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: 9188625
• 负责人: STUART J KAHN
• 金额: $ 49万
• 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 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188625
• 关键词: Adverse effects; Affect; Agitation; Aminopterin; Area; Biological Assay; 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; Folic Acid Antagonists; Genetic; Headache; Health; 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; Reporting; Resistance; Rest; Risk; SLC19A1 gene; Safety; Severities; Testing; Thymidylate Synthase; Time; Toxic effect; Translating; United States; Uracil; base; cellular development; clinical biomarkers; cost; enantiomer; experience; improved; in vivo; indexing; meetings; novel; placebo controlled study; preclinical study; 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、缓解和复发的鳞状和炎性皮肤病，影响世界人口的1-3%，导致2012年美国的年度总成本为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/或各种全身性治疗，其中甲氨蝶呤（MTX）是最广泛使用的口服全身性药物。尽管MTX作为单药治疗具有相对有效性，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主要由于对药物不耐受而停止口服MTX。虽然许多努力已经针对基于遗传因素和其活性代谢物的定量来确定对MTX的不良和/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），具有比MTX更好疗效和/或安全性的改良抗叶酸剂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Syndrome 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（即活性代谢物的聚谷氨酰化），以及更低的肝脏和CNS毒性，这些特性可能转化为更好的疗效和/或安全性。除了将LD-AMT鉴定为MTX的潜在改善之外，获得抗叶酸剂抗性的机制性理解通常对于用LD-AMT或MTX治疗炎症具有重要的临床意义，其可能通过鉴定临床生物标志物来预测最佳反应或在开始治疗之前的毒性风险。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，并提出一种新的假设驱动的抗叶酸剂耐药性机制解释，将LD-AMT推向临床。