New Combination Drug Improves Gastroprotection, Adherence Compared With EC Naproxen Alone

Deborah Brauser

November 06, 2009

November 6, 2009 (San Diego, California) — PN400 (Vimovo, Pozen Inc, AstraZeneca), an investigational drug consisting of immediate-release esomeprazole 20 mg and enteric-coated (EC) naproxen 500 mg, reduces the incidence of nonsteroidal anti-inflammatory drug (NSAID)–associated gastric ulcers for patients on long-term NSAID maintenance therapy who are at risk, according to 2 phase 3 studies presented here at the American College of Gastroenterology 2009 Annual Scientific Meeting.

PN400 improves upper gastrointestinal (UGI) tolerability, including dyspepsia, better than EC naproxen alone, which may help lower the rate of NSAID discontinuance resulting from UGI adverse events (AEs) and/or duodenal ulcers, announced lead investigator Jay Goldstein, MD, professor of medicine at the University of Illinois at Chicago, during his presentation of the results in a podium session.

"[UGI] tolerability and patient satisfaction are important issues that impact persistence with prescribed chronic NSAID therapy," Dr. Goldstein pointed out.

"Patients who take NSAIDs chronically often stop because they can't tolerate the side effects," Dr. Goldstein later explained to Medscape Gastroenterology. "By ensuring the fixed combination delivery of an agent that would help reduce those symptoms, people can take their medication with fewer symptoms and for a longer period of time."

2 Phase 3 Studies Conducted

In their 2 multicenter studies, Dr. Goldstein and his team enrolled 854 Helicobacter pylori–negative patients (study A, n = 434; study B, n = 420) requiring chronic NSAID therapy and deemed "at risk for ulcers." This meant that they were either 18 to 49 years old with a history of gastric or duodenal ulcers within the past 5 years or were 50 years of age or older.

Patients were randomly assigned to either PN400 twice daily (study A, n = 218; study B, n = 210) or twice-daily EC naproxen alone (study A, n = 216; study B, n = 210) for a total of 6 months.

The primary endpoint for both studies was the incidence of gastric ulcers. UGI tolerability endpoints were secondary and consisted of changes from baseline in patient-reported Severity of Dyspepsia Assessment scores and Overall Treatment Evaluation of Dyspepsia ratings.

In addition, the investigators also examined the discontinuation rate resulting from NSAID-associated UGI AE.

PN400 Significantly Reduced UGI Symptoms

At the end of the 6-month treatment period, "the cumulative incidence of gastric ulcers was significantly lower in the PN400 groups in both studies," reported Dr. Goldstein.

In addition, both PN400 study groups reported significantly improved Severity of Dyspepsia Assessment scores in pain intensity (P < .001 and P = .004, respectively), nonpain symptoms (P < .001 and P < .001), and satisfaction (P < .001 and P = .003) compared with patients taking EC naproxen alone.

The groups treated with PN400 also reported higher Overall Treatment Evaluation of Dyspepsia ratings, at 45.6% and 42.9%, compared with 27.8% and 34.4% for those treated with just EC naproxen. PN400-treated patients also had fewer overall AEs, including erosive gastritis, erosive duodenitis, and dyspepsia.

"This was especially important because when we asked the patients if symptoms of dyspepsia were important to them, over 80% said yes," said Dr. Goldstein. "I think that really speaks volumes for these types of studies."

Finally, there was significantly less discontinuation resulting from UGI AEs and/or duodenal ulcers in the PN400 groups when compared with the EC naproxen groups at 3.2% and 8% vs 12.0% and 11.0% (P < .001 and P = .009, respectively).

"Our data suggest that optimizing adherence to gastroprotection may improve NSAID tolerability and may result in sustained use," said Dr. Goldstein. "And based on its formulation, PN400 may provide a treatment option for at-risk patients and clinically impact long-term NSAID therapy."

When asked why a patient should not just take 2 over-the-counter medications, Dr. Goldstein replied that, "The issue with taking 2 therapies is that it always requires patient adherence and their persistence in using the medication correctly and longitudinally. With this 1 tablet, if you take your pain pill, you're also taking your protecting agent.

"I think the main point of the study is that clinicians need to listen to their patients about how they are using their medications, what is blocking their use of medications, and how [clinicians] should optimally educate patients about the side effects and the importance of medication use," said Dr. Goldstein.

He concluded, "We're taking a step forward in focusing on what patients don't do well and trying to improve on it. This, coupled with patient education, may lead to better outcomes and better patients."

Will Help with NSAID Adherence

"I think the beauty of this study is that it's a combination of 2 large phase 3 studies that looked at a novel agent that combines a commonly used over-the-counter anti-inflammatory medication with a proton pump inhibitor that is known to decrease toxicity from nonsteroidals and showed a significant decease in the complications and symptoms related to nonsteroidals," said session moderator Carol A. Burke, MD, gastroenterologist and director of the Center for Colon, Polyp, and Cancer Prevention at the Cleveland Clinic Foundation in Ohio, to Medscape Gastroenterology. Dr. Burke was not involved with this study.

"As a gastroenterologist, I know that most patients are taking nonsteroidals on a frequent basis. And many of the individuals that are older with comorbidities are taking aspirin and other medications that can cause an increased risk of complications of ulcers," said Dr. Burke.

She added, "What I like about this particular agent is that it showed a decrease in the risk for ulcers and [UGI] symptoms. This is helpful and something I would recommend to my patients because if I tell them to buy an anti-inflammatory medication as well as another drug to take in addition to that, then my patients will probably say okay and then not take that other medication.

"When they're in pain, they're going to be driven by their symptoms from their arthritis or muscle problems or whatever and they're going to forget that they need to take something to keep them from getting a complication related to their use of anti-inflammatory medications.

"So, I think this is a novel agent and I just hope that when it becomes available, that it is competitively priced for our patients," Dr. Burke concluded.

This study was supported by Pozen and AstraZeneca. Dr. Goldstein has disclosed research grants, consulting fees, and speaker's bureau fees from Pfizer, AstraZeneca, TAP, Novartis, Pozen, and Takeda/Sucampo; research grants and consulting fees from GlaxoSmithKline and Logical Therapeutics; and consulting fees only from Given, Merck, Amgen, Astellas Pharma US, PLX, and Proctor & Gamble. Dr. Burke has disclosed no relevant financial relationships.

American College of Gastroenterology 2009 Annual Scientific Meeting: Abstract 12. Presented October 26, 2009.