The Treatment of Methotrexate Resistant Rheumatoid Arthritis With Aminopterin

氨基蝶呤治疗甲氨蝶呤耐药性类风湿性关节炎

• 批准号: 7746965
• 负责人: STUART J KAHN
• 金额: $ 51.86万
• 依托单位: SYNTRIX BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7746965
• 关键词: Adult; Adverse effects; American; Aminopterin; Biological Availability; Biological Response Modifier Therapy; Cells; Chronic; Clinical; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; Development; Disease; Disease remission; Disease-Modifying Second-Line Drugs; Disorientation; Dosage Forms; Dose; Double-Blind Method; Drug Kinetics; Economics; Enrollment; Failure; Fatigue; Feasibility Studies; Folate; Folic Acid Antagonists; Goals; Headache; Healthcare Systems; Human; Individual; Inferior; Inflammatory; Injectable; Intestinal Absorption; Life Expectancy; Liver; Medicine; Memory; Methotrexate; Nausea; Neuraxis; North America; Oral; Outcome; Patients; Pharmaceutical Economics; Pharmaceutical Preparations; Pharmacotherapy; Phase; Placebo Control; Placebos; Population; Randomized; Recombinant Proteins; Reference Standards; Relative (related person); Research Personnel; Resistance; Rheumatoid Arthritis; Rheumatology; Safety; Small Business Innovation Research Grant; Staging; Stomatitis; Structure; Testing; Tissues; Transaminases; Variant; absorption; alternative treatment; base; cost; cost effective; disability; discontinuation trial; disorder control; effective therapy; functional disability; gastrointestinal; improved; irritation; joint destruction; life time cost; meetings; open label; public health relevance; response; standard of care; subcutaneous; uptake

DESCRIPTION (provided by applicant): The long term goal of this project is to develop aminopterin (AMT), an antifolate medication, as an improved treatment for patients with rheumatoid arthritis (RA) and other inflammatory diseases. This application focuses on RA which occurs in ~1% of the population, and is associated with progressive joint destruction, functional disability and decreased life expectancy. Methotrexate (MTX), an antifolate used alone or in combination with other medicines, is the current mainstay and reference standard for RA treatment. Oral MTX, however, is poorly absorbed by many individuals which contribute to ineffective responses in 30-40% of RA patients and remission in only 20%. Furthermore, only half the patients with effective responses tolerate MTX for 5 years because of its side effects. Especially troubling are gastrointestinal and central nervous system side effects that include nausea, stomatitis, liver irritation, headache, fatigue, disorientation and poor memory. Alternative treatments include oral drugs that are more toxic, injectable MTX, or injectable recombinant proteins (biologics) that are very expensive. A well-absorbed oral antifolate that is less toxic would be an important, cost-effective option that sets a new standard for RA treatment. Our clinical trials have established that AMT, which is similar in structure to MTX, has near 100% oral absorption while sparing many of the side effects that involve the gastrointestinal and central nervous systems. Thus, we hypothesize that AMT, compared to MTX, will provide RA patients with better disease control and less side effects. If AMT is effective in patients who fail MTX treatment, then AMT will have important economic consequences by obviating treatments with expensive biologics. Therefore, in this application we propose the AFFORD (Aminopterin First For Rheumatoid Disease) clinical trial. The AFFORD trial investigates if RA patients with inadequate responses to MTX can be treated effectively with AMT. Initially, all enrolled patients receive AMT and subsequently those with an effective response to AMT enter a double-blind stage comparing AMT and placebo-control. The AFFORD trial, in a rapid, cost-effective fashion, will determine if AMT can effectively treat a significant proportion of MTX-resistant RA patients. The trial will use standard criteria to determine safety and efficacy. The specific aims of the AFFORD trial and this SBIR Fast-Track application are to: 1) Evaluate the efficacy of oral AMT in the treatment of MTX-resistant RA patients. 2) Assess the safety of oral AMT in the treatment of MTX-resistant RA patients. Completion of the AFFORD trial will firmly establish if AMT is a safe and effective treatment for MTX- resistant RA patients. For most RA patients MTX is a critical component of their therapy, and the clinical development of a superior antifolate for RA will have a large, positive, and cost-effective impact for millions of RA patients. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is a leading cause of human disability effecting ~1% of the population. Methotrexate, the current mainstay of RA treatment, is both poorly absorbed and tolerated by many individuals contributing to ineffective responses in 30-40% of patients, remission in only 20% and even less effective long term use. This project is developing aminopterin; a better absorbed and tolerated medicine, as an important new cost- effective treatment option for RA.

描述（由申请人提供）：该项目的长期目标是开发氨基蝶呤（AMT），一种抗叶酸药物，作为类风湿关节炎（RA）和其他炎症性疾病患者的改进治疗方法。该应用程序的重点是RA，发生在约1%的人群中，并与进行性关节破坏，功能残疾和预期寿命降低有关。甲氨蝶呤（MTX）是一种抗叶酸剂，单独使用或与其他药物联合使用，是目前治疗RA的主要药物和参考标准。然而，口服MTX被许多个体吸收不良，这导致30-40%的RA患者无效反应，仅20%缓解。此外，由于副作用，只有一半有效反应的患者耐受MTX 5年。特别令人不安的是胃肠道和中枢神经系统的副作用，包括恶心，口腔炎，肝刺激，头痛，疲劳，定向障碍和记忆力差。替代治疗包括毒性更大的口服药物，注射MTX或非常昂贵的注射重组蛋白（生物制剂）。一种吸收良好的口服抗叶酸剂，毒性较小，将是一个重要的，具有成本效益的选择，为RA治疗制定了新的标准。我们的临床试验已经确定，AMT在结构上与MTX相似，具有接近100%的口服吸收，同时保留了许多涉及胃肠道和中枢神经系统的副作用。因此，我们假设AMT与MTX相比，将为RA患者提供更好的疾病控制和更少的副作用。如果AMT对MTX治疗失败的患者有效，那么AMT将通过避免昂贵的生物制剂治疗而产生重要的经济后果。因此，在本申请中，我们提出了AFFORD（氨基蝶呤优先用于风湿病）临床试验。AFFORD试验调查了对MTX反应不足的RA患者是否可以用AMT有效治疗。最初，所有入组的患者均接受AMT，随后对AMT有有效反应的患者进入双盲阶段，比较AMT和安慰剂对照。AFFORD试验将以一种快速、具有成本效益的方式确定AMT是否能有效治疗相当一部分MTX耐药的RA患者。该试验将使用标准标准来确定安全性和有效性。AFFORD试验和SBIR快速通道申请的具体目的是：1）评价口服AMT治疗MTX耐药RA患者的疗效。2)评估口服AMT治疗MTX耐药RA患者的安全性。AFFORD试验的完成将坚定地确定AMT是否是MTX耐药RA患者的安全有效治疗。对于大多数RA患者，MTX是其治疗的关键组成部分，并且用于RA的上级抗叶酸剂的临床开发将对数百万RA患者产生巨大的、积极的和成本效益的影响。公共卫生相关性：风湿性关节炎（RA）是影响约1%人口的人类残疾的主要原因。甲氨蝶呤是目前RA治疗的主要药物，许多个体吸收和耐受性较差，导致30-40%的患者无效反应，仅20%的患者缓解，长期使用效果甚至更差。该项目正在开发氨基蝶呤;一种吸收和耐受性更好的药物，作为RA的一种重要的新的具有成本效益的治疗选择。