Clinical Evaluation of GI Safer Naproxen for the Treatment of Osteoarthritis

胃肠道更安全的萘普生治疗骨关节炎的临床评价

• 批准号: 7925188
• 负责人: Upendra Marathi
• 金额: $ 79.86万
• 依托单位: PLX OPCO, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925188
• 关键词: Acute; Adult; Adverse event; Age; Anti Inflammatory Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Arthritis; Capital; Cardiovascular system; Cessation of life; Chronic; Chronic Disease; Clinical; Clinical Research; Clinical Trials; Clinical assessments; Coxibs; Data; Degenerative polyarthritis; Development; Disease; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Endoscopy; Environment; Evaluation; Event; Funding; Gelatin; Grant; Health Care Costs; Human; Incidence; Inflammation; Inflammatory; Injury; Investigational New Drug Application; Investments; Lecithin; Life; Mucous Membrane; Naproxen; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Non-Steroidal Anti-Inflammatory Agents; Oral; PTGS2 gene; Pain; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phospholipids; Randomized; Research Design; Risk; Rodent; Safety; Small Business Innovation Research Grant; Study Subject; Surface; Testing; Therapeutic Equivalency; Toxic effect; Ulcer; United States Food and Drug Administration; arm; base; capsule; cardiovascular disorder risk; cardiovascular risk factor; celecoxib; chronic pain; comparative effectiveness; comparative efficacy; cyclooxygenase 2; design; effectiveness research; gastrointestinal; healthy volunteer; improved; inhibitor/antagonist; lipophilicity; non-drug; programs; public health relevance; research clinical testing; safety study; standard of care

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.

描述(申请人提供)：PLX制药公司正在开发非类固醇抗炎药(NSAIDs)的配方，这种制剂降低了对胃肠道(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的情况下提供有效缓解疼痛的药物。目前对骨关节炎(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，因为几乎所有非类固醇抗炎药(NSAIDs)，特别是选择性环氧合酶-2(COX-2)抑制剂，都被证明增加了严重CV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非甾体抗炎药的选择，因为它似乎很少或没有增加心血管不良事件的风险。然而，尽管它具有良好的心血管安全性，但众所周知，萘普生会导致严重的胃肠道毒性，在某些情况下甚至危及生命。方法：使用基于磷脂的药物传递系统，提高有效的非甾体抗炎药--非甾体抗炎药-的胃肠道安全性。这种名为NAPROXEN-PC(PL 3100)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)的非共价预结合来增加NAPROXen的脂亲性，从而提高NAPROXN的胃肠道安全性。这项RC3资助申请的主要目标是通过进行临床内窥镜评估标准处方剂量的NAPROXEN-PC与NAPROXEN相比的胃肠道安全性来继续开发NAPROXEN-PC。具体目的：完成一项随机、积极对照、平行设计、概念验证的II期临床试验，评估在55岁或55岁以上的健康志愿者中服用500毫克萘普生-PC或萘普生BID 14天后胃十二指肠黏膜损伤的发生率。这项拟议的概念验证研究是对萘普生-PC在人体中的胃肠道安全性的第一次评估，并将比较在处方抗炎剂量下NAPROXEN-PC和NAPROXEN的胃肠道安全性。就资金而言，该产品目前处于“死亡谷”；合作需要对该产品的胃肠道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奖励机制将允许PLX跨越这个死亡之谷。如果与萘普生相比，NAPROXEN-PC制剂具有更好的胃肠道安全性，具有同等的止痛和抗炎效果，它将代表着一种重要的新药，用于治疗数百万骨关节炎和相关的慢性炎症性疾病患者。 公共卫生相关性：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提供有效止痛的药物。萘普生已成为大多数轻/中度慢性炎症适应症的非甾体抗炎药的选择，因为它似乎很少或没有增加心血管不良事件的风险。然而，尽管它具有良好的心血管安全性，但众所周知，萘普生会导致严重的胃肠道毒性，在某些情况下甚至危及生命。一种名为NAPROXEN-PC(PL 3100)的口服药物产品正在开发中，该产品使用一种名为磷脂酰胆碱(PC)的天然衍生磷脂，使用非药物机制来提高NAPROXen的胃肠道安全性。这项RC3拨款申请的目的是进行一项临床评估，将标准处方剂量下的NAPROXEN-PC与NAPROXEN进行比较。这项拟议的概念验证研究是对萘普生-PC在人体中的胃肠道安全性的第一次评估，并将比较在处方抗炎剂量下NAPROXEN-PC和NAPROXEN的胃肠道安全性。就资金而言，该产品目前处于“死亡谷”；合作需要对该产品的胃肠道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奖励机制将允许PLX跨越这个死亡之谷。如果与萘普生相比，NAPROXEN-PC制剂具有更好的胃肠道安全性，具有同等的止痛和抗炎效果，它将代表着一种重要的新药，用于治疗数百万骨关节炎和相关的慢性炎症性疾病患者。