Why Vonoprazan Is More Effective For Erosive Esophagitis Than a Proton Pump Inhibitor

L Laine et al. Gastroenterol 2023; 164: 61-71. Open Access! Vonoprazan Versus Lansoprazole for Healing and Maintenance of Healing of Erosive Esophagitis: A Randomized Trial

Editorial: DA Katzka, PJ Kahrilas. Gastroenterol 2023; 164: 14-15. Open Access! Potassium-Competitive Acid Blocker Suppression of Gastric Acid in Erosive Esophagitis: Is Stronger and Longer Better?

Methods: Adults with erosive esophagitis were randomized to once-daily vonoprazan, 20 mg, or lansoprazole, 30 mg, for up to 8 weeks (healing phase, n=1024). Patients with healing were rerandomized to once-daily vonoprazan, 10 mg, vonoprazan, 20 mg, or lansoprazole, 15 mg, for 24 weeks (maintenance phase, n=878). 

Key findings: (see graphical abstract)

  • In the healing phase, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on the exploratory analysis of healing: 92.9 vs 84.6% (difference, 8.3%). It is noted that studies in Asian populations found smaller differences in healing between these medications.
  • Vonoprazan had superior healing Los Angeles Classification Grade C/D esophagitis at week 2 (difference, 17.6%)
  • Vonoprazan was superior with regard to maintenance of healing Grade C/D esophagitis (20 mg vs lansoprazole (difference, 15.7%) and 10 mg vs lansoprazole (difference, 13.3%).
  • The entire group maintenance healing rates in this trial were lower than in a prior randomized trial in Japan. In the current study at 24 weeks, vonoprazam 20 mg, vonprazan 10 mg and lansoprazole 15 mg had maintenance of healing in 81%, 79%, and 72% respectively compared with 98%, 95%, and 83% in the trial from Japan

The editorial provides a lot of insight into this now FDA-approved therapy for H pylori. Vonoprazan’s application to expand FDA approval is underway: FDA Accepts Review of NDA for Vonoprazan From Phathom Pharmaceuticals (June 3, 2022).

Key points from editorial:

  • Among their shortcomings, PPIs are far from perfect in healing high-grade (Los Angeles class C and D) esophagitis, resulting in the common practice of twice-daily dosing. Furthermore, up to 35% of patients with Los Angeles class C and D esophagitis remain unhealed at 8 weeks, even with twice-daily PPI use.5,6
  • Mechanism of action: Vonoprazan is a potassium-competitive acid blocker (PCAB) . It, reversibly binds to the α-subunit of H+, K+-ATPase to compete with potassium binding. Vonoprazan is acid stable, eliminating the need for enteric coating and allowing for rapid onset of action. Because it achieves high and sustained (half-life is approximately 9 hours) concentrations rapidly in the parietal cell secretory canaliculi, maximal acid inhibition is achieved quickly after a single dose.
  • Because it is not metabolized through the hepatic CYP2C19 or CYP3A4 enzymes, vonoprazan is much less prone to drug–drug interactions.
  • Safety: For the issue of long-term adverse events associated with PPI use…, the proposed mechanisms for these primarily relate to the effects of chronic acid inhibition and/or hypergastrinemia, and there is no reason to think that a PCAB would be any different than a PPI.

My take: There are a lot of individuals with ongoing heartburn & reflux despite PPI treatment. It is likely that vonoprazan will be targeted for patients with more severe erosive esophagitis and refractory symptoms. It is likely that the cost to U.S. patients will be substantially higher than the cost of PPIs.

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Understanding FDA Approval of Vonoprazan-Based Therapies for Helicobacter Pylori

Pharmacy Times (5/4/22): FDA Approves Pair of Vonoprazan Treatments for Helicobacter Pylori Infection

“The (FDA) has approved 2 vonoprazan-based medications for the treatment of Helicobacter pylori (H. pylori) infection.

Phathom Pharmaceuticals announced the approvals of both the Voquezna Triple Pak (vonoprazan, amoxicillin, clarithromycin) and Voquezna Dual Pak (vonoprazan, amoxicillin) based on positive safety and efficacy data from the phase 3 PHALCON-HP trial.”

WD Chey et al. Gastroenterol 2022; 163: 608-619. Open Access! Vonoprazan Triple and Dual Therapy for Helicobacter pylori Infection in the United States and Europe: Randomized Clinical Trial

Key findings from this randomized, controlled trial with treatment-naive 1046 adults:

  • In all patients, vonoprazan triple and dual therapy were superior to lansoprazole triple therapy (80.8% and 77.2%, respectively, vs 68.5% (both superior)
  • In patients with clarithromycin resistance, vonoprazan triple therapy was effective in 65.8%, dual therapy in 69.6%, vs lansoprazole triple therapy 31.9% (both superior)
  • Vonoprazan increases intragastric pH rapidly “and maintains it to a greater degree than PPI; this has been associated with higher H pylori eradication rates” (in prior studies as well)

The associated editorial: CA Fallone (Open Access!) The Current Role of Vonoprazan in Helicobacter pylori Treatment

Based on this new information, the author proposes the treatment algorithm below and notes that “the role of increased acid suppression by PPI substitution with vonoprazan should be examined in other H pylori regimens.” The author favors bismuth quadruple therapy in those with clarithromycin resistance as non-bismuth quadruple therapy utilizes an unnecessary antibiotic (clarithromycin).

Other points:

  • Metronidazole resistance is fairly common, but bismuth quadruple therapy can overcome much of the metronidazole resistance
  • Levofloxacin resistance is quite high in certain regions and should only be used with caution, given recent warnings from the US Food and Drug Administration of aortic rupture in susceptible individuals
  • Rifabutin can cause some bone marrow suppression

My take: With the more widespread availability of susceptiblity testing (beyond clarithromycin), I anticipate more targeted treatments. At the same time, vonoprazan-based treatments are likely to be important in increasing eradication rates.

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