controlled Trials.

This meta-analysis aimed to investigate the efficacy and safety of potassium-competitive acid blockers (P-CABs) and proton pump inhibitors (PPIs) in treating erosive esophagitis (EE). PubMed, Embase, Cochrane Library, and Web of Science were systematically searched using predefined search terms up to January 2024. Relevant randomized controlled trials were included. The outcoming were the EE healing rate and treatment-related adverse events incidence. Nine randomized controlled trials involving 4012 patients were included. Patients receiving P-CAB exhibited a significantly better overall healing rate compared with PPI at week 2 [risk ratio (RR) = 1.06], but no statistical difference was observed at week 4 and week 8. Subgroup analysis revealed that P-CAB demonstrated a higher healing rate for patients with Los Angeles (LA) grade C/D, regardless of the assessment at week 2 (RR = 1.17), week 4 (RR = 1.10), or week 8 (RR = 1.08). However, no significant difference was found between PPI and P-CAB for patients with LA grade A/B at week 2, week 4, or week 8. Furthermore, patients treated with P-CAB had lower recurrence rates during maintenance therapy compared with PPI (RR = 0.79). In terms of safety, P-CAB was associated with a lower incidence of headache compared with PPI (RR = 0.32), with no statistical difference found in any treatment-related adverse events between the two groups. P-CAB was found to be safe and effective for EE treatment compared with PPI, particularly in 2-week short-term treatment, severe EE (LA grade C/D) treatment, or maintenance therapy. Limitations such as potential heterogeneity among included trials should be considered in the interpretation of these findings.

Mathematical model of the relationship between pH holding time and erosive esophagitis healing rates.

Effective suppression of gastric acid secretion promotes healing of erosive esophagitis. Treatment guidelines recommend proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs). Emerging evidence also supports potassium-competitive acid blockers (P-CABs). The aim was to construct a mathematical model to examine the relationship between pH holding time ratios (HTRs) and erosive esophagitis healing rates with H2RAs, PPIs and P-CABs. By literature search, we identified studies of H2RAs, PPIs or P-CABs that reported mean pH >4 HTRs at steady state (days 5-8) and erosive esophagitis healing rates after 4 and/or 8 weeks. We aggregated treatments by drug class and developed a non-linear, mixed-effects model to explore the relationship between pH >4 HTRs and healing rates. The pH dataset included 82 studies (4297 participants; 201 dosage arms); healing rate data came from 103 studies (43,417 patients; 196 treatment arms). P-CABs achieved the longest periods with intragastric pH >4, and the highest healing rates after 4 and 8 weeks. The predicted probabilities of achieving ≥90% healing rates at 8 weeks were 74.1% for P-CABs, 17.3% for PPIs and 0% for H2RAs. P-CABs provide the longest duration with intragastric pH >4 and, accordingly, the highest healing rates of erosive esophagitis.

Current Advances in Diagnosis, Therapeutics, and Surgical Interventions for the Management of Refractory Gastroesophageal Reflux Disease (GERD): An Update.

Gastroesophageal reflux disease (GERD) is a chronic illness characterized by complications arising from the reflux of stomach contents, which significantly lower the quality of life, increase morbidity, and increase medical expenses associated with treating the condition. The main goal of treatment in GERD is symptomatic relief, relapse prevention, and healing of erosive esophagitis. The treatment mainly involves lifestyle changes to control acid production and proton pump inhibitors (PPIs) as the first line of treatment. Endoscopic interventions or anti-reflux surgery may be beneficial in relieving symptoms in people whose symptoms are triggered by reflux. In this review, we discuss the pathophysiology and newer diagnostic and treatment modalities including available surgical management options to manage refractory GERD.

