A New Gut Feeling: Where Might Vonoprazan Fit in Therapy?

Proton pump inhibitors (PPIs) are among the most widely prescribed medications worldwide. Omeprazole (Prilosec; AstraZeneca) alone ranked as the eighth most commonly prescribed drug in the US in 2019, with more than 52 million prescriptions written.¹ PPIs have long been a cornerstone of therapy for gastroesophageal reflux disease (GERD), erosive esophagitis (EE), and Helicobacter pylori infection (HPI).

Although PPIs are generally safe and effective for short-term management, their use is limited by a delayed onset of action, nocturnal acid breakthrough, dependence on meal timing, and variable patient response influenced by CYP2C19 metabolism. Additionally, emerging evidence has raised concerns about potential risks associated with long-term use, including dementia and osteoporosis. These limitations have spurred the development of novel acid-suppressive agents such as vonoprazan (Voquesna; Phathom Pharmaceuticals), a potassium-competitive acid blocker that provides more rapid, potent, and sustained acid inhibition.

Vonoprazan is the first potassium-competitive acid blocker (PCAB) approved in the US. It works by competing with potassium ions to directly and reversibly inhibit the H⁺/K⁺ ATPase proton pump, inhibiting gastric acid secretion. PPIs also block this pump to decrease gastric acid secretion, but they bind irreversibly and require activation in an acidic environment because they are prodrugs.² Vonoprazan’s direct and reversible binding enables a faster onset of action, more sustained acid suppression, and dosing that is independent of gastric acid levels or meal timing.

Efficacy in Gastrointestinal Conditions

A study that explored acid-inhibitory effects of vonoprazan vs esomeprazole and rabeprazole, each given orally for 7 days, found that the mean gastric pH on days 1 and 7 were higher after administration of vonoprazan versus the comparators. Additionally, vonoprazan showed better rates of nocturnal acid suppression, with an approximately 4-hour longer duration of acid suppression than esomeprazole or rabeprazole. When comparing vonoprazan directly with esomeprazole, the percentage of time with pH greater than 4 was 67.9% ± 28.3% vs 12.9% ± 10.9%, respectively, on Day 1, and 75.2% ± 26.4% vs 44.8% ± 17.3%, respectively, on Day 7.³ Vonoprazan is also metabolized by CYP3A4 instead of CYP2C19, resulting in less genetic variability in metabolism and enhanced effectiveness.² Together, these distinctions highlight vonoprazan’s potential to overcome several limitations of traditional PPIs, particularly in patients requiring rapid and consistent acid suppression for varying disease states.

Building on its pharmacological advantages, clinical studies have demonstrated vonoprazan’s efficacy in treating erosive esophagitis (EE). In a 2023 randomized controlled trial published in Gastroenterology, adult patients with EE were given either 20 mg of vonoprazan or 30 mg of lansoprazole once daily for 8 weeks. Patients who showed healing were re-randomized to receive either 10 mg or 20 mg of vonoprazan or 15 mg of lansoprazole. Percentage of healing by week 8 endoscopy and maintenance of healing at week 24 endoscopy were the primary end points. Vonoprazan achieved a healing rate of 92.9%, compared to 84.6% with lansoprazole, demonstrating noninferiority with a difference of 8.3% (95% CI, 4.5%–12.2%). For patients with severe EE (LA Grade C/D), vonoprazan demonstrated superiority, with a 17.6% higher healing rate compared to lansoprazole (difference, 17.6%; 95% CI, 7.4-27.4%). These findings suggest that vonoprazan could be a more effective treatment option for those with severe EE.⁴

With benefits demonstrated in EE, vonoprazan is now being explored for its role in non-erosive reflux disease (NERD). A randomized trial conducted in the US investigated adult subjects who experienced heartburn more than 4 days per week. Patients were randomized to receive either vonoprazan 10mg, 20mg, or placebo. Some patients were already on vonoprazan, so they remained at the same dose for 20 weeks. Results showed that the percentage of 24-hour heartburn-free days was 27.7% of patients on placebo, compared to 44.8% for vonoprazan 10 mg (least squares mean difference, 17.1%; P < .0001) and 44.4% for vonoprazan 20 mg (least squares mean difference, 16.7%; P < .0001), showing that vonoprazan has a greater trend toward symptom relief than placebo.⁵

For patients with PPI-resistant GERD without endoscopic findings, a study followed 26 patients who switched their medication from a PPI to vonoprazan during a 12-week period. Results showed that 18 patients reported an improvement in symptoms (69.2%), 6 reported no change (23.1%), and 2 showed an exacerbation of symptoms (7.7%).⁶ These findings show a direction of improvement for patients with PPI-resistant GERD switching to vonoprazan, but more extensive research directly comparing vonoprazan to a proton pump inhibitor for this disease state is needed.

