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: 7054333
• 负责人: JOHN A ZEBALA
• 金额: $ 79.1万
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7054333
• 关键词: clinical research; clinical trials; methotrexate; psoriasis

DESCRIPTION (provided by applicant): Aminotrexate(tm) (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 particular level 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 accumulate significantly 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 potentially be 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 without becoming 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 2 sequential Phase 2/3 clinical trials. In the first Phase 2 dose-finding clinical trial to be conducted in SBIR Phase I (36 subjects, 12 weeks per subject, 6-12 month enrollment period), 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 in maximum efficacy and best time-to-response while not resulting in treatment-emergent toxicities or intolerance. We will then carry this oral AMT dose forward into the Phase 3 double-blind, randomized clinical trial to be conducted in SBIR Phase II (390 subjects, 26 weeks per subject, 30-36 month enrollment period) to test AMT vs. MTX head-to-head via the following Specific Aims: (1) Compare the efficacy of oral AMT and oral MTX in the treatment of subjects with moderate-to-severe plaque psoriasis who have not previously received 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 primary efficacy end-point is improvement in area under the PASI-N curve at Week 26, where PASI-N is the mean percent reduction in the Psoriasis Area-and-Seve'rity Index (PASI). Secondary efficacy and neurocognitive end-points include: proportion of subjects achieving PASI 50 and PASI 75 at Week 10 and Week 26; time to PASI 75 (Kaplan Meier); physician Global Assessment (PGA); Dermatology Life Quality (DLQI), Psoriasis Symptom Assessment (PSA); and neurocognitive scores from MMSE, FAClT-Fatigue, and FACT/GOG-Ntx. At the conclusion of the Phase 2 and 3 clinical trials proposed herein, we aim to have the necessary efficacy and safety data required for a Product License Application (NDA,) to the FDA for the use of AMT in psoriasis.

说明（由申请人提供）：Aminotrexate（tm）（AMT）是一种与MIX同类的抗叶酸剂，我们已经确定MIX在人体中的口服生物利用度接近100%，患者间变异系数低于MTX，并且被细胞和组织吸收更快。关于非中枢神经系统毒性和对解毒剂甲酰四氢叶酸的反应，AMT与MTX无法区分。因此，我们假设（临床假设1）口服AMT比口服MTX在更大比例的中重度银屑病患者中有效，和/或比口服MTX更快地达到特定水平的症状改善。我们还发现，在等效剂量的AMT和MTX下，人CSF和动物脑实质积累的AMT显著少于MTX。因此，我们还假设（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/或患者发生较轻的给药后神经毒性。因此，与MTX相比，AMT的耐受性可能更好，从而导致对AMT的长期依从性更好。如果对AMT有反应的患者比例大于MTX，和/或可以治疗更长时间而不会对副作用产生不耐受，则AMT可能对银屑病的护理标准产生重大影响，并通过避免成本密集型生物治疗而产生关键的药物经济学后果。本SBIR快速通道提案旨在通过进行一系列2个连续2/3期临床试验来检验上述假设。在SBIR I期进行的第一项II期剂量探索临床试验中（36名受试者，每名受试者12周，6-12个月的招募期），具体目的将是：（1）：评估口服AMT在治疗中重度斑块状银屑病中的安全性;（2）建立口服AMT在中重度斑块状银屑病中的剂量-反应关系;和（3）使用PASI评分和安全性评估，确定将每周剂量分成两片，每12小时给药一次是否优于每周给药一次。根据II期研究结果，我们将选择能够产生最大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的口服AMT剂量。然后，我们将把这种口服AMT剂量推进到SBIR II期的III期双盲随机临床试验中。（390例受试者，每例受试者26周，30-36个月入组期），通过以下特定目的测试AMT与MTX的头对头比较：（1）比较口服AMT和口服MTX在治疗先前未接受MTX的中重度斑块状银屑病受试者中的功效;（2）通过比较不良事件和实验室参数，并对两种药物的神经认知和CNS相关副作用进行具体评估，比较AMT和MTX的安全性和耐受性。主要疗效终点是第26周PASI-N曲线下面积的改善，其中PASI-N是Psb面积和严重度指数（PASI）的平均百分比降低。次要疗效和神经认知终点包括：第10周和第26周达到PASI 50和PASI 75的受试者比例;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、FACIT-疲劳和FACT/GOG-Ntx的神经认知评分。在本文提出的2期和3期临床试验结束时，我们的目标是获得向FDA申请AMT治疗银屑病的产品许可证（NDA）所需的必要疗效和安全性数据。