Comparison of Potassium-Competitive Acid Blockers and Proton Pump Inhibitors in Patients With Gastroesophageal Reflux Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This meta-analysis evaluated the efficacy and safety of potassium-competitive acid blockers (PCABs) compared to proton pump inhibitors (PPIs) in treating gastroesophageal reflux disease (GERD). A comprehensive literature search was conducted across multiple databases, and 11 randomized controlled trials comparing PCABs with PPIs were included. The primary outcome was the healing of erosive esophagitis (EE), with secondary outcomes, including relief of heartburn symptoms and adverse events. The analysis included 11 studies and a pooled sample of 4,108 GERD patients. Results showed that PCABs were significantly more effective in healing EE compared to PPIs (OR: 1.67, 95% CI: 1.24-2.24, p<0.01). PCABs also demonstrated a higher rate of complete resolution of heartburn symptoms, although this difference did not reach statistical significance (OR: 1.43, 95% CI: 0.98-2.09, p=0.06). In terms of safety, there was no significant difference in adverse events between PCABs and PPIs (OR: 0.91, 95% CI: 0.79-1.04, p=0.18), including serious adverse events. The superior efficacy of PCABs can be attributed to their unique pharmacological properties, which allow for more rapid and potent acid suppression compared to PPIs. However, the long-term safety profile of PCABs, particularly newer agents, requires further investigation. The study was limited by the predominance of vonoprazan among the PCABs studied and the focus on patients with EE rather than non-erosive reflux disease. In conclusion, this meta-analysis suggests that PCABs are more effective than PPIs in treating GERD, particularly in healing EE, while maintaining a comparable safety profile. Future research should focus on evaluating a wider range of PCABs, assessing their efficacy in non-erosive reflux disease, and investigating their long-term safety in GERD management.

A systematic review with meta‐analysis: Efficacy and safety of potassium‐competitive acid blocker compared with proton pump inhibitor in the maintenance of healed erosive esophagitis

AbstractIntroductionProton pump inhibitor (PPI) is the mainstay therapy for the maintenance of healed erosive esophagitis (EE). It is unknown whether potassium‐competitive acid blockers (PCABs) are more efficacious and safer than PPIs.MethodsOnly randomized controlled trials (RCTs) comparing PCABs to PPIs in the maintenance of healing rates of endoscopically proven healed EE and indexed in MEDLINE, EMBASE, and CENTRAL until 3 February 2024, were included. A fixed‐effects model meta‐analysis was performed to pool primary efficacy outcome (maintenance of healing rates at week 24) and safety data (any treatment‐emergent adverse event or TEAE). The risk of bias was assessed using Cochrane's Risk of Bias 2 (RoB2) tool.ResultsFour RCTs with a total of 2554 patients were eligible for inclusion. All trials were of low risk of bias. Compared to lansoprazole 15 mg, the maintenance rates of healed EE at week 24 were significantly higher with vonoprazan 10 mg (RR 1.13; 95% CI 1.07–1.19) and vonoprazan 20 mg (RR 1.15; 95% CI 1.10–1.21). Likewise, compared to lansoprazole 15 mg, any TEAEs were significantly greater with vonoprazan 20 mg (RR 1.10; 95% CI 1.01–1.20) but not vonoprazan 10 mg.ConclusionVonoprazan 10 and 20 mg were superior to lansoprazole 15 mg in the maintenance of the healing of EE. Any TEAEs were greater with vonoprazan 20 mg.

Heartburn Relief Is the Major Unmet Need for Drug Development in Gastroesophageal Reflux Disease: Threshold Value Analysis

Background and AimsHeartburn symptoms contribute to healthcare-seeking among patients with gastroesophageal reflux disease (GERD). Despite clinical guidance, management is often dictated by insurance restrictions. Several potassium-competitive acid blockers (PCABs) are under development as a new class of therapy. We performed economic analyses to align GERD drug development with the needs of gastroenterologists, insurers and patients in a value-based environment. MethodsA decision-analytic model was constructed to compare vonoprazan 20 mg daily (an example of a PCAB), common over-the-counter or prescription proton pump inhibitor regimens, and no treatment over a 1-year time horizon. Clinical responses were evaluated based on the proportions of heartburn-free days in a recent phase 3 multicenter trial. Healthcare utilization for persistent reflux symptoms was derived from national observational studies compared with healthy control subjects. Costs and quality-adjusted life years were reported. ResultsWithout insurance coverage for appropriate therapy, patients spend $4443 and insurers spend $3784 on average per year for inadequately treated GERD symptoms. Our model estimates that PCABs could save at least $3000 in annual costs to patients and insurers, could generate quality-adjusted life year gains (+0.06 per year), and could be cost-saving to insurers as a covered option at a price up to $8.57 per pill, if these drugs are able to demonstrate similar effectiveness to proton pump inhibitors in future trials evaluating heartburn relief and erosive esophagitis healing to regulators. Threshold prices reflect pricing after all pharmacy benefits manager rebates and discounts. DiscussionWe demonstrate that aiming GERD-related drug development toward heartburn relief appears critical to align cost-effective incentives for industry and insurers with those of patients and gastroenterologists.

