In the treatment of Helicobacter pylori infection, combination therapies using the oral potassium-competitive acid blocker vonoprazan were superior to standard proton pump inhibitor (PPI)–based triple therapy, producing higher eradication rates, according to combined data from a U.S. and a European phase 3 randomized, controlled trial.
Vonoprazan has been submitted to the Food and Drug Administration for approval with a Fast Track designation in combination with amoxicillin and clarithromycin (triple therapy) or amoxicillin alone (dual therapy) for treating H. pylori infection. It has already been approved in Japan for the treatment of gastric and duodenal ulcers, reflux esophagitis, secondary prevention of low-dose aspirin– or nonsteroidal anti-inflammatory drug–induced gastric mucosal damage, and for first and second-line H. pylori eradication therapy.
Study Details
The study included 1,046 treatment-naive patients who had dyspepsia, a recent or new diagnosis of a nonbleeding peptic ulcer, a history of a peptic ulcer, or long-term stable use of an NSAID. Patients were randomized to PPI-based triple therapy (lansoprazole, amoxicillin, clarithromycin), vonoprazan triple therapy (plus amoxicillin, clarithromycin), or vonoprazan dual therapy (amoxicillin). The treatment period was 14 days, followed by 13C urea breath test (UBT) 4 weeks after treatment.
The researchers conducted several analyses, including: Modified intention-to-treat analyses, which included all enrollees; per protocol analyses, which included patients who took at least 75% of each study medication and underwent 13C UBT in the expected time frame; and a safety population of all patients who took at least one study drug.
Among patients with H. pylori strains that were not resistant to clarithromycin, the PPI-based triple-therapy group had an eradication rate of 78.8%, compared with 84.7% in the vonoprazan triple-therapy group (P < .0001), and 78.5% in the vonoprazan dual-therapy group (P = .0037). In the per protocol analysis, PPI-based triple therapy eradicated H. pylori 82.1% of the time, compared with 90.4% in the vonoprazan triple-therapy group (P < .0001) and 81.2% in the vonoprazan dual-therapy group (P = .0077). Both vonoprazan treatment groups were noninferior to PPI-based triple therapy.
A prespecified exploratory analysis found that vonoprazan triple therapy outperformed PPI-based triple therapy in the modified intention-to-treat population (P = .0408) and the per protocol population (P = .0059).
Among patients with clarithromycin-resistant strains of H. pylori, in the modified intention-to-treat population, 31.9% achieved eradication with PPI triple therapy, compared with 65.8% in the vonoprazan triple-therapy group, and 69.6% in the vonoprazan dual-therapy group. In the per protocol population, the numbers were 29.0% versus 67.2% and 79.5%, respectively (P < .0001 for both versus PPI triple therapy).
Among all patients, in the modified intention-to-treat population, 68.5% achieved eradication with PPI triple therapy, 80.8% with vonoprazan triple therapy (P =. 0001), and 77.2% with vonoprazan dual therapy (P = .0063)*. In the per protocol population, the numbers were 70.0%, 85.7% (P < .0001), and 81.1% (P = .0013), respectively.
Safety outcomes were similar among the three groups, with treatment-emergent adverse events occurring in 34.5% of the PPI triple-therapy group (1.2% discontinued), 34.1% of the vonoprazan triple-therapy group (2.3% discontinued), and 29.9% in the vonoprazan dual-therapy group (0.9% discontinued).
Fighting Against Resistance
The efficacy of PPI-based clarithromycin-based triple therapy has fallen below 80% in the United States and Europe over the past few decades, largely because of antibiotic resistance, said William Chey, MD, during a presentation of the results at the annual meeting of the American College of Gastroenterology. Chey is a professor of medicine and director of the GI physiology laboratory at Michigan Medicine.
Vonoprazan is more stable in acid than are PPIs, and produces greater and more durable acid reduction, according to Chey. That’s important for two reasons: One is that some antibiotics are acid-labile, and so may have their efficacy directly impacted in a more acidic environment. The other factor is that most antibiotics work better on bacteria that are actively replicating, and H. pylori reproduces better in a more neutral environment. “So, you increase the replication, you increase the bioavailability of the antibiotics. And therefore, hopefully, that underlies why we see it working better in the patients with [antibiotic] resistance,” Chey said in an interview.
It remains to be seen whether or not the drug will receive FDA approval, but he pointed to other regimens like bismuth quadruple therapy and rifabutin-based triple therapy that are already available. “If I had the choice, I would never use a PPI-based triple therapy again. People should not be doing that,” said Chey.
“More successful H. pylori eradication regimens are certainly needed, and these results are particularly relevant and interesting given the increasing failure of initial treatment regimens,” said Kimberly Harer, MD, who moderated the session. She noted that the secondary analysis of patients with clarithromycin-resistant infections was particularly relevant. “The superiority analysis indicating vonoprazan triple therapy resulted in increased H. pylori eradication compared to lanzoprazole triple therapy was especially interesting,” said Harer, who is a clinical lecturer at University of Michigan Health, Ann Arbor.
One downside to the study is that it didn’t compare vonoprazan combinations to quadruple therapy of a PPI, bismuth, tetracycline, and a nitroimidazole, said Joseph Jennings, MD, who was asked to comment on the study. Other treatment approaches include sequential antibiotics and other combinations. Jennings also highlighted the findings that the vonoprazan regimens were superior against clarithromycin-resistant strains. “The more different regimens we can add to the armamentarium, the better chance we have because the resistant patterns fluctuate all throughout the world,” said Jennings, who is an assistant professor of medicine at Georgetown University and director of the center for GI bleeding at MedStar Georgetown University Hospital, both in Washington.
He also pointed out that physicians can face a conundrum when patients fail multiple lines of therapy and have testing done that shows high levels of resistance. Some have allergies that prevent them from turning to other antibiotics. “That’s a market where lots of doctors struggle. Something like this would be a nice add-on,” said Jennings.
The study was funded by Phathom Pharmaceuticals.** Chey has consulted and/or received research support from Abbvie, Alfasigma, Allakos, Alnylam, Bayer, Bioamerica, Cosmo, Intrinsic Medicine, Ironwood, Modify Health, My GI Health, My Nutrition Health, Nestle, Phathom Pharmaceuticals, QOL Medical, Redhill, Salix/Valeant, Takeda, Urovant, and Vibrant. Harer and Jennings have no relevant financial disclosures.
*Correction, 10/29/21 : An earlier version of this article misstated the percentage of patients in the modified intention-to-treat population who achieved eradication with vonoprazan triple therapy.
**Correction, 10/29/21: An earlier version of this article misstated the name of Phathom Pharmaceuticals.
This story originally appeared on MDedge.com, part of the Medscape Professional Network.