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）：牛皮癣是一种慢性，受遗传影响，恢复和复发的鳞状和炎症性皮肤疾病，影响了世界人口的1-3％，2012年在美国，每年52亿美元的年总成本为52亿美元。大约20％的患者需要中等程度的phitevere plaperpations Photopties Photothers Photothers Photothers（Miders oferections），这是一种耐药性（Mirtose），这是一种耐药性（MIRETIDER），这是一种耐药性（Mirters），这是一项多样性的（或者）。是大多数使用的口服全身剂。尽管MTX具有相对有效性，但作为一种单一疗法，在40％的患者中，它的基线牛皮癣区域和严重性指数（PASI 75）的降低并未大于75％，并且在60％的患者中未能实现缓解（即> PASI 90）。此外，多达30％的中度至重度斑块牛皮癣的患者中断口服MTX主要是由于对药物的不耐受。尽管已经大力基于遗传因素和其活性代谢产物的定量来确定对MTX的差和/或有毒反应背后的机制，但大多数MTX失败仍无法解释。鉴于MTX的功效和安全性限制和生物制剂的成本与MTX相比（约合20,000美元，每年$ 300），与MTX相比，具有更好效率和/或安全性的改进的抗粮食抗体有明显的市场机会，但在MTX和MTX之间的价格更高。 LD-氨基翅目（LD-AMT）是由Syntrix Biosystems开发的专利组合物，其研究表明，与MTX相比，细胞摄取更大（即对活性代谢物的聚谷氨酸化），并且肝脏和CNS毒性较小，可能会转化为更好的效率和效率和/或安全性。除了将LD-AMT识别为MTX的潜在改善外，还可以通过识别临床生物标志物来预测最佳的临床生物标志物或在开始治疗前预测毒性的最佳反应或毒性风险，从而获得对抗叶酸耐药性的机械理解，这对治疗LD-AMT或MTX的炎症具有​​重要的临床意义。该U44快速轨道提案旨在通过在安慰剂对照的2期试验中测试LD-AMT来提高LD-AMT的功效，并推进一种新型假设驱动的抗牙基耐药性的解释。