The Treatment of Methotrexate Resistant Rheumatoid Arthritis With Aminopterin

描述(申请人提供)：该项目的长期目标是开发氨基喋呤(AMT)，一种抗叶酸药物，作为类风湿性关节炎(RA)和其他炎症性疾病患者的改进治疗方法。这项应用侧重于类风湿性关节炎，它发生在约1%的人口中，并与渐进性联合破坏、功能残疾和预期寿命缩短有关。甲氨蝶呤(MTX)是一种单独或与其他药物联合使用的抗叶酸药物，是目前治疗RA的主要药物和参考标准。然而，口服MTX很难被许多人吸收，这导致30-40%的RA患者无效反应，只有20%的患者缓解。此外，由于MTX的副作用，只有一半有效反应的患者对MTX耐受5年。尤其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、肝脏刺激、头痛、疲劳、定向障碍和记忆力差。替代疗法包括毒性更大的口服药物、可注射的MTX或非常昂贵的可注射重组蛋白(生物制品)。一种吸收良好、毒性较低的口服抗叶酸将是一种重要的、具有成本效益的选择，它为RA的治疗设定了一个新的标准。我们的临床试验证明，AMT在结构上与MTX相似，几乎100%口服吸收，同时避免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，与MTX相比，AMT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将通过避免使用昂贵的生物制剂进行治疗而产生重要的经济后果。因此，在本申请中，我们建议进行GRAVE(氨基蝶呤优先治疗类风湿疾病)临床试验。CAVE试验调查对MTX反应不足的RA患者是否可以有效地使用AMT治疗。最初，所有登记的患者都接受了AMT，随后那些对AMT有效的患者进入了比较AMT和安慰剂对照的双盲阶段。以快速、成本效益高的方式进行的CAPRE试验将确定AMT是否能有效地治疗相当大比例的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。CAVE试验和这项SBIR Fast-Track应用的具体目的是：1)评估口服AMT治疗MTX耐药RA患者的疗效。2)评价口服AMT治疗MTX耐药RA患者的安全性。CAVE试验的完成将确定AMT是否是对MTX耐药的RA患者安全有效的治疗方法。对于大多数RA患者来说，MTX是他们治疗的关键组成部分，临床上开发一种用于RA的高级抗叶酸将对数百万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：类风湿性关节炎(RA)是人类残疾的主要原因，影响到约1%的人口。甲氨蝶呤是目前治疗RA的主要药物，许多人对甲氨蝶呤的吸收和耐受性很差，导致30-40%的患者无效，只有20%的患者缓解，长期使用效果更差。该项目正在开发氨基喋呤，这是一种吸收和耐受性更好的药物，作为治疗类风湿关节炎的一种重要的新成本效益选择。

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.