A randomized, double-blind study to evaluate the acid-inhibitory effect of vonoprazan (20 mg and 40 mg) in patients with proton-pump inhibitor-resistant erosive esophagitis

Abstract

Background: Standard treatment for patients with erosive esophagitis (EE) is proton-pump inhibitors (PPIs), but some patients are resistant to PPIs. We aimed to evaluate the acid-inhibitory effects and efficacy of a novel potassium-competitive acid blocker (vonoprazan) in patients with PPI-resistant EE.

Methods: This randomized, double-blind, multicenter study of vonoprazan evaluated gastric and esophageal pH over a 24-hour period as the primary endpoint and EE healing rate as the secondary endpoint. Following a 7 to 14-day run-in period (lansoprazole 30 mg treatment), patients with endoscopically confirmed PPI-resistant EE received vonoprazan 20 mg or 40 mg for 8 weeks.

Results: Patients were randomized to receive vonoprazan 20 mg (n = 9) or 40 mg (n = 10). Over a 24-hour period; both groups showed a significant increase from baseline in the percentage of time gastric pH ≥ 4, referred to as pH 4 holding time ratio (HTR): an increase from 73.21% to 96.46% in the 20 mg group, and from 69.97% to 100.00% in the 40 mg group. Increases from baseline in esophageal pH 4 HTRs were not significant. The 40 mg group showed greater increases in gastric and esophageal pH 4 HTRs compared with the 20 mg group, but differences between groups were not significant. After 8 weeks' treatment, the healing rate in subjects with baseline EE grades A-D was 60.0% (3/5 patients) in the 20 mg group and 71.4% (5/7 patients) in the 40 mg group. Vonoprazan was generally well tolerated. One patient (40 mg group) experienced four treatment-emergent adverse events (TEAEs) (unrelated to study drug), leading to study discontinuation.

Conclusions: Vonoprazan 20 mg and 40 mg effectively inhibited gastric acid secretion over a 24-hour period with significantly increased gastric pH 4 HTR, and resulted in an EE healing rate > 60.0% in this study. Vonoprazan treatment may be valuable for patients with PPI-resistant EE.

Keywords: TAK-438; erosive esophagitis; esophageal pH monitoring; gastroesophageal reflux; lansoprazole; potassium-competitive acid blocker; proton-pump inhibitors; vonoprazan.

Conflict of interest statement

Conflict of interest statement: YS, MS, HO, KK, and AN are employees of Takeda Pharmaceutical Company Limited. KI, NH, EU, and KA are all paid consultants for Takeda Pharmaceutical Company Limited. Takeda Pharmaceutical Company Limited was involved in the study design, data collection, data analysis and preparation of the manuscript.

Figures

Figure 1.

Study design and treatment periods.

Figure 2.

Patient disposition (CONSORT flow chart).

Figure 3.

Gastric and esophageal pH profiles of nonhealed patients, according to baseline and week 8 erosive esophagitis grades: (a) nonhealed patient one, LA grade B at baseline, LA grade B at week 8; (b) nonhealed patient two, LA grade D at baseline, LA grade D at week 8; (c) nonhealed patient three, LA grade B at baseline, LA grade B at week 8; (d) nonhealed patient four, LA grade D at baseline, LA grade D at week 8.* *Baseline EE grades as assessed by CAC, week 8 EE grades as assessed by investigator. EE, erosive esophagitis; LA, Los Angeles; CAC, central adjudication committee.

Figure 4.

Patterns of gastric and esophageal pH for healed patients, nonhealed patients, and patients for whom baseline erosive esophagitis was classified as grade 0 by the central adjudication committee: (a) gastric pH, 20 mg vonoprazan group; (b) gastric pH, 40 mg vonoprazan group; (c) esophageal pH, 20 mg vonoprazan group; (d) esophageal pH, 40 mg vonoprazan group. *As assessed by CAC. EE, erosive esophagitis; HTR, holding time ratio; CAC, central adjudication committee.

Figure 5.

Time courses of serum gastrin, pepsinogen I and pepsinogen II.