Background: Peptic ulcer disease (PUD) is a common gastrointestinal disorder frequently caused by Helicobacter pylori (H. pylori) infection or the use of non-steroidal anti-inflammatory drugs. It is associated with significant morbidity, particularly when complicated by upper gastrointestinal bleeding. Proton pump inhibitors have long been the standard of care for acid suppression. However, they have limitations, including delayed onset of action, food dependency, and variability in metabolism influenced by genetic polymorphisms.
Objective: This review evaluates the comparative efficacy and safety of novel acid-suppressing agents, including potassium-competitive acid blockers such as vonoprazan, tegoprazan, and keverprazan, as well as anaprazole, a structurally modified proton pump inhibitor.
Methodology: Findings from several phase three randomized controlled trials were analyzed. These trials compared newer agents with traditional proton pump inhibitors in terms of ulcer healing, symptom relief, rebleeding prevention, and tolerability.
Results: Vonoprazan was shown to be as effective as intravenous pantoprazole in preventing rebleeding after endoscopic hemostasis. Tegoprazan and keverprazan achieved similar or superior healing rates compared to lansoprazole. Anaprazole showed consistent efficacy with reduced variability due to its partial non-enzymatic metabolism.
Conclusion: These emerging therapies offer promising alternatives by providing more consistent acid suppression, faster symptom resolution, and improved safety profiles compared to conventional proton pump inhibitors.

Peptic ulcer, Proton pump inhibitors, Potassium-competitive acid blockers, Acid suppression, Rebleeding, Polymorphism.

Peptic ulcer disease is a common gastrointestinal condition characterized by mucosal injury due to the corrosive effects of gastric acid and pepsin. It poses a significant global health burden, especially when complicated by upper gastrointestinal bleeding (UGIB), which remains a major cause of hospitalization, morbidity, and mortality.[1-4] The most frequent etiologies of PUD include infection with Helicobacter pylori and the chronic use of non-steroidal anti-inflammatory drugs (NSAIDs). Regional variations in incidence are evident, with higher rates observed in Asian populations compared to Western countries. For instance, studies have reported a PUD incidence of 17.2% in Shanghai, markedly higher than the 4.1% observed in Western populations.[5-8]

The cornerstone of PUD management is acid suppression therapy, primarily using proton pump inhibitors (PPIs). PPIs work by irreversibly inhibiting the H⁺/K⁺-ATPase enzyme in gastric parietal cells, effectively reducing gastric acid secretion. Their introduction significantly improved outcomes in acid-related disorders, including PUD, gastroesophageal reflux disease (GERD), and H. pylori eradication regimens. Despite their clinical success, PPIs have notable limitations.[9-12] These include a short plasma half-life, delayed onset of action, and the need for acid activation, which reduces their effectiveness in the fasting state and can lead to persistent nocturnal symptoms. Moreover, their metabolism is significantly influenced by cytochrome p450 family 2 subfamily c member 19 (CYP2C19) genetic polymorphisms, which affect drug bioavailability and therapeutic outcomes, particularly among Asian populations with a higher prevalence of poor metabolizer phenotypes.[13-16]

In response to these shortcomings, newer classes of acid-suppressing agents have been developed. Potassium-competitive acid blockers (P-CABs) represent a significant advancement. Unlike PPIs, P-CABs inhibit acid secretion by reversibly blocking the H⁺/K⁺-ATPase enzyme without requiring activation in an acidic environment. This results in a faster onset and more consistent acid suppression, independent of food intake.[17-20] Vonoprazan, one of the most studied P-CABs, has demonstrated potent and long-lasting acid inhibition and has shown efficacy comparable to or superior to PPIs in treating GERD, H. pylori infection, and peptic ulcers. However, its effectiveness in preventing rebleeding after endoscopic hemostasis for bleeding ulcers is yet to be fully established. To address this, ongoing clinical trials aim to evaluate vonoprazan’s role in high-risk PUD populations.[21-23]

Other P-CABs, such as tegoprazan and keverprazan, have also emerged with promising clinical data. Tegoprazan, developed and approved in South Korea, has demonstrated rapid acid suppression and healing rates comparable to esomeprazole in gastric ulcers and erosive esophagitis. Keverprazan, recently approved in China, has shown non-inferiority to lansoprazole in phase II studies for duodenal ulcer healing and is under further investigation in larger trials. These agents may provide improved symptom relief and mucosal healing, especially in patients who respond poorly to traditional PPIs.[24] Meanwhile, innovations within the PPI class continue with the development of anaprazole, which features structural modifications that reduce its dependency on CYP2C19 metabolism. Unlike conventional PPIs, anaprazole includes a furan ring and undergoes partial non-enzymatic metabolism, offering more stable pharmacokinetics and a potentially better safety profile. Preliminary studies have shown comparable efficacy to rabeprazole in healing duodenal ulcers, and phase III trials are underway to validate these findings in larger and genetically diverse patient populations. These studies also aim to assess the influence of H. pylori infection status and CYP2C19 polymorphisms on anaprazole’s clinical performance.[25]

In summary, while PPIs remain a foundational therapy for PUD, their pharmacologic limitations and variable patient responses have driven the development of novel acid-suppressive therapies. P-CABs like vonoprazan, tegoprazan, and keverprazan offer rapid and sustained acid suppression, while modified PPIs such as anaprazole seek to overcome metabolic variability. These emerging therapies are being rigorously evaluated through phase III trials to determine their comparative efficacy and safety, to improve clinical outcomes in patients with acid-related gastrointestinal disorders.[26]