Efficacy in H. Pylori

Vonoprazan’s clinical applications extend beyond various gastrointestinal conditions. It has also demonstrated effectiveness in eradicating H. pylori. The current standard of care for treating a H. pylori infection is optimized bismuth quadruple therapy, which involves a PPI, bismuth subsalicylate, tetracycline, and metronidazole.⁷ Traditional triple therapy with PPI, amoxicillin, and clarithromycin is discouraged unless cultures confirm clarithromycin sensitivity.

A literature review compared vonoprazan plus amoxicillin dual therapy with triple therapy regimens, including PPI-based (PPI, amoxicillin, and clarithromycin) and vonoprazan-based (vonoprazan, amoxicillin, and clarithromycin) combinations. The analysis found that vonoprazan/amoxicillin dual therapy was not inferior to vonoprazan-based triple therapy [RR = 1.03 (95% CI: 0.97–1.10) and 1.02 (95% CI: 0.98–1.08), respectively] and superior to omeprazole- or lansoprazole-based triple therapy (RR = 1.15, 95% CI: 1.05–1.25, p = 0.001). For clarithromycin-resistant strains, vonoprazan/amoxicillin dual therapy exhibited superiority to vonoprazan-based triple therapy (86.7% vs. 71.4%, RR = 1.20, 95% CI: 1.03–1.39, p = 0.02). For clarithromycin-sensitive strains, vonoprazan-based dual therapy was inferior to vonoprazan-based triple therapy (83.0% vs. 92.8%, RR = 0.90, 95% CI: 0.85–0.95, p = 0.0002).⁸

These findings suggest that the choice between vonoprazan-based dual therapy or triple therapy should be tailored to the individual’s clarithromycin resistance status.

Supporting these results, a 2024 study randomized a group of 400 patients diagnosed with H.pylori to receive either vonoprazan-based triple therapy or conventional PPI-based therapy. The study reported a statistically significant eradication rate of 86% with vonoprazan-based triple therapy compared with 74.5% using PPI-based regimens (p = 0.004).⁹ These results highlight the potential of vonoprazan-containing regimens as a more effective option for H. pylori treatment compared with standard PPI-based therapy.

When compared directly with optimized bismuth quadruple therapy, a 2024 multicenter randomized controlled trial compared 2 groups of treatment-naive patients. One group was treated with vonoprazan, amoxicillin, and bismuth, while the other group was treated with standard quadruple therapy. Results showed no significant difference in eradication rates (ITT: 83.7% vs. 83.2%; PP: 90.9% vs. 89.7%), although vonoprazan was associated with significantly fewer adverse effects (13.7% vs. 28.6%, p < 0.001).¹⁰ Overall, with the various studies completed, the findings suggest regimens containing vonoprazan may offer a more effective and better-tolerated treatment option for patients with H. pylori than the current standard of care.

Vonoprazan’s Safety Profile

Despite growing evidence supporting vonoprazan’s efficacy in both acid-related disorders and H. pylori eradication, its long-term safety relative to PPIs remains an important area of investigation. Observational studies have reported that long-term use of PPIs increases the risk for osteoporosis due to reduced calcium absorption, so much so that the FDA published a safety report highlighting this issue. Prolonged use (typically >1 year) can also increase the risk of hypomagnesemia, increasing the risk for cardiac arrhythmias and seizures.

Recent studies have also shown a causative relationship between PPI usage beyond 4.4 years and dementia.¹¹ These findings warranted further investigation, causing the American Geriatrics Society to advise a limit for duration in PPI therapy in elderly patients. A pharmacovigilance analysis using the Japanese Adverse Drug Event Report database revealed that PPIs were more frequently associated with interstitial lung disease, with lansoprazole also associated with microscopic colitis.¹²

Vonoprazan has been generally well-tolerated in recent clinical trials, although data on long-term use are limited. The VISION trial, a 3-year multicenter study conducted in Japan, compared a 10 mg dose of vonoprazan with a 15 mg dose of lansoprazole used as maintenance therapy for 260 weeks in patients with healed erosive esophagitis. Because vonoprazan leads to greater production of gastrin than PPIs, it can theoretically lead to hyperplasia of enterochromaffin-like cells and increase the risk of gastric carcinoid tumors. The study primarily explored any changes in gastric mucosal histopathology between both the vonoprazan and PPI groups. Vonoprazan showed a greater rate of hyperplasia of parietal, foveolar, and G-cells at week 156 than the lansoprazole group, but no increased risk of gastric cancer, atrophic gastritis, or neuroendocrine tumors.¹³

