GI-Safer Naproxen Formulation RandD for the Treatment of Osteoarthritis and Related

DESCRIPTION (provided by applicant): ABSTRACT: This application is a Phase I/Phase II Fast-Track SBIR application. Osteoarthritis (OA), the clinical syndrome of joint pain and dysfunction caused by joint degeneration, affects more people than any other joi nt disease. There are no consistently effective methods for preventing OA or slowing its progression, and so symptomatic treatments represent the standard of care, the foundation of which are the non-steroidal anti-inflammatory drugs (NSAIDs). Such treatme nts for OA require consideration of not only gastrointestinal (GI) risk, but also cardiovascular (CV) risk; non-selective NSAIDs acting on both cyclooxygenase-1 (COX-1) and COX-2 universally increase the risk of GI injury, whereas nearly all NSAIDs, especi ally the selective COX-2 inhibitors, have been shown to increase the risk of serious CV events. The withdrawal of rofecoxib and valdecoxib from the market amplify the continuing need for an NSAID with minimal CV and GI risks. Naproxen has become the NSAID of choice for most mild/moderate chronic inflammatory indications, including OA, 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 GI t oxicity that is sometimes life-threatening. The activities proposed in this grant application are intended to advance a new naproxen formulation (Naproxen-PC) that not only improves the GI safety of naproxen using a non-COX mechanism, but also may enhance anti-inflammatory activity compared with naproxen. Naproxen-PC improves GI safety by increasing the lipophilicity of the NSAID via non- covalent pre-association with a surface-active phospholipid, namely phosphatidylcholine (PC). This oil-based formulation of PC-associated naproxen (Naproxen-PC) has been shown in rodent models to have remarkably lower (~85%) GI toxicity, while retaining the efficacy and general safety profile of unmodified naproxen. Recently, novel methods have been developed to profile bio active lipids in a model of joint inflammation, including products of both cyclooxygenase (COX) and lipoxygenase (LOX). Preliminary data assaying a range of bioactive lipids suggests that Naproxen-PC may have enhanced anti-inflammatory efficacy, as reflect ed in the attenuation of pro-inflammatory eicosanoids (including prostaglandin E2 (PGE2), leukotriene B4 (LTB4), 12- hydroxyeicosatetraenoic acid (12-HETE), and 5-HETE), while sparing anti-inflammatory eicosanoids (13- hydroxyoctadecadienoic acid (13-HODE) ), compared with unmodified naproxen, in a rodent model of joint inflammation. The major objective of this Fast-Track SBIR application is to confirm the preliminary data described above and continue and expand the development of Naproxen-PC and initiate cl inical studies. In Phase I, initial activities will focus on expanding and confirming the enhanced anti-inflammatory activity of Naproxen-PC seen in animal models. Also, in partnership with a commercial manufacturer, we propose to optimize the laboratory f ormulation of Naproxen-PC so that it may be softgel encapsulated and manufactured for clinical trials. Several lead prototypes resulting from this optimization will be identified that appear commercially viable, which will be tested in established animal m odels with both GI safety and analgesic and anti-inflammatory efficacy endpoints. The results of these experiments will allow selection of a single, validated lead Naproxen-PC formulation. In Phase II, the lead formulation will be manufactured as 250 mg Na proxen-PC gelcaps according to regulatory standards, further tested for stability, then advanced into clinical trials. Initially, a single-dose bioequivalence (BE) study, comparing Naproxen-PC with unmodified naproxen, will be completed in healthy voluntee rs; this pharmacokinetics study will provide BE data for Naproxen-PC FDA approval via the accelerated 505(b)(2) regulatory route, and provide data on the sy