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）：银屑病是一种慢性、遗传影响、缓解和复发性鳞状和炎症性皮肤病，影响世界人口的 1-3%，2012 年美国每年的总费用为 52 亿美元。大约 20% 的中重度慢性斑块状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制剂。尽管 MTX 作为单一疗法相对有效，但在 40% 的患者中，其基线银屑病面积和严重程度指数 (PASI 75) 的降低幅度不超过 75%，并且在 60% 的患者中未能实现缓解（即 > PASI 90）。此外，高达 30% 的中重度斑块状银屑病患者停止口服 MTX，主要是因为对该药物不耐受。尽管人们已经根据遗传因素和活性代谢物的定量来确定 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 的功效和安全性限制以及生物制剂与 MTX 相比的成本（每年约 20,000 美元与 300 美元），相比 MTX 具有更好功效和/或安全性的改良抗叶酸药物存在明显的市场机会，但其价格介于 MTX 和生物制剂之间。 LD-氨基蝶呤 (LD-AMT) 是 Syntrix Biosystems 开发的一种专利组合物，研究表明其比 MTX 具有更高的细胞摄取（即活性代谢物的多谷氨酰化），并且肝脏和中枢神经系统毒性更低，这些特性可能会转化为更好的功效和/或安全性。除了确定 LD-AMT 是对 MTX 的潜在改善之外，总体上了解抗叶酸剂耐药性的机制对于用 LD-AMT 或 MTX 治疗炎症具有重要的临床意义，可以通过在开始治疗之前识别临床生物标志物来预测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 2 期试验中测试 LD-AMT 的功效，并提出一种新的假设驱动的抗叶酸耐药机制解释，将 LD-AMT 推向临床。