Aminotrexate A Novel Strategy to Replace Methotrexate in Psoriasis

氨基氨蝶呤是替代甲氨蝶呤治疗银屑病的新策略

• 批准号: 7490872
• 负责人: JOHN A ZEBALA
• 金额: $ 62.69万
• 依托单位: SYNTRIX BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-11 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490872
• 关键词: Academic Medical Centers; Adherence; Adverse effects; Adverse event; Affect; Agitation; Animals; Antidotes; Area; Bioavailable; Biological Availability; Brain; Caring; Cells; Chronic; Chronic small plaque psoriasis; Class; Clinical; Clinical Trials; Data; Dermatology; Development; Disease remission; Disorientation; Dose; Double-Blind Method; Effectiveness; End Point; Enrollment; Event; Fatigue; Folic Acid; Folic Acid Antagonists; Head; Hepatotoxicity; Hour; Human; Inflammatory; Laboratories; Leucovorin; Licensing; Memory; Methotrexate; Neurocognitive; Oral; Oral Administration; Patients; Pharmaceutical Economics; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Phototherapy; Population; Psoriasis; Quality of life; Reaction; Relapse; Relative (related person); Reporting; Research Institute; Research Personnel; Safety; Score; Series; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Standards of Weights and Measures; Supplementation; Symptoms; Systemic Therapy; Tablets; Testing; Texas; Time; Tissues; Toxic effect; United States; United States Food and Drug Administration; Variant; Week; cost; dosage; experience; indexing; neurotoxicity; novel strategies; programs; response; skin disorder

Aminotrexate¿ (AMT) is an antifolate in the same class as MIX that we have established is nearly 100%orally bioavailable in humans with a lower interpatient coefficient of variation than MTX, and is much more rapidly taken up by cells and tissues. With regard to non-CNS toxicities and response to the antidote leucovorin, AMT is indistinguishable from MTX. Accordingly, we hypothesize (clinical hypothesis 1) that oral AMT will be efficacious in a greater maximum fraction of patients with moderate-to-severe psoriasis than oral MTX, and/or reach a particularlevel of symptom improvement quicker than after oral MTX. We have also discovered that at equipotent doses of AMT and MTX, human CSF and animal brain parenchyma accumulatesignificantly less AMT than MTX. As such, we also hypothesize (clinical hypothesis 2) that oral AMT will result in fewer patients with postdosing neurotoxicity,and/or patients experiencing less severe postdosing neurotoxicity. As a result, AMT may potentiallybe better tolerated, resulting in better long-term adherence to AMT compared to MTX. If a greater fraction of patients with respond to AMT than to MTX, and/or can be treated longer withoutbecoming intolerant to the side-effects, AMT could have a major impact on the standard of care in psoriasis and would have critical pharmacoeconomic consequences by obviating cost-intensive biologic treatments. This SBIR Fast-Track proposal aims to test the above hypotheses by conducting a series of two sequential Phase 2/3 clinical trials. In the first Phase 2 dose-findingclinical trial to be conducted in SBIR Phase I (36 subjects, 12 weeks per subject, 6-12 month enrollmentperiod), the Specific Aims will be to: (1):assess the safety of oral AMT in the treatment of moderate-to-severe plaque psoriasis; (2) establish the dose- response relationship of oral AMT in moderate-to-severe plaque psoriasis; and (3) determine if splitting the weekly dose over two tablets, given every 12 hours, is preferred over giving the fully weekly dose once, using PASI scoring and safety assessments. From the Phase 2 study results we will select the dose of oral AMT that results inmaximum efficacy and best time-to-response while not resulting in treatment-emergenttoxicities or intolerance. We will then carry this oral AMT dose forward into the Phase 3 double-blind, randomizedclinical trial to be conducted in SBIR Phase II (390 subjects, 26 weeks per subject, 30-36 month enrollmentperiod) to test AMT vs. MTX head-to-head via the followingSpecific Aims: (1) Compare the efficacy of oral AMT and oral MTX in the treatment of subjectswith moderate-to-severe plaque psoriasis who have not previouslyreceived MTX; and (2) Compare the safety and tolerance of AMT with MTX by comparing adverse events and laboratory parameters, expanded with a specific assessment of neurocognitive and CNS related-side effects of both drugs. The primaryefficacy end-point is improvementin area under the PASI-N curve at Week 26, where PASI-N is the mean percent reduction in the PsoriasisArea-and-Seve'rity Index (PASI). Secondary efficacy and neurocognitiveend-points include: proportion of subjects achievingPASI 50 and PASI 75 at Week 10 and Week 26; time to PASI 75 (Kaplan Meier); physicianGlobal Assessment (PGA); Dermatology Life Quality (DLQI), Psoriasis Symptom Assessment (PSA); and neurocognitive scores from MMSE, FAClT-Fatigue, and FACT/GOG-Ntx. At the conclusionof the Phase 2 and 3 clinical trials proposed herein, we aim to have the necessary efficacy and safety data requiredfor a Product License Application (NDA,) to the FDA for the use of AMT in psoriasis.