Potassium-competitive acid blockers and proton-pump inhibitors for healing of erosive esophagitis: a systematic review and network meta-analysis.

Proton-pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs) are recommended for erosive esophagitis (EE), with good safety and tolerance. However, it is unclear which is the best treatment option for EE. This study aimed to evaluate the comparative efficacy of P-CABs and PPIs for healing EE patients, seeking an appropriate treatment choice in the 4- or 8-week treatment and standard or double dose. A systematic review and network meta-analysis. Relevant databases were searched to collect randomized controlled trials of PPIs and P-CABs in the treatment of EE up to 31 May 2023. Studies on standard or double-dose PPIs or P-CABs which were published in English and assessed 4- or 8-week healing effects in EE were included. A network meta-analysis was performed to evaluate the efficacy of the treatments under the frequentist framework. Sensitivity and subgroup analyses of patients with different baseline EE were also conducted. In all, 34 studies involving 25,054 patients and 9 PPIs, 6 P-CABs, or placebo treatment interventions were included. The pooled 4-week healing rate was significantly statistically lower than the pooled 8-week healing rate for most treatments. Besides, the higher healing rate of double-dose treatment than standard-dose treatment was not observed in the initial treatment of most drugs. The main analysis only included studies conducted for both patients with and without severe EE at baseline, and the proportion of severe EE included in the study was >10%, Keverprazan 20 mg qd ranked best with a surface under the cumulative ranking curve (SUCRA) value of 84.7, followed by Ilaprazole 10 mg qd with a SUCRA value of 82.0, for the healing rate at 8 weeks. Sensitivity analysis showed that the results were robust. Subgroup analysis showed that most P-CABs had higher healing rates than PPIs, particularly for patients with severe EE. And the healing rate of Keverprazan 20 mg qd at 8 weeks ranked best in the subgroup without or with severe EE at baseline. This study showed that an 8-week treatment seemed more effective than the 4-week treatment for healing EE patients. The healing effect of Keverprazan (20 mg qd) ranked best in 8-week treatment, for both severe and non-severe EE patients. The study protocol was registered with INPLASY (registration number INPLASY2023120053).

PBPK modeling to predict the pharmacokinetics of pantoprazole in different CYP2C19 genotypes.

Pantoprazole is used to treat gastroesophageal reflux disease (GERD), maintain healing of erosive esophagitis (EE), and control symptoms related to Zollinger-Ellison syndrome (ZES). Pantoprazole is mainly metabolized bycytochrome P450 (CYP)2C19, converting to 4'-demethyl pantoprazole. CYP2C19 is a genetically polymorphic enzyme, and the genetic polymorphism affects the pharmacokinetics and/or pharmacodynamics of pantoprazole. In this study, we aimed to establish the physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of pantoprazole in populations with various CYP2C19 metabolic activities. A comprehensive investigation of previous reports and drug databases was conducted to collect the clinical pharmacogenomic data, physicochemical data, and disposition properties of pantoprazole, and the collected data were used for model establishment. The model was evaluated by comparing the predicted plasma concentration-time profiles and/or pharmacokinetic parameters (AUC and Cmax) with the clinical observation results. The predicted plasma concentration-time profiles in different CYP2C19 phenotypes properly captured the observed profiles. All fold error values for AUC and Cmax were included in the two-fold range. Consequently, the minimal PBPK model for pantoprazole related to CYP2C19 genetic polymorphism was properly established and it can predict the pharmacokinetics of pantoprazole in different CYP2C19 phenotypes. The present model can broaden the insight into the individualized pharmacotherapy for pantoprazole.

