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（由申请人提供）：PLX Pharma Inc.正在开发非甾体类抗炎药（NSAIDS）的制剂，这些抗炎药（NSAID）降低了胃肠道（GI）粘膜损伤的风险。挑战：慢性疼痛的患者需要药物可提供有效的疼痛，而不会增加心血管疾病或胃肠道毒性的风险。目前对骨关节炎（OA）的护理标准以及其他疼痛和炎症的慢性疾病不仅需要考虑胃肠道（GI）风险，而且还需要心血管（CV）风险，因为几乎所有非甾体类抗炎性药物（NSAID）几乎所有非甾体类抗炎性药物（NESAID），尤其是在选择性的cycloxypose-2）（cox-2）（cox-2）（cox-2）（cox-2）（cox-2）（均为cox-2）。事件。对于大多数温和/中度的慢性炎症适应症，萘普生已成为选择的NSAID，因为它似乎几乎没有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CV安全性，但众所周知，萘普生会引起严重的诱因，在某些情况下，威胁生命的胃肠道毒性。该方法：使用基于磷脂的药物输送系统，提高有效的，心脏的NSAID（萘普生）的胃肠道安全性。这种称为Naproxen-PC（PL 3100）的口服药物旨在通过使用非共价磷脂的磷脂前磷脂（即，磷脂型磷脂基胆碱（PC））提高萘普生的亲脂性来提高萘普生的胃肠道安全性。该RC3赠款应用的主要目的是通过标准处方剂量进行纳普罗克森PC的GI安全性进行临床内镜评估来继续开发Naproxen-PC。具体目的：完成II期随机，主动控制的，平行设计的，概念证明的临床试验，评估了胃duo粘粘膜损伤的发生率，如内窥镜检查，在55岁或更老的健康志愿者中，在500 mg Naproxen-PC或Naproxen-PC或Naproxen bid bid 14天后。拟议的概念证明研究是对人类中萘普生PC的GI安全性的首次评估，并将在处方抗炎剂量下比较萘普生PC与拿破仑的GI安全性。该产品目前居住在资金的“死亡谷”中；合作需要对该产品的GI保护能力进行临床评估（以及将伴随它的大量投资），但是当前的资金环境限制了为拟议研究提供资金的资本。 RC3赠款机制将允许PLX跨越这个死亡山谷。与萘普生相比，如果萘普生-PC制剂具有改善的胃肠道安全性，具有等效性镇痛和抗炎功效，它将代表着数百万骨关节炎和相关慢性炎性疾病的重要新药。 公共卫生相关性：慢性疼痛的患者需要药物可提供有效的疼痛，而不会增加心血管疾病或胃肠道毒性的风险。对于大多数温和/中度的慢性炎症适应症，萘普生已成为选择的NSAID，因为它似乎几乎没有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CV安全性，但众所周知，萘普生会引起严重的诱因，在某些情况下，威胁生命的胃肠道毒性。正在开发一种称为Naproxen-PC（PL 3100）的口服药物，以使用非药物的机制来提高萘普生的胃肠道安全性，并使用称为磷脂酰胆碱（PC）的自然衍生的磷脂。该RC3赠款应用的目的是对萘普生PC的GI安全性进行临床评估，而萘普生则以标准处方剂量进行临床评估。拟议的概念证明研究是对人类中萘普生PC的GI安全性的首次评估，并将在处方抗炎剂量下比较萘普生PC与拿破仑的GI安全性。该产品目前居住在资金的“死亡谷”中；合作需要对该产品的GI保护能力进行临床评估（以及将伴随它的大量投资），但是当前的资金环境限制了为拟议研究提供资金的资本。 RC3赠款机制将允许PLX跨越这个死亡山谷。与萘普生相比，如果萘普生-PC制剂具有改善的胃肠道安全性，具有等效性镇痛和抗炎功效，它将代表着数百万骨关节炎和相关慢性炎性疾病的重要新药。