氨蝶呤（AMT）是一种与MIX同类的抗叶酸剂，我们已经确定其口服率接近100 在人体内的生物利用度比MTX低，患者间变异系数低，吸收快得多 细胞和组织。关于非CNS毒性和对解毒剂甲酰四氢叶酸的反应，AMT是 与MTX没有区别。因此，我们假设（临床假设1），口服AMT将有效， 中重度银屑病患者的最大比例高于口服MTX，和/或达到特定水平 比口服MTX后症状改善更快。我们还发现，在同等剂量的AMT和 MTX、人脑脊液和动物脑组织中AMT的蓄积量明显低于MTX。因此，我们也 假设（临床假设2）口服AMT将导致更少的患者发生给药后神经毒性，和/或 给药后神经毒性不太严重的患者。因此，AMT可能会更好地耐受， 从而导致与MTX相比对AMT更好的长期依从性。如果大部分患者对 AMT比MTX，和/或可以治疗更长时间而不会对副作用产生耐受性，AMT可能具有 对银屑病治疗标准产生重大影响，并将产生关键的药物经济学后果， 避免了成本密集的生物治疗。本SBIR快速通道提案旨在通过以下方式检验上述假设： 进行一系列两个连续的2/3期临床试验。在第一个2期剂量探索临床试验中， 在SBIR I期（36例受试者，每例受试者12周，6-12个月入组期）中进行，具体目的将 目的是：（1）：评估口服AMT治疗中重度斑块状银屑病的安全性;（2）确定剂量- 中重度斑块状银屑病患者口服AMT的反应关系;（3）确定是否将每周一次的AMT分为 使用PASI评分，每12小时给药一次超过两片的剂量优于每周给药一次 和安全评估。根据2期研究结果，我们将选择导致最大剂量的口服AMT剂量。 疗效和最佳缓解时间，同时不会导致治疗后出现的毒性或不耐受。然后我们将 将此口服AMT剂量用于SBIR的3期双盲、随机临床试验 II期（390名受试者，每名受试者26周，入组期30-36个月）通过直接测试AMT与MTX 具体目的：（1）比较口服AMT和口服MTX治疗慢性乙型肝炎的疗效。 中重度斑块型银屑病患者既往未接受MTX治疗;（2）比较两组患者的安全性和耐受性 通过比较不良事件和实验室参数，对AMT与MTX进行了详细的评估， 两种药物的神经认知和CNS相关副作用。主要疗效终点是面积的改善 在第26周的PASI-N曲线下，其中PASI-N是银屑病面积和严重度的平均百分比降低 索引（PASI）。次要疗效和神经认知终点包括：符合PASI 50的受试者比例 和第10周和第26周的PASI 75;至PASI 75的时间（Kaplan Meier）;医生总体评估（PGA）; 皮肤病生活质量（DLQI）、银屑病症状评估（PSA）;以及来自MMSE的神经认知评分， FACT-疲劳和FACT/GOG-Ntx。在本文提出的2期和3期临床试验结束时，我们的目标是 具有向FDA提交产品许可申请（NDA）所需的必要有效性和安全性数据， AMT治疗银屑病。