The Treatment of Methotrexate Resistant Rheumatoid Arthritis With Aminopterin

项目描述（由申请人提供）：该项目的长期目标是开发氨蝶呤（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。该应用主要针对约1%的人群中发生的RA，并与进行性关节破坏、功能残疾和预期寿命下降有关。甲氨蝶呤（MTX）是一种单独使用或与其他药物联合使用的抗叶酸盐，是目前治疗类风湿性关节炎的主流和参考标准。然而，口服甲氨蝶呤被许多人吸收不良，导致30-40%的RA患者无效，只有20%的RA患者缓解。此外，由于MTX的副作用，只有一半有有效反应的患者能耐受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、口炎、肝脏刺激、头痛、疲劳、定向障碍和记忆力差。其他治疗方法包括毒性更大的口服药物，注射甲氨蝶呤，或注射非常昂贵的重组蛋白（生物制剂）。一种吸收良好、毒性较低的口服抗叶酸盐将是一种重要的、具有成本效益的选择，为类风湿关节炎的治疗设定了新的标准。我们的临床试验已经证实，与MTX结构相似的AMT具有接近100%的口服吸收，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，我们建议进行氨蝶呤优先治疗类风湿性疾病的临床试验。AFFORD试验调查对MTX反应不足的RA患者是否可以用AMT有效治疗。最初，所有入组患者接受AMT治疗，随后，对AMT有有效反应的患者进入双盲阶段，将AMT与安慰剂对照进行比较。以一种快速、具有成本效益的方式进行的AFFORD试验将确定AMT是否能有效治疗相当比例的mtx耐药类风湿性关节炎患者。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)评估口服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试验的完成将确定AMT对于MTX耐药类风湿性关节炎患者是否是一种安全有效的治疗方法。对于大多数类风湿性关节炎患者来说，MTX是其治疗的关键组成部分，而抗叶酸药物的临床开发将对数百万类风湿性关节炎患者产生巨大的、积极的和具有成本效益的影响。公共卫生相关性：类风湿关节炎（RA）是影响约1%人口的人类残疾的主要原因。甲氨蝶呤是目前治疗类风湿性关节炎的主要药物，许多人吸收和耐受不良，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。这个项目正在开发氨基蝶呤；一种更好的吸收和耐受性的药物，作为一种重要的新的经济有效的治疗RA的选择。

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.