Efficacy and safety of HIP1601 (dual delayed-release esomeprazole) 40 mg in erosive esophagitis compared to HGP1705 (delayed-release esomeprazole) 40 mg: a multicenter, randomized, double-blind, non-inferiority study

BackgroundProton-pump inhibitors (PPIs) are the most effective drugs for treating acid-related disorders. However, once-daily dosing with conventional PPIs fail to fully control acid secretion over 24 h. This study aimed to compare the efficacy and safety of HIP1601 (dual delayed-release esomeprazole) and HGP1705 (delayed-release esomeprazole) in patients with erosive esophagitis (EE).MethodsWe enrolled 213 patients with EE randomized in a 1:1 ratio to receive 40 mg HIP1601 (n = 107) or HGP1705 (n = 106) once daily for 4 or 8 weeks. The primary endpoint was the EE healing rate, confirmed by endoscopy up to week 8. GERD-related symptoms and treatment-emergent adverse events were compared between both groups.ResultsBy week 8, the estimated healing rates of EE were 97.8% and 96.8% in the HIP1601 and HGP1705 groups, respectively, with a 95% confidence interval of -4.7 to 7.2. After 4 or 8 weeks of treatment, the EE healing rate at week 4, complete resolution rate of symptoms, time to sustained resolution of symptoms, and number of rescue medications used were similar in both groups. The proportion of heartburn- and acid regurgitation-free nights by week 4 were higher in the HIP1601 group compared to the HGP1705 group, but the difference did not reach clinical significance (87.7% vs. 85.8%, P = 0.514, 87.5% vs. 85.8%, P = 0.774). The number of adverse events did not differ significantly between the two groups.ConclusionsThe efficacy and safety of HIP1601 40 mg were comparable to those of HGP1705 40 mg for the treatment of EE and symptomatic improvement of GERD.Trial registrationNCT04080726 (https://classic.clinicaltrials.gov/ct2/show/NCT04080726), registration date: 25/10/2018.

Lansoprazole plus levosulpiride versus esomeprazole in participants with gastroesophageal reflux disease and erosive esophagitis: a double blinded randomized control trial.

The aim was to compare the efficacy and safety of lansoprazole plus levosulpiride over esomeprazole. This randomized control trial recruited 1000 participants having symptomatic gastroesophageal reflux disease (GERD) and erosive esophagitis and they were blindly randomized into two groups in a 1:1 ratio with appropriate concealment. Group 1 was given lansoprazole plus levosulpiride combination twice daily whereas group 2 was prescribed only esomeprazole twice daily. The primary efficacy endpoint was the healing of erosive esophagitis and GERD at week 49. Secondary assessments included improvement in quality of life. Participants' quality of life was assessed before starting the treatment and post-treatment using a short-form health survey questionnaire (SF-36). The lansoprazole plus levosulpiride group had significantly lower rates of positive postintervention GERD and erosive esophagitis status, and higher rates of sustained resolution of heartburn compared to the esomeprazole alone group. However, the lansoprazole plus levosulpiride group also had a higher risk of nausea. Lansoprazole plus levosulpiride is a more effective and safe treatment for GERD than esomeprazole alone. Participants in the lansoprazole plus levosulpiride group showed a significantly higher rate of sustained resolution of GERD, lower rates of postintervention GERD and erosive esophagitis status, and a higher incidence of nausea compared to the esomeprazole alone group. Although quality of life worsened in both groups, adverse effects did not significantly differ. These findings strongly support the use of lansoprazole plus levosulpiride as a preferred treatment option for GERD and erosive esophagitis, which could have significant clinical implications for managing this common condition.

Esophagoprotective agent in the treatment of gastroesophageal reflux disease in children

Gastroesophageal reflux disease (GERD) prevalence in children and adolescents is estimated as high. GERD has a wide variety of clinical signs that significantly reduce the patients' quality of life. Typical symptoms include heartburn, belching, and regurgitation (regurgitation). Extraesophageal symptoms are mainly represented by complaints indicating the involvement of the respiratory, ENT organs, and oral cavity organs in the process. In addition, gastroesophageal reflux disease is a major risk factor for Barrett's esophagus and esophageal adenocarcinoma. The main factors predisposing to the development of gastroesophageal reflux disease in children are obesity, overeating, congenital anomalies of the esophagus, surgical interventions at the cardioesophageal junction, immature autonomic nervous system, nervous system diseases, administration of certain drugs, as well as vices such as smoking and alcohol drinking in adolescence. The mainstay of treatment of gastroesophageal reflux disease is antisecretory therapy with proton pump inhibitors. However, some patients using proton pump inhibitors at a standard dosage fail to achieve the clinical and endoscopic remission of the disease. The causes of the gastroesophageal reflux disease refractoriness to the adequate therapy most often include impaired barrier function and increased esophageal mucosal permeability. The use of esophagogastroprotective agents contributes to the optimization of therapy of gastroesophageal reflux disease and aims at achieving the disease remission in a larger number of patients. Clinical case reports of diagnosis and treatment of patients aged 12 and 16 years with gastroesophageal reflux disease are presented. The use of the esophagoprotective agent provided rapid relief of both esophageal and extraesophageal symptoms of the gastroesophageal reflux disease. In addition, complete healing of erosive esophagitis was achieved during its therapy.

