Pozen Initiates New Phase III - Analyst Blog

This morning, Pozen (POZN) initiated phase III studies on PA-325/40, a fixed-dose combination of 325mg enteric coated aspirin and 40mg of immediate release omeprazole. The phase III program will consist of two pivotal trials conducted under a Special Protocol Assessment (SPA) agreed upon with the U.S. FDA, and one long-term safety study.

The two pivotal programs will enroll approximately 500 patients per study at over 100 sites around the U.S. The primary endpoint of the pivotal studies is the cumulative incidence of gastric ulcers over the six-month treatment period for PA32540 versus 325 mg of enteric-coated aspirin. The long-term study will enroll approximately 400 patients and assess safety over a period of one year.

Pozen is developing PA-325/40 for use in the secondary prevention of heart attacks and strokes in patients at risk for associated gastric ulcers. Aspirin is the No. 1 recommended agent for at-risk patients, with some 50 million Americans take daily aspirin therapy for secondary prevention of heart attacks and strokes.

However, according to data presented at the American College of Gastroenterology and at the American Heart Association meeting, the use of low-dose aspirin for cardiovascular disease prophylaxis is associated with a 2- to 4-fold increase in gastro-intestinal (GI) complications, including gastric ulcers. Enteric coating is not a sufficient to reduce the risk of GI bleeding, and thus the majority of patients that should be taking 325mg aspirin are non-compliant or taking suboptimal low-dose (81mg) "baby" aspirin instead.

Pozen’s PA-325/40 is designed to provide immediate-release omeprazole as a GI-protectant for patients taking full-dose 325mg daily aspirin therapy. If the phase III trials meet the primary endpoint of reduction in cumulative incidence of gastric ulcers, we expect PA-325/40 to be approved by the U.S. FDA with the full cardiovascular label claims of regular enteric-coated aspirin. This is a significant market opportunity in our view, considering less than 15% of the 50 million Americans on daily aspirin therapy are taking a GI-protectant such as omeprazole.

Recently, data from a retrospective analysis of patients that use Sanofi-Aventis (SNY) / Bristol-Myers’ (BMY) Plavix (clopidogrel) showed an increased risk of major adverse cardiovascular events (MACE) by as much as 50% while taking a proton pump inhibitor (PPI) such as AstraZeneca’s (AZN) omeprazole (Prilosec) or esomeprazole (Nexium). The data included analysis of outcomes from 16,700 patients who underwent percutaneous coronary intervention and continued Plavix for 12 months after the procedure.

Approximately 9,900 were not given a PPI at any time during Plavix treatment and 6,800 were given overlapping PPI therapy. The analysis showed a 12-month MACE event rate of about 25% among PPI users, compared with 18% of patients who were not given PPI (MACE hazard ratio of 1.50 for PPI users versus nonusers).

The current Plavix label discourages use of a PPI due to this potential limiting effect on the drug’s effectiveness. The majority of Plavix use for secondary prevention of heart attacks and strokes is with enteric-coated aspirin.

Strengthening this label warning by the U.S. FDA could work to greatly limit the potential uptake for Pozen’s PA-325/40 product. However, we note the retrospective analysis that potentially showed a reduced effectiveness for Plavix while on a PPI was with commercially available delayed release PPIs dosed at the same time as taking Plavix. Pozen is currently conducting a drug-drug interaction study with their immediate release omeprazole doses both at the same time and 12 hours apart from Plavix.

The omeprazole used in PA-325/40 is an immediate release formulation, not the commercially available delayed-release found in Prilosec or Nexium. We suspect that dosing an immediate release omeprazole 12 hours apart (say at night) from Plavix (in the morning) will dramatically reduce the potential negative interactions between the two drugs.

We are optimistic on the development plans for PA-325/40. Besides the potential use as a secondary preventative agent for cardiovascular disease, significant literature exists showing a potential reduction in risk for developing precancerous adenomas on high-dose aspirin regimen.

Four separate government-funded randomized controlled trials concluded that aspirin is a benefit in the prevention of adenomas and significantly reduces the risk of colon cancer. However, the dangerous GI tolerability has greatly limited large outcome-based clinical studies or wide-spread use of high-dose aspirin in colon cancer prevention. We believe that Pozen’s PA-325/40, and phase II PA-650/40, have the potential to be a game-changer with respect to colon cancer prevention. This also helps mitigate the potential downside risk to pushing forward with development despite the recent negative Plavix/PPI headlines.
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