The most common adverse effects reported were gastrointestinal disorders and infections and infestations. The lansoprazole group exhibited greater rates of gastrointestinal-related disorders, with 62.2% of patients experiencing GI-related disorders in the vonoprazan group and 80.6% of patients in the lansoprazole group. The researchers concluded that there were no differences in treatment-related adverse effects between both groups, but there was a greater proportion of patients who discontinued the medication because of an adverse event in the vonoprazan group.¹³ These results show that preliminary data are promising for the long-term safety of vonoprazan, although more research is needed to explore the long-term implications of these histological changes.

Conclusion

Vonoprazan offers several clinical advantages, including rapid onset, reliable acid suppression, and independence from food intake. Its higher healing rates in erosive esophagitis and superior success in H. pylori eradication highlight its value as a promising new addition to therapy. Although additional studies are needed to explore long-term safety, current evidence suggests that vonoprazan is well-positioned to reshape the treatment landscape for acid-related disorders.

REFERENCES

1. Shanika LGT, Reynolds A, Pattison S, et al. Proton pump inhibitor use: systematic review of global trends and practices. Eur J Clin Pharmacol. 2023;79:1159–1172. doi:10.1007/s00228-023-03534-z

2. St Onge E, Phillips B. Vonoprazan: a new potassium-competitive acid blocker. J Pharm Technol. 2023;39(3):139-146. doi:10.1177/87551225231166531

3. Sakurai Y, Mori Y, Okamoto H, et al. Acid-inhibitory effects of vonoprazan 20 mg compared with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects--a randomised open-label cross-over study. Aliment Pharmacol Ther. 2015;42(6):719-730. doi:10.1111/apt.13325

4. Laine L, DeVault K, Katz P, et al. Vonoprazan versus lansoprazole for healing and maintenance of healing of erosive esophagitis: a randomized trial. Gastroenterol. 2023;164(1):61-71. doi:10.1053/j.gastro.2022.09.04

5. Laine L, Spechler S, Yadlapati R, et al. Vonoprazan is efficacious for treatment of heartburn in non-erosive reflux disease: a randomized trial. Clin Gastroenterol Hepatol. 2024;22(11):2211-2220.e10. doi:10.1016/j.cgh.2024.05.004

6. Niikura R, Yamada A, Hirata Y, et al. Efficacy of vonoprazan for gastroesophageal reflux symptoms in patients with proton pump inhibitor-resistant non-erosive reflux disease. Intern Med. 2018;57(17):2443-2450. doi:10.2169/internalmedicine.0492-17

7. Schoenfeld P. ACG clinical guideline: treatment of Helicobacter pylori infection. Am J Gastroenterol. 2024;119(9):1730-1753.

8. Zhang WL, Lin BS, Li YY, Ding YM, Han ZX, Ji R. Efficacy and safety of vonoprazan and amoxicillin dual therapy for helicobacter pylori eradication: a systematic review and meta-analysis. Digestion. 2023;104(4):249-261. doi:10.1159/000529622

9. Elsabaawy M, Shaban A, Al-Arab AE, Elbahr O, Edrees A, Afify S. Vonoprazan a novel potassium competitive acid blocker; another leap forward. Prz Gastroenterol. 2024;19(2):135-142. doi:10.5114/pg.2024.139426

10. Liang JW, Xiong S, Jia YG, et al. Comparison of vonoprazan bismuth-containing triple therapy with quadruple therapy in Helicobacter pylori-infected treatment-naive patients: a prospective multicenter randomized controlled trial. J Gastroenterol Hepatol. 2024;39(11):2293-2298. doi:10.1111/jgh.16679

11. Maideen NMP. Adverse effects associated with long-term use of proton pump inhibitors. Chonnam Med J. 2023;59(2):115-127. doi:10.4068/cmj.2023.59.2.115

12. Kambara H, Hosohata K, Nakatsuji T, et al. Safety profile of vonoprazan compared with proton pump inhibitors: insight from a pharmacovigilance study. Pharmazie. 2020;75(10):527-530. doi:10.1691/ph.2020.0604

13. Haruma K, Kinoshita Y, Yao T, et al. Randomised clinical trial: 3-year interim analysis results of the VISION trial to evaluate the long-term safety of vonoprazan as maintenance treatment in patients with erosive oesophagitis. BMC Gastroenterol. 2023;23(1):139. doi:10.1186/s12876-023-02772-w