Review of the clinical development of fexuprazan for gastroesophageal reflux-related disease.

Proton pump inhibitors (PPIs) are a mainstay treatment for acid peptic disorders such as gastroesophageal reflux disease (GERD). Although PPIs are considered first-line medications for acid suppression, they have notable limitations such as requiring acid-mediated activation, short half-life and duration of action, and metabolic variability. Fexuprazan is a newly developed potassium-competitive acid blocker (P-CAB), which inhibits acid generation and secretion in a competitive and reversible manner. Fexuprazan, like other P-CABs, has significantly different pharmacodynamic and pharmacokinetic properties than PPIs with potential advantages including rapid, robust, and durable acid suppression, lack of CYP2C19 metabolism, independence from food intake, and no requirement for activation into an active form. Completed clinical trials of fexuprazan have demonstrated comparable efficacy to PPIs for the healing of erosive esophagitis and relief of GERD-related esophageal symptoms without concerning safety signals. Ongoing clinical trials are evaluating fexuprazan for the prevention of NSAID-induced peptic ulcer disease, non-erosive GERD, and acute and chronic gastritis, as well as healing efficacy and maintenance of erosive esophagitis (EE). Fexuprazan is approved in South Korea for the treatment of EE and at the time of this writing is being considered for regulatory approval in several other countries. In this article, we summarize and discuss the pharmacology, efficacy, and safety of fexuprazan.

A translational pharmacokinetic/pharmacodynamic approach supports optimal vonoprazan dosing for erosive oesophagitis and Helicobacter pylori infection.

Treatment of acid-related disorders relies on gastric acid suppression. The percentage of time intragastric pH is >4 (pH >4 holding time ratio [HTR]) is important for healing erosive oesophagitis; and the pH >6 HTR is critical for eradication of Helicobacter pylori infection, as bacterial replication is active and antibiotic effectiveness is optimised. Vonoprazan, a potassium-competitive acid blocker approved in the USA and other countries, suppresses gastric acid secretion in a predictable, rapid and consistent manner, extended over prolonged periods. To explore the relationship between vonoprazan exposure and pH HTR through a pharmacokinetic/pharmacodynamic (PK/PD) model. We pooled data from Phase 1 studies with intragastric pH measurements. Pharmacokinetic profiles were predicted for study participants using an existing population pharmacokinetic model. Pharmacokinetic and pharmacodynamic data were merged, and three direct-link PK/PD models were derived and used to simulate pH HTRs with between-participant variability for pH >4, >5 and >6, for vonoprazan doses of 20 mg once and twice daily. We used data from five Phase 1 studies to derive the PK/PD model. These included 245 participants (95.1% male, 50.6% Japanese and 49.4% non-Asian). Pre-dose, the mean pH >4 HTR was 6.4%, pH >5 3.2% and pH >6 1.2%. After 7 days of dosing, simulations predicted pH >4 HTRs of 89.7% and 98.1%, and pH >6 HTRs of 53.1% and 75.3%, for vonoprazan 20 mg once and twice daily, respectively. Vonoprazan 20 mg once- and twice-daily dosing demonstrated high, dose-dependent, 24-hour intragastric acid control in this PK/PD model, supporting clinical efficacy data in patients with acid-related disorders.

Long-term (18 Years) Results of Patients With Long-segment Barrett Esophagus Submitted to Acid Suppression-duodenal Diversion Operation: Better Than Nissen Fundoplication?

