Clinical Evaluation of GI Safer Naproxen for the Treatment of Osteoarthritis

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DESCRIPTION (provided by applicant): PLx Pharma Inc. is developing formulations of non-steroidal anti-inflammatory agents (NSAIDs) that have a reduced risk of causing injury to the gastrointestinal (GI) mucosa. The Challenge: Patients in chronic pain require medication that provides effective pain relief without increasing the risk of cardiovascular disease or gastrointestinal toxicity. The current standard of care for osteoarthritis (OA) and other chronic disorders of pain and inflammation requires consideration of not only gastrointestinal (GI) risk, but also cardiovascular (CV) risk, as nearly all non-steroidal anti-inflammatory drugs (NSAIDs), especially the selective cyclooxygenase-2 (COX- 2) inhibitors, have been shown to increase the risk of serious CV events. Naproxen has become the NSAID of choice for most mild/moderate chronic inflammatory indications, as it appears to have little or no increased risk of cardiovascular adverse events. However, in spite of its favorable CV safety profile, naproxen is well known to induce serious, and in some cases life-threatening, GI toxicity. The Approach: Improve the GI safety of an efficacious, cardioneutral NSAID, naproxen, using a phospholipid-based drug delivery system. This oral drug product, called Naproxen-PC (PL 3100), is intended to improve the GI safety of naproxen using a non-COX mechanism, by increasing the lipophilicity of naproxen via non-covalent pre-association with a surface-active phospholipid, namely phosphatidylcholine (PC). The major objective of this RC3 grant application is to continue the development of Naproxen-PC by conducting a clinical endoscopic assessment of the GI safety of Naproxen-PC compared with naproxen at a standard prescription dose. Specific Aim: Complete a Phase II randomized, actively controlled, parallel-design, proof-of-concept clinical trial evaluating the incidence of gastro duodenal mucosal damage, as assessed by endoscopy, in healthy volunteers age 55 or older, following administration of 500 mg Naproxen-PC or naproxen BID for 14 days. The proposed proof-of-concept study is the first evaluation of the GI safety of Naproxen-PC in humans and will compare the GI safety of Naproxen-PC versus naproxen at prescription anti-inflammatory doses. This product currently resides in the "Valley of Death" with respect to funding; the clinical evaluation of the GI protective ability of this product is required for partnering (and the substantial investment that would accompany it), but the current funding environment has limited the capital available to fund the proposed study. The RC3 grant mechanism will allow PLx to span this Valley of Death. If the Naproxen-PC formulation is shown to possess improved GI safety with equivalent analgesic and anti-inflammatory efficacy compared with naproxen, it will represent an important new pharmaceutical for literally millions of patients with osteoarthritis and related chronic inflammatory diseases. PUBLIC HEALTH RELEVANCE: Patients in chronic pain require medication that provides effective pain relief without increasing the risk of cardiovascular disease or gastrointestinal toxicity. Naproxen has become the NSAID of choice for most mild/moderate chronic inflammatory indications, as it appears to have little or no increased risk of cardiovascular adverse events. However, in spite of its favorable CV safety profile, naproxen is well known to induce serious, and in some cases life-threatening, GI toxicity. An oral drug product called Naproxen-PC (PL 3100) is being developed to improve the GI safety of naproxen using a non-pharmaceutical mechanism, using a naturally derived phospholipid called phosphatidylcholine (PC). The objective of this RC3 grant application is to conduct a clinical assessment of the GI safety of Naproxen-PC compared with naproxen at a standard prescription dose. The proposed proof-of-concept study is the first evaluation of the GI safety of Naproxen-PC in humans and will compare the GI safety of Naproxen-PC versus naproxen at prescription anti-inflammatory doses. This product currently resides in the "Valley of Death" with respect to funding; the clinical evaluation of the GI protective ability of this product is required for partnering (and the substantial investment that would accompany it), but the current funding environment has limited the capital available to fund the proposed study. The RC3 grant mechanism will allow PLx to span this Valley of Death. If the Naproxen-PC formulation is shown to possess improved GI safety with equivalent analgesic and anti-inflammatory efficacy compared with naproxen, it will represent an important new pharmaceutical for literally millions of patients with osteoarthritis and related chronic inflammatory diseases.