Exploring Potassium-Competitive Acid Blockers: The Next Generation of PPIs

The management of acid-related diseases is rapidly evolving, as novel drugs such as potassium-competitive acid blockers (P-CABs) have entered the market. As peptic ulcer and gastroesophageal disease incidences have increased, clinicians will be assisted by understanding the underlying mechanisms, and associated efficacy of this therapeutic option.

A review of these drugs, including an overview of the mechanisms of action, therapeutic benefits, and possible adverse side effects, was recently published in World Journal of Gastrointestinal Pharmacology and Therapeutics.¹

History of P-CABs

First developed in the early 1980s, P-CABs bind reversibly to K+ ions, blocking the H+ K+ATPase enzymes, preventing acid production.¹ The first 2 of this group of drugs were SCH28080, an antisecretory drug, and AZD0865, a potent inhibitor of H+ K+ATPase enzymes. Phase 2 and 3 clinical trials found that AZD0865 demonstrated a similar efficacy to esomeprazole in treating esophagitis, as well as in providing symptomatic relief of nonerosive reflux disease. Despite its promising potential, further trials were not conducted to the occurrence of hepatotoxicity.

YH-1885, or Revanex, was the first P-CAB used in clinical practice.1However, this drug was not superior to currently existing proton pump inhibitors (PPIs). TAK-438, or Vonoprazan fumarate was the second drug introduced into clinical practice, which became popular due to its superior properties, including rapid-action onset, long action duration, and “consistent and potent acid suppression” compared with traditional PPIs.¹

P-CABs are weak bases,¹ which inhibit the H+ K+ ATPase enzyme. The acid dissociation constant (pKa) values of linaprazan and vonoprazan are 6.1 and 9.3, respectively, rendering these drugs less prone to cross membranes and likely to concentrate in the acid-secreting canaliculi of parietal cells.

Using P-CABs as a Treatment

Both PPIs and H2 receptor antagonists are the treatment of choice for gastroesophageal reflux disease (GERD). According to the review authors, the primary goals in treating this condition are providing patients with symptomatic relief, healing and remaining remission of erosive esophagitis, and preventing complications while improving patients’ quality of life.¹

There are currently numerous unmet needs in GERD treatment, including failure to achieve complete healing in erosive esophagitis, relapse of symptoms within 6 months of maintenance therapy initiation, continued symptoms in nonerosive reflux disease (NERD) despite standard dose PPI therapy, and the “clinically disappointing” treatment of extraesophageal manifestations of GERD.²

Despite the presence of unmet therapeutic needs, P-CABs can be an effective treatment option for several conditions, including peptic ulcer disease, Helicobacter pylori (H pylori) eradication, and the prevention of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric mucosal damage.¹

In Japan, vonoprazan has been approved to treat both gastric and duodenal ulcers.³ In 2 randomized, controlled trials, approximately 93.5% of patients with gastric ulcers treated with vonoprazan and 93.8% of patients treated with lansoprazole achieved a cure. A difference of only 0.3% was noted in the cure rate between the 2 medications. In patients with duodenal ulcers, 95.5% and 98.3% of patients on vonoprazan and lansoprazole reached a cure, with a cure rate difference of 2.8%. Treatment-emergent adverse events were slightly lower in patients with gastric ulcers treated with vonoprazan, and 1 death was reported in the vonoprazan-treated duodenic ulcer group. Researchers concluded that vonoprazan 20 mg is similar in tolerability to lansoprazole 30 mg.¹,⁴

In 2017, a multicenter study was conducted to assess the safety and efficacy of vonoprazan-based triple therapy in eradicating H pylori. The therapy comprised of treatment with vonoprazan, amoxicillin, and clarithromycin or metronidazole.¹,⁵

Researchers of a per-protocol analysis of first- and second-line therapies found that eradication among the 799 patients in the study cohort was 94.4% and 97.1%, respectively. Adverse event incidence rate was 4.4%, leading researchers to conclude that vonoprazan-based triple therapy was both safe and effective for the eradication of H pylori.¹,⁵

Additional clinical studies, conducted in Japan, assessed whether P-CABs demonstrated superiority to PPIs in H pylori eradication therapy.⁶ Researchers retrospectively reviewed 573 patients who received clarithromycin, amoxicillin, and either lansoprazole, rabeprazole, esomerprazole, or vonoprazan twice daily for 1 week. Eradication was overall successful; patients receiving vonoprazan had a “significant and superior”¹ eradication rate of 83% and 85% in the intention-to-treat and per-protocol analysis groups.¹, ⁶

Treatment of endoscopic submucosal dissection (ESD)-induced artificial ulcers via vonoprazan was “not found to be superior to any PPIs,” according to Dr Rawla and colleagues. One randomized, prospective study compared the effects of vonoprazan and lansoprazole treatment in patients with early gastric cancers between April 2015 and May 2017.⁷ Researchers found no significant difference between the 2 groups in terms of area and shrinkage ratio of ulcers at 4 and 8 weeks.¹,⁷ As such, researchers concluded that both drugs are equally as effective at treating ESD-induced artificial ulcers.

Finally, vonoprazan 10 mg and 20 mg were both well-tolerated and effective in preventing NSAID-induced peptic ulcer recurrence.¹ In Japan, daily vonoprazan 10 mg dosing has been approved to treat this condition. “It is foreseen that vonoprazan could become the primary treatment option for NSAID related adverse events in high-risk patients,” Dr Rawla and colleagues wrote.¹

Adverse Events With P-CAB Use

Despite the overall positive clinical data for P-CABs, there does exist the potential for adverse reactions and treatment-associated adverse events. Early P-CABs, including SCH28080 and AZD0865, are no longer used clinically due to their short duration of action and associated hepatotoxicity.¹

A phase 3, double-blinded, placebo-controlled, parallel-group, multicenter study of Japanese patients found that treatment-emergent adverse events were 27.7% and 28% with vonoprazan 10 mg and 20 mg treatment, respectively.⁸ The most common event was nasopharyngitis, and most events were mild.

The Future of P-CABs

Robust clinical data have allowed the development of new P-CAB drugs to continue. One such drug is tegoprazan, which was recently studied in a phase 1, randomized, double-blinded, placebo-controlled study conducted in South Korea.⁹ Fifty-six healthy volunteers received 50 mg, 100 mg, 200 mg, and 400 mg doses; researchers measured both plasma concentration and metabolite M1 via liquid chromatography-mass spectrometry. Few mild adverse events were reported, and study investigators concluded that tegoprazan is well-tolerated in healthy patients.

“This study could…successfully elucidate the pharmacokinetics of the drug and its metabolite as well as the pharmacodynamics of gastric pH, thus providing clinical evidence that the drug can be used to treat acid-related disorders,” Dr Rawla and colleagues noted.¹

Tegoprazan is currently approved for use in Korea under the brand name K-Cab. Vonoprazan (Takecab®, Takeda) is currently approved for use in Japan. Pending successful clinical trial results, researchers indicate that these drugs should be submitted to the US Food and Drug Administration for phase 4 research and monitoring.¹⁰ According to the National Institutes of Health National Center for Advancing Translational Sciences, revaprazan is approved for use in Korea but has not yet been approved in either Europe or the United States.¹¹ ¹²

“Over the past 40 years, there have been tremendous changes in the treatment of acid-related diseases, from diet and surgery to H2 receptor antagonists and then PPIs,” Dr Rawla and colleagues concluded. “Because of the tolerability and enhanced effectiveness of P-CABs, it is very likely that they will change the future of treatment of acid-related disorders.”¹

References

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