Editorial: towards extended acid suppression - the search continues

Acid-suppression therapy with proton pump inhibitors (PPIs) is associated with well-established benefits in managing gastro-oesophageal reflux disease (GERD) and other acid-related disorders. However, a number of questions still remain unanswered.1, 2 These include management of patients with GERD symptoms who do not respond adequately to PPI therapy, the optimal treatment and prevention of NSAID-related GI injury, best combination of anti-secretory and antibiotic therapy for the eradication of Helicobacter pylori infection, and treatment of patients with nonvariceal upper GI bleeding. Despite their clinical efficacy, when given once daily, currently available delayed-release PPIs (DR-PPIs) may not adequately control intra-gastric acidity during the night in a significant proportion of both healthy subjects and GERD patients, in whom symptom relief remains suboptimal. According to a US survey,3 although most prescription PPI users are on a once-daily regimen, a substantial proportion of patients take these drugs twice-daily, despite this being off-label. Patients on PPI therapy often continue to experience GERD symptoms and supplement their prescription PPIs with other GERD medications, which may be obtained over-the-counter. One in four patients are dissatisfied with PPI therapy for GERD.3 Over the past decade, many new drugs, or alternative formulations of existing drugs, have been investigated but only two, instant release omeprazole (IR-omeprazole) and modified-release dexlansoprazole (MR-dexlansoprazole), have been introduced in some countries. These new approaches represent a measurable, but small, incremental advance in the pharmacological control of acid secretion over the DR-PPIs,4, 5 but fall short of achieving the pharmacologic profile that has been considered desirable to control acidity in patients with more complex clinical problems.6, 7 Several compounds are under investigation to provide a significant advance over current treatments.8 Some have already entered phase I or II studies, while others are still in preclinical development. Novel PPIs have been synthesised, but few have reached clinical testing. Tenatoprazole (a nonbenzimidazole derivative) and AGN 201904-Z (an omeprazole pro-drug) display a half-life longer than that of current PPIs (about 9 and 4 h, respectively, vs. 1.5–2.0 h) and a better control of intra-gastric acidity at night, with few episodes of nocturnal acid breakthrough (NAB).9 The next generation of drugs that suppress gastric acidity are the acid pump antagonists (also called potassium-competitive acid blockers, P-CABs), which are K+-competitive inhibitors of the gastric proton pump.8, 10 While PPIs have a unique mechanism of action based on their chemistry, P-CABs have a structural specificity for their target, the K+-binding region of the H+,K+-ATPase. P-CABs are lipophilic, weak bases that have high pKa values and are stable at low pH. These properties allow them to concentrate in acidic environments. For example, the concentration of a P-CAB with a pKa of 6.0 would theoretically be expected to be 100,000-fold higher in the parietal cell canaliculus (pH = 1.0) than in the plasma (pH 7.4). On entering an acidic environment, P-CABs are instantly protonated and it is in this form that they are thought to bind to and inhibit the enzyme.8, 10 Therefore, these agents will produce more rapid acid inhibition and will be able to elevate gastric pH to a higher level than PPIs. The main differences between P-CABs and PPIs are outlined in Table 1. Despite sharing the same mechanism of action, P-CABs represent a heterogeneous class of drugs. Indeed, they belong to several different chemical classes, namely imidazopyridines, pyrimidines, imidazonaphthyridines, quinolones, benzimidazole carboxamides and pyrrole derivatives.8 Sakurai et al.11 reported the acid-inhibitory effect of vonozopran, a new P-CAB (20 mg once daily), compared with esomeprazole (20 mg once daily) or rabeprazole (10 mg once daily) in healthy, male volunteers. Acid suppression (evaluated as pH holding time ratios) with vonoprazan was significantly greater than that with esomeprazole or rabeprazole on both days 1 and 7, confirming a more rapid and sustained anti-secretory effect. These results are relevant since they have been obtained in CYP2C19 extensive metabolizers, the dominant genotype both in Japanese and Caucasian populations.12 The mean 24-h intragastric pH was higher than, and the pH 4 holding time similar to, that recently reported after esomeprazole 20 mg q.d.s.13 When compared with standard doses of other PPIs, esomeprazole (40 mg once daily) provided more effective control of gastric acid in patients with symptomatic GERD.14 Vonoprazan appears, therefore, superior to the best PPI currently available and displays a pharmacological profile with the potential to truly address the unmet clinical needs in GERD and other acid-related diseases. Indeed, available clinical data, albeit so far only in Japanese patients, suggest that this is the case.15 Declaration of personal interests: Carmelo Scarpignato has served as a speaker, consultant and/or advisory board member for Alfa Wassermann, AstraZeneca, Boeheringer-Ingelheim, Giuliani Pharmaceuticals, Pfizer, Recordati, Sigma-Tau, Shire, Takeda and Warner-Chilcott, and has in the past received funding from Giuliani Pharmaceuticals and Pfizer. Richard H Hunt has served as a speaker, a consultant and an advisory board member for AstraZeneca, Danone, GSK, Merck, Pfizer, Takeda. Declaration of funding interests: None.

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