To determine late results of AS-DD procedure in long-segment (LSBE) and extralong-segment BE (ELSBE) using subjective and objective measurements to ascertain the histological impact over intestinal metaplasia (IM) and progression to EAC. Barrett esophagus (BE) is a known precursor of esophageal adenocarcinoma (EAC), and Nissen fundoplication has proven to be unable to stop mixed reflux among them. Our group proposed a surgical procedure that handles pathophysiological changes responsible for BE. This prospective study included 127 LSBE and ELSBE subjects submitted to clinical and functional analyses. They were presented to selective vagotomy, fundoplication, partial gastrectomy with Roux-en-Y reconstruction. The changes in IM were determined in both groups. Follow-up was completed at a mean of 18 years in 81% of the cases. Visick I-II scores were seen in 88% of LSBE and 65% in ELSBE ( P < 0.01). There was significant healing of erosive esophagitis and esophageal peptic ulcers, and strictures were resolved in 71%. There was 38% of IM regression in LSBE. Two cases in each group progressed to EAC at a mean of 15 years. Pathologic acid reflux was abolished in 91% and duodenal in 100%. There was a regression of low-grade dysplasia to IM in 80%. AS-DD permanently eliminates pathologic refluxate to the esophagus. The progression to HGD/EAC is lower compared to medical treatment, with an 8-fold reduction in LSBE and 2.2-fold in ELSBE. AS-DD seems to influence IM behaviors, and it is a tool that could reduce and delay progression to EAC.

Randomized controlled trial to evaluate the efficacy and safety of fexuprazan compared with esomeprazole in erosive esophagitis

Fexuprazan, a novel potassium-competitive acid blocker, reversibly suppresses the K+/H+-ATPase enzyme in proton pumps within gastric parietal cells. Fexuprazan's suppression of gastric acid was maintained in healthy individuals for 24 h in a dose-dependent manner. To compare fexuprazan to esomeprazole and establish its efficacy and safety in patients with erosive esophagitis (EE). Korean adult patients with endoscopically confirmed EE were randomized 1:1 to receive fexuprazan 40 mg or esomeprazole 40 mg once daily for eight weeks. The primary endpoint was the proportion of patients with healed EE confirmed by endoscopy at week 8. The secondary endpoints included the healing rate of EE at week 4, symptom response, and quality of life assessment. Safety profiles and serum gastrin levels were compared between the groups. Of the 263 randomized, 218 completed the study per protocol (fexuprazan 40 mg, n = 107; esomeprazole 40 mg, n = 111). Fexuprazan was non-inferior to esomeprazole regarding the healing rate at week 8 [99.1% (106/107) vs 99.1% (110/111)]. There were no between-group differences in the EE healing rate at week 4 [90.3% (93/103) vs 88.5% (92/104)], symptom responses, and quality of life assessments. Additionally, serum gastrin levels at weeks 4 and 8 and drug-related side effects did not significantly differ between the groups. Fexuprazan 40 mg is non-inferior to esomeprazole 40 mg in EE healing at week 8. We suggest that fexuprazan is an alternative promising treatment option to PPIs for patients with EE.

A comparison of efficacy and safety of potassium-competitive acid blocker and proton pump inhibitor in gastric acid-related diseases: A systematic review and meta-analysis.

Potassium-competitive acid blocker (PCAB) is a recent alternative to proton pump inhibitor (PPI) for potent acid suppression. The current systematic review and meta-analysis aimed to compare the efficacy and safety of PCAB versus PPI in treating gastric acid-related diseases. We searched up to June 5, 2022, for randomized controlled trials of gastric acid-related diseases that included erosive esophagitis, symptomatic gastroesophageal reflux disease (GERD), peptic ulcers, and Helicobacter pylori infection. The pooled risk ratio (RR) was evaluated for the efficacy outcome and treatment-emergent adverse events (TEAEs) as the safety outcome. Sensitivity analyses were performed to test the robustness of the study findings. Of the 710 screened studies, 19 studies including 7023 participants were analyzed. The RRs for the healing of erosive esophagitis with Vonoprazan versus PPI were 1.09 (95% confidence interval [CI] 1.03-1.14), 1.03 (95% CI 1.00-1.07), and 1.02 (95% CI 1.00-1.05) in Weeks 2, 4, and 8, respectively. There were no differences in the improvement of GERD symptoms and healing of gastric and duodenal ulcers between PCAB and PPI. The pooled eradication rates of H.pylori were significantly higher in Vonoprazan versus PPI first-line treatment (RR 1.13; 95% CI 1.04-1.22). The overall RR of TEAEs with Vonoprazan versus PPI was 1.08 (95% CI 0.89-1.31). Overall, the risk of bias was low to some concerns. Furthermore, sensitivity analyses confirmed the robustness of the study's conclusion. Vonoprazan is superior to PPI in first-line H.pylori eradication and erosive esophagitis but non-inferior in other gastric acid-related diseases. Likewise, short-term safety is comparable in both treatment groups.

