Clinical Evaluation of GI Safer Naproxen for the Treatment of Osteoarthritis

描述（由申请人提供）：PLx Pharma Inc.正在开发非甾体抗炎药（NSAIDs）的配方，该制剂可降低对胃肠道（GI）粘膜造成损伤的风险。挑战：慢性疼痛患者需要在不增加心血管疾病或胃肠道毒性风险的情况下有效缓解疼痛的药物。目前骨关节炎（OA）和其他慢性疼痛和炎症疾病的护理标准不仅需要考虑胃肠道（GI）风险，还需要考虑心血管（CV）风险，因为几乎所有非甾体抗炎药（NSAIDs），特别是选择性环氧化酶-2 （COX- 2）抑制剂，已被证明会增加严重心血管事件的风险。萘普生已成为大多数轻/中度慢性炎症适应症的首选非甾体抗炎药，因为它似乎很少或没有增加心血管不良事件的风险。然而，尽管萘普生具有良好的心血管安全性，但众所周知，它会引起严重的胃肠道毒性，在某些情况下甚至会危及生命。方法：使用基于磷脂的给药系统，提高一种有效的、心脏中性的非甾体抗炎药萘普生的胃肠道安全性。这款名为naproxen -PC （pl3100）的口服药物旨在通过非cox机制，通过与表面活性磷脂（即磷脂酰胆碱（PC））的非共价预结合，增加萘普生的亲脂性，从而提高萘普生的GI安全性。这项RC3拨款申请的主要目的是通过对萘普生- pc与标准处方剂量的萘普生进行GI安全性的临床内镜评估，继续开发萘普生- pc。具体目的：完成一项II期随机、主动对照、平行设计、概念验证的临床试验，在55岁或以上的健康志愿者中，在给予500mg萘普生pc或萘普生BID 14天后，通过内窥镜评估胃十二指肠粘膜损伤的发生率。拟议的概念验证研究是对萘普生- pc在人体中的GI安全性的首次评估，并将比较萘普生- pc与处方抗炎剂量萘普生的GI安全性。该产品目前在资金方面处于“死亡之谷”；合作需要对该产品的GI保护能力进行临床评估（以及随之而来的大量投资），但目前的资金环境限制了可用于资助拟议研究的资金。RC3授权机制将允许PLx跨越这个死亡之谷。如果与萘普生相比，萘普生- pc制剂具有更好的胃肠道安全性和相同的镇痛和抗炎功效，它将成为数百万骨关节炎和相关慢性炎症性疾病患者的重要新药。

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.