Efficacy and resistance mechanisms of LD-aminopterin in psoriasis

LD-氨基蝶呤治疗银屑病的疗效及耐药机制

• 批准号: 8792437
• 负责人: STUART J KAHN
• 金额: $ 22.5万
• 依托单位: SYNTRIX BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-02-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792437
• 关键词: Adverse effects; Affect; Agitation; Aminopterin; Area; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Canis familiaris; Caring; Chronic; Chronic small plaque psoriasis; Clinic; Clinical; Clinical Research; Coupled; Cyclic GMP; DHFR gene; DNA; Disease remission; Disorientation; Dose; Effectiveness; Failure; Fatigue; Feeling; Folate; Folic Acid Antagonists; Genetic; Headache; Hepatotoxicity; Human; In Vitro; Inflammation; Inflammatory; Intestines; Isoenzymes; Legal patent; Liver; Marketing; Memory impairment; Methods; Methotrexate; Mitochondria; Mus; Nuclear; Oral; Patients; Pharmaceutical Economics; Pharmaceutical Preparations; Phase II Clinical Trials; Phototherapy; Placebo Control; Placebos; Population; Price; Property; Protons; Psoriasis; Reaction; Relapse; Relative (related person); Reporting; Resistance; Rest; Risk; Safety; Severities; Testing; Thymidylate Synthase; Time; Toxic effect; Translating; United States; Uracil; base; cellular development; cost; enantiomer; experience; improved; in vivo; indexing; meetings; novel; placebo controlled study; preclinical study; public health relevance; resistance mechanism; response; skin disorder; uptake

DESCRIPTION (provided by applicant): Psoriasis is a chronic, genetically influenced, remitting and relapsing scaly and inflammatory skin disorder that affects 1-3% of the world's population, resulting in total annual costs of $5.2 billion in the United States in 2012. Approximately 20% of patients with moderate-to-severe chronic plaque psoriasis require phototherapy and/or a variety of systemic treatments, where methotrexate (MTX) is the mostly widely used oral systemic agent. Despite the relative effectiveness of MTX, as a monotherapy, it does not achieve greater than a 75% reduction in the baseline psoriasis area-and-severity index (PASI 75) in 40% of patients, and fails to achieve remission (i.e. > PASI 90) in 60% of patients. Furthermore, up to 30% of patients with moderate-to-severe plaque psoriasis discontinue oral MTX primarily because of intolerance to the drug. While much effort has been directed to identifying the mechanism behind poor and/or toxic responses to MTX based on genetic factor and quantitation of its active metabolites, the majority of MTX failures remain unexplained. Given the efficacy and safety limitations of MTX and the cost of biologics compared to MTX (~$20,000 vs. $300 per year), there is a clear market opportunity for an improved antifolate with better efficacy and/or safety than MTX, but that is priced between MTX and biologics. LD-Aminopterin (LD-AMT) is a patented composition developed by Syntrix Biosystems that studies indicate has greater cellular uptake (i.e. polyglutamylation to the active metabolites) than MTX, and less liver and CNS toxicity, properties that may translate into better efficacy and/or safety. In addition to identifying LD-AMT as a potential improvement on MTX, gaining a mechanistic understanding of antifolate resistance in general has important clinical implications for treating inflammation with LD-AMT or MTX, by possibly identifying clinical biomarkers to predict optimal response or risk of toxicity in advance of initiating treatment. This U44 Fast-Track proposal aims to advance LD-AMT to the clinic by testing LD-AMT for efficacy in a placebo-controlled phase 2 trial and advancing a novel hypothesis-driven mechanistic explanation for antifolate resistance.

描述（由申请人提供）：牛皮癣是一种慢性的、受遗传影响的、缓解和复发的鳞状和炎症性皮肤病，影响着世界上1-3%的人口，2012年在美国造成的年总成本为52亿美元。大约20%的中重度慢性斑块型银屑病患者需要光疗和/或各种全身治疗，其中甲氨蝶呤（MTX）是最广泛使用的口服全身药物。尽管MTX相对有效，但作为单一疗法，40%患者的基线银屑病面积和严重程度指数（PASI 75）降低不超过75%，60%患者未能实现缓解（即PASI 90）。此外，高达30%的中重度斑块型银屑病患者停止口服甲氨蝶呤，主要是因为对该药不耐受。基于遗传因素和MTX活性代谢物的定量，已经有很多研究致力于确定MTX不良反应和/或毒性反应背后的机制，但大多数MTX失败仍然无法解释。考虑到MTX的疗效和安全性限制以及与MTX相比生物制剂的成本（每年约20,000美元对300美元），有明显的市场机会出现一种疗效和/或安全性优于MTX的改良抗叶酸盐，但其定价介于MTX和生物制剂之间。ld -氨基蝶呤（LD-AMT）是Syntrix生物系统公司开发的一种专利组合物，研究表明，与MTX相比，LD-AMT具有更大的细胞摄取（即多谷氨酰化为活性代谢物），并且对肝脏和中枢神经系统的毒性更小，这些特性可能转化为更好的疗效和/或安全性。除了确定LD-AMT作为MTX的潜在改善外，获得抗叶酸耐药的机制理解对于使用LD-AMT或MTX治疗炎症具有重要的临床意义，通过可能识别临床生物标志物来预测开始治疗前的最佳反应或毒性风险。这项U44快速通道提案旨在通过在安慰剂对照的2期试验中测试LD-AMT的疗效，并提出一种新的假说驱动的抗叶酸耐药机制解释，将LD-AMT推向临床。