Vonoprazan Versus Lansoprazole for Healing and Maintenance of Healing of Erosive Esophagitis: A Randomized Trial

For decades, proton pump inhibitors (PPIs) have been the mainstay of treatment for erosive esophagitis. The potassium-competitive acid blocker vonoprazan provides more potent acid inhibition than PPIs, but data on its efficacy for erosive esophagitis are limited. Adults with erosive esophagitis were randomized to once-daily vonoprazan, 20 mg, or lansoprazole, 30 mg, for up to 8 weeks. Patients with healing were rerandomized to once-daily vonoprazan, 10 mg, vonoprazan, 20 mg, or lansoprazole, 15 mg, for 24 weeks. Primary end points, percentage with healing by week 8 endoscopy, and maintenance of healing at week 24 endoscopy, were assessed in noninferiority comparisons (noninferiority margins, 10%), with superiority analyses prespecified if noninferiority was demonstrated. Analyses of primary and secondary end points were performed using fixed-sequence testing procedures. Among 1024 patients in the healing phase, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on the exploratory analysis of healing (92.9 vs 84.6%; difference, 8.3%; 95% confidence interval [CI], 4.5%-12.2%). Secondary analyses showed vonoprazan was noninferior in heartburn-free days (difference, 2.7%; 95% CI,-1.6% to 7.0%), and superior in healing Los Angeles Classification Grade C/D esophagitis at week 2 (difference, 17.6%; 95% CI, 7.4%-27.4%). Among 878 patients in the maintenance phase, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on the secondary analysis of maintenance of healing (20 mg vs lansoprazole: difference, 8.7%; 95% CI, 1.8%-15.5%; 10 mg vs lansoprazole: difference, 7.2%; 95% CI, 0.2%-14.1%) and secondary analysis of maintenance of healing Grade C/D esophagitis (20 mg vs lansoprazole: difference, 15.7%; 95% CI, 2.5%-28.4%; 10 mg vs lansoprazole: difference, 13.3%; 95% CI, 0.02%-26.1%). Vonoprazan was noninferior and superior to the PPI lansoprazole in healing and maintenance of healing of erosive esophagitis. This benefit was seen predominantly in more severe erosive esophagitis. (ClinicalTrials.gov: NCT04124926).

S470 Development and Utilization of a Pharmacokinetic/Pharmacodynamic Model for Vonoprazan to Assess the Relationship Between Dose, Exposure, and pH Holding Time Ratio