Vonoprazan versus pantoprazole: A multicenter, randomized, open-label, noninferiority trial (n = 194) compared oral vonoprazan to intravenous pantoprazole in patients with high-risk bleeding peptic ulcers (Forrest Ia–IIb) who had achieved successful endoscopic hemostasis. The 30-day rebleeding rates were 7.1% in the vonoprazan group and 10.4% in the pantoprazole group (risk difference (HR) −3.3%; 95% confidence interval (CI) −11.2 to 4.7; P = 0.002 for noninferiority), meeting the predefined noninferiority margin. Kaplan–Meier survival analysis showed no significant difference in the timing of rebleeding between groups (HR 0.67; 95% CI 0.25–1.75; P = 0.409). These findings indicate that vonoprazan provides a comparable level of protection against rebleeding as standard intravenous PPI therapy, with the added advantage of being administered orally.[27]

Tegoprazan versus lansoprazole: A phase III, double-masked randomized controlled trial (RCT, n=306) assessed tegoprazan 50/100 mg vs. lansoprazole 30 mg in gastric ulcers. At 8 weeks, healing rates were 100%, 97.85%, and 100% (Per-protocol set (PPS)). The difference between tegoprazan 100 mg and lansoprazole was <8.54% (95% CI −7.66 to 2.43, P = 0.0137), confirming noninferiority. Symptom relief was rapid, and treatment-emergent adverse events (TEAEs) were mild (~10%). Tegoprazan demonstrated comparable efficacy with a faster onset of action.[28]

Anaprazole versus rabeprazole: A phase III, double-blind RCT (n=448) compared anaprazole 20 mg vs rabeprazole 10 mg in duodenal ulcers. Four-week healing was 90.9% vs 93.7% (FAS; difference −2.8%, 95% CI −7.7 to 2.2%), confirming noninferiority. Pain relief occurred within 2 days in most patients. Outcomes were consistent across CYP2C19 genotypes and H. pylori status. Safety was comparable, with rare hepatic/thyroid events.[29]

Keverprazan versus lansoprazole: A phase III, double-blind RCT (n=360) compared keverprazan 20 mg vs. lansoprazole 30 mg in duodenal ulcers. At 6 weeks, healing rates were 94.4% vs 93.3% (Full analysis set (FAS); difference 1.2%, 95% CI −4.0 to 6.5%), confirming noninferiority. Symptom relief was similar, with more belching improvement in the keverprazan group. Mild liver enzyme elevations were noted but resolved post-treatment.[30]

This synthesis highlights the evolving role of P-CABs and novel PPIs in PUD management. Vonoprazan, tegoprazan, and keverprazan demonstrated rapid acid suppression and healing rates comparable or superior to PPIs, with vonoprazan showing efficacy even in high-risk bleeding ulcers. Anaprazole achieved similar outcomes to rabeprazole with reduced metabolic variability, potentially improving treatment consistency across genetic profiles.

The key advantage of P-CABs is their immediate, sustained acid suppression independent of food intake or CYP2C19 polymorphisms. This could particularly benefit Asian populations with a high prevalence of poor metabolizers, where PPIs often underperform. These drugs may also shorten hospital stays in bleeding ulcer cases by enabling earlier oral therapy. Collectively, these findings support considering P-CABs as frontline therapy in selected PUD patients.

Table 1: Study characteristics

Table 2: Key efficacy and safety outcomes

Limitations: Most trials were conducted in Asian populations, which may limit global applicability. Follow-up durations (4–8 weeks) were short and focused on healing, not recurrence or long-term safety. Several studies were industry-sponsored, raising potential bias. Rare adverse events and cost-effectiveness were not evaluated. Future research should address these gaps through long-term, multinational studies.

Emerging acid-suppressing therapies such as vonoprazan, tegoprazan, keverprazan, and anaprazole show comparable or superior efficacy to conventional PPIs. Their rapid onset, consistent acid suppression, and favorable safety profiles position them as promising alternatives in PUD treatment, particularly for patients with rapid symptom relief needs or PPI resistance.

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No funding

Corresponding Author:
Samatha Ampeti, PhD
Independent Researcher
Department of Content, medtigo India Pvt Ltd, Pune, India
Email: ampetisamatha9@gmail.com

Co-Authors:
Mansi Srivastava, Sonam Shashikala BV, Raziya Begum Sheikh, Patel Nirali Kirankumar, Shubham Ravindra Sali
Independent Researcher
Department of Content, medtigo India Pvt Ltd, Pune, India

All authors contributed to the conceptualization, investigation, and data curation by acquiring and critically reviewing the selected articles. They were collectively involved in the writing – original draft preparation and writing – review & editing to refine the manuscript. Additionally, all authors participated in the supervision of the work, ensuring accuracy and completeness. The final manuscript was approved by all named authors for submission to the journal.

Not applicable

None

None

https://doi.org/10.63096/medtigo30612315

Mansi S, Samatha A, Sonam SBV, Raziya BS, Patel NK, Shubham RS. Advances in Peptic Ulcer Treatment: Role of Vonoprazan, Tegoprazan, Keverprazan, and Anaprazole. medtigo J Pharmacol. 2025;2(3):e30612315. doi:10.63096/medtigo30612315 Crossref