GI-Safer Naproxen Formulation R&D for the Treatment of Osteoarthritis and Related

摘要：本申请为I/ II期快速通道SBIR申请。骨关节炎（OA）是由关节退行性变引起的关节疼痛和功能障碍的临床综合征，比任何其他关节疾病影响更多的人。没有一贯有效的方法来预防骨性关节炎或减缓其进展，因此对症治疗代表了标准的护理，其基础是非甾体抗炎药（NSAIDs）。此类OA治疗不仅需要考虑胃肠道（GI）风险，还需要考虑心血管（CV）风险；同时作用于环氧化酶-1 （COX-1）和COX-2的非选择性非甾体抗炎药普遍会增加胃肠道损伤的风险，而几乎所有非甾体抗炎药，尤其是选择性COX-2抑制剂，已被证明会增加严重心血管事件的风险。罗非昔布和伐地昔布从市场上的退出扩大了对CV和GI风险最小的非甾体抗炎药的持续需求。萘普生已成为大多数轻/中度慢性炎症适应症（包括OA）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CV安全性，但众所周知，它会诱发胃肠道毒性，有时会危及生命。本次资助申请中提出的活动旨在推进一种新的萘普生制剂（naproxen - pc），该制剂不仅通过非cox机制提高萘普生的GI安全性，而且与萘普生相比，还可能增强抗炎活性。萘普生-PC通过与表面活性磷脂，即磷脂酰胆碱（PC）的非共价预结合，增加非甾体抗炎药的亲脂性，从而提高GI安全性。这种油基配方的pc相关萘普生（萘普生- pc）在啮齿类动物模型中具有显著降低的胃肠道毒性（约85%），同时保留了未改性萘普生的有效性和一般安全性。最近，研究人员开发了新的方法来分析关节炎症模型中的生物活性脂质，包括环氧化酶（COX）和脂氧化酶（LOX）的产物。初步数据分析了一系列生物活性脂质，表明萘普生- pc可能具有增强的抗炎功效，反映在减少促炎二十烷酸(包括前列腺素E2 (PGE2)，白三烯B4 (LTB4)， 12-羟基二十烷四烯酸（12- hete）和5-HETE)，同时保留抗炎二十烷酸（13-羟基十八烷二烯酸（13- hode）），在啮齿动物关节炎症模型中，与未修饰的萘普生相比。这项快速通道SBIR申请的主要目的是确认上述初步数据，继续和扩大萘普生- pc的开发并启动临床研究。在I期，初始活动将侧重于扩大和确认在动物模型中看到的萘普生- pc增强的抗炎活性。此外，我们建议与一家商业制造商合作，优化萘普生- pc的实验室配方，使其可以软胶囊化并用于临床试验。该优化产生的几个主要原型将被确定为具有商业可行性，这些原型将在已建立的动物模型中进行GI安全性和镇痛和抗炎功效终点的测试。这些实验的结果将允许选择一个单一的，有效的萘普生- pc先导配方。在II期，先导制剂将按照监管标准生产250毫克的萘普生- pc凝胶帽，进一步测试其稳定性，然后进入临床试验。首先，将在健康志愿者中完成一项单剂量生物等效性（BE）研究，比较萘普生- pc与未修饰的萘普生；该药代动力学研究将为FDA通过加速的505(b)(2)监管途径批准萘普生-PC提供BE数据，并提供萘普生-PC的系统安全性数据。然后，在55岁或以上的骨关节炎患者服用500 mg萘普生- pc或萘普生BID 12周后，将进行一项比较概念验证临床试验，检查镇痛疗效、一般安全性和胃肠道溃疡发生率，内镜下评估。该资助提案中包含的开发活动将显著推进萘普生- pc的商业化开发。如果在随后的验证性临床试验中显示，与萘普生相比，萘普生- pc配方具有改善的GI安全性，以及相同的镇痛和可能更好的抗炎功效，它将代表骨关节炎和相关慢性炎症性疾病患者的重要新治疗方法。几乎所有目前可用的非甾体抗炎药（NSAIDs），包括萘普生、布洛芬和阿司匹林，都会造成严重的胃肠道损伤，每年导致大量住院和死亡。与此同时，数百万美国人需要每天接受关节炎和相关疾病的治疗。这项拨款申请是为了允许继续开发萘普生- pc，这是一种新的萘普生配方，即使反复服用也能显著减少胃肠道损伤。萘普生已成为反复使用的非甾体抗炎药的选择，包括治疗骨关节炎，因为与几乎所有其他非甾体抗炎药不同，它不会增加心脏病发作、中风或其他心血管事件的可能性。

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 joint 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 treatments 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, especially 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 toxicity 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 bioactive 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 reflected 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 clinical 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 formulation 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 models 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 Naproxen-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 volunteers; 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 systemic safety of Naproxen- PC. Then, a comparative proof-of-concept clinical trial will be conducted examining analgesic efficacy, general safety and the incidence of gastrointestinal ulcers, assessed endoscopically, in patients with osteoarthritis aged 55 years or older, following administration of 500 mg Naproxen-PC or naproxen BID for 12 weeks. The development activities encompassed in this grant proposal will significantly advance the Naproxen-PC development toward commercialization. If the Naproxen-PC formulation is shown in subsequent confirmatory clinical trials to possess an improved GI safety profile, together with equivalent analgesic and perhaps superior anti-inflammatory efficacy compared with naproxen, it will represent an important new treatment for patients with osteoarthritis and related chronic inflammatory diseases. PUBLIC HEALTH RELEVANCE Nearly all currently available non-steroidal anti-inflammatory drugs (NSAIDs), including naproxen, ibuprofen, and aspirin, cause significant GI damage, which results in a large number of hospitalizations and deaths annually. At the same time, many millions of Americans need daily treatment for arthritis and related conditions. This grant request is to allow the continued development of Naproxen-PC, a new formulation of naproxen that significantly reduces GI injury, even when taken repeatedly. Naproxen has become the NSAID of choice for repeated administration, including in the treatment of osteoarthritis, because unlike almost all other NSAIDs, it doesn't increase the possibility of heart attack, stroke, or other cardiovascular events.