Introduction: Vonoprazan, a potassium-competitive acid blocker, suppresses gastric acid secretion rapidly and potently over prolonged periods. Gastric acid suppression is key to the healing and maintenance of erosive esophagitis (EE) and the eradication of Helicobacter pylori infection. The daily fraction of time that gastric pH is >4 (the pH >4 holding time ratio [HTR]) is critical for healing of EE; pH >6 HTR is important for eradication of H. pylori infection. Here, we develop and utilize a pharmacokinetic (PK)/pharmacodynamic (PD) model to investigate the relationship between vonoprazan treatment and intragastric pH HTR. Methods: Data from prior Phase 1 single and multiple dose studies with pH measurements were pooled. An existing population PK model was used to estimate individual model parameters and predict PK profiles for study participants on each day with pH measurements. The area under the concentration-time curve between 0 and 24 hours post-dose (AUC0–24h) was merged with pH HTR PD study data. Three direct link PK/PD models characterizing the relationship between AUC0–24h and HTRs for pH >4, >5, and >6 were then derived. The models were used to simulate pH HTRs with between-subject variability; results were summarized as mean and 80% prediction intervals. Results: Data from 245 participants in five different Phase 1 studies were used to derive the PK/PD model. Demographics: 95.1% male; 50.6% Japanese; 49.4% Western. The estimates and 95% confidence intervals for all model parameters are shown in Table. Simulations showed that vonoprazan 20 mg once-daily (QD) and 20 mg twice-daily (BID) are predicted to give pH >4 HTRs of 89.7% and 98.1%, respectively, by Day 7 (Figure). HTRs for pH >6 were 53.1% for vonoprazan 20 mg QD and 75.3% for BID. Conclusion: These results indicate that vonoprazan provides high, dose-dependent pH HTRs and, therefore, consistent, dose-dependent control of 24-hour intragastric acidity. These pH HTRs may explain the high EE healing rates and, when combined with antimicrobials, H. pylori eradication rates seen with vonoprazan in clinical trials.Figure 1.: Predicted Mean and 80% Prediction Interval pH Holding Time Ratio at Days 0 (pre-treatment), 1, 7 and 14. BID, twice daily; QD, once daily. Table 1. - Estimates and 95% CIs for Model Parameters Parameter Role pH >4 Estimate (95% CI) pH >5 Estimate (95% CI) pH >6 Estimate (95% CI) E0 TV (logit) -2.74 (3.77%)(-2.84 to -2.64) -3.18 (1.56%)(-3.27 to -3.09) -3.48 (0.514%)(-3.54 to -3.42) Asian-effect (%) -12.8 (-17.3 to -8.41) -9.23 (-12.7 to -5.74) -5.63 (-8.11 to -3.15) BSV 0.388 (0.310 to 0.465) 0.276 (0.192 to 0.361) 3.16e-05 (-0.286 to 0.286) EC50 TV (ng/mL) 48.2 (43.9 to 52.4) 58.8 (53.1 to 64.5) 99.5 (86.2 to 113) gamma 1.39 (1.20 to 1.58) 1.34 (1.17 to 1.52) 1.62 (1.30 to 1.94) Weight effect (1/kg) 1.50 (0.803 to 2.19) 1.81 (1.19 to 2.44) - BSV 0.319 (0.259 to 0.379) 0.310 (0.252 to 0.368) 0.235 (0.102 to 0.368) Emax TV (logit) 4.80 (102%)(4.53 to 5.07) 4.83 (102%)(4.44 to 5.23) 2.17 (91.9%)(1.65 to 2.70) Weight effect (1/kg) - - -0.0187 (-0.0265 to -0.0108) BSV 1e-04 (6.80e-05 to 0.000132) 1e-04 (5.42e-05 to 0.000146) 0.781 (0.505 to 1.06) ET50 TV (days) 0.432 (0.384 to 0.481) 0.427 (0.369 to 0.485) 0.348 (0.274 to 0.422) delta 1 (fixed) 1 (fixed) 1 (fixed) RUV add.err. (logit) 0.528 (0.475 to 0.580) 0.545 (0.493 to 0.596) 0.498 (0.457 to 0.539) E0 and Emax were estimated on the logit-scale as the pH holding time ratios were logit-transformed; back-transformed estimates on the original percent scale are given for these parameters in round brackets. add.err., additive error; BSV, between subject variability; CI, confidence interval; E0, baseline effect; Emax, theoretical maximum effect achieved at infinite exposure and time; EC50, exposure (AUC) required to achieve 50% of maximum effect (Emax); ET50, time required to achieve 50% of maximum effect; RUV, residual unexplained variability; TV, typical value.

Acid Suppressive Drugs

Histamine H2 receptor antagonists (H2RAs) suppress gastric acid production by blocking H2 receptors in parietal cells. Studies have shown that proton pump inhibitors (PPIs) are superior to H2RAs as a treatment for acid-related disorders, such as peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD). PPIs reduce gastric acid production by irreversibly inhibiting the H+/K+ ATPase pump, and they also increase gastric emptying. Although PPIs have differing pharmacokinetic properties, each PPI is effective in managing GERD and PUDs. However, PPIs have some limitations, including short plasma half-lives, breakthrough symptoms (especially at night), meal-associated dosing, and concerns associated with long-term PPI use. Potassium-competitive acid blockers (P-CABs) provide more rapid and profound suppression of intragastric acidity than PPIs. P-CABs are non-inferior to lansoprazole in healing erosive esophagitis and peptic ulcers, and may also be effective in improving symptoms in patients with non-erosive reflux disease. Acid suppressive drugs are the most commonly used drugs in clinical practice, and it is necessary to understand the pharmacological properties and adverse effects of each drug.