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(申请人提供)：牛皮癣是一种慢性、受遗传影响、缓解和复发的鳞片状和炎症性皮肤病，影响世界人口的1%-3%，导致2012年美国每年的总成本为52亿美元。大约20%的中到重度慢性斑块型银屑病患者需要光疗法和/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用药。尽管MTX相对有效，但作为一种单一疗法，在40%的患者中，它对牛皮癣的基线面积和严重程度指数(PASI 75)的降幅不超过75%，在60%的患者中未能实现缓解(即&GT；PASI 90)。此外，多达30%的中到重度斑块型牛皮癣患者停止服用MTX，主要是因为对该药物不耐受。虽然基于遗传因素和对MTX活性代谢物的定量，人们已经致力于确定MTX不良和/或毒性反应背后的机制，但大多数MTX失败的原因仍不清楚。考虑到MTX的疗效和安全性限制，以及与MTX相比，生物制品的成本(每年约2万美元对300美元)，显然存在比MTX更有效和/或更安全的改良抗叶酸的市场机会，但价格介于MTX和生物制品之间。LD-氨基蝶呤(LD-AMT)是Syntrix BiosSystems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(即对活性代谢物的多谷氨酰化)，更低的肝脏和中枢神经系统毒性，这些特性可能会转化为更好的疗效和/或安全性。除了确定LD-AMT是MTX的潜在改进外，了解抗叶酸耐药性的一般机制对于使用LD-AMT或MTX治疗炎症具有重要的临床意义，因为它可能在开始治疗之前确定临床生物标记物来预测最佳反应或毒性风险。这项U44快速通道建议旨在通过在安慰剂对照的第二阶段试验中测试LD-AMT的有效性，并提出一种新的假设驱动的抗叶酸抵抗机制解释，将LD-AMT推向临床。