Novel first-in-class Therapeutics for Rheumatoid Arthritis

风湿性关节炎的新型一流治疗药物 Biotherapeutics Inc（BTI）是一家新兴的生物技术公司，协同结合了先进的 计算建模与平移实验，以加速新产品的开发， 精准医疗与健康这SBIR应用程序将推进一个新的口头一流的发展 治疗类风湿性关节炎（RA）。 我们的产品：我们已经确定了一个小分子治疗家族，可以结合并激活一种新的 具有免疫和代谢功能的治疗靶点。这个项目的目标是发展我们的领先优势 结合激动剂，作为一种口服的，一流的治疗类风湿关节炎。 背景：RA是一种致残性慢性炎症性疾病，在美国影响150万患者，与 每年社会总成本超过390亿美元。有限的治疗效果和大量的安全性问题， 在目前市场上的治疗剂类别中，导致开发 更安全和更有效的RA治疗剂，具有新的作用机制。我们的新候选药物 激活一种新发现的具有治疗特性的途径，改善疾病的严重程度， 在RA动物模型中的炎症，抑制免疫细胞中的炎症反应加上调节 成纤维细胞样滑膜细胞（FLS）活化。这个SBIR第一阶段项目将开发我们的铅结合激动剂 对于RA，验证其治疗有效性和安全性，并表征其在治疗过程中激活FLS的机制。 RA.具体目标是： AIM 1.进行药代动力学（PK）和安全性研究，以确定口服生物利用度、组织分布 和半衰期以及大鼠14天重复给药毒性。 AIM 2.表征我们的先导化合物对人成纤维细胞样滑膜细胞代谢的影响 通过分析代谢谱和评估关键代谢酶活性来确定活性。 AIM 3.比较先导化合物与目前批准的RA治疗剂在以下方面的疗效： 通过临床评分、关节组织病理学、炎症标志物和流式细胞术分析两种大鼠模型。 预期结果：验证我们的先导化合物作为治疗类风湿关节炎的新型候选治疗药物 i）抑制RA患者活化FLS中增加的糖酵解使用，ii）改善滑膜炎， iii）具有良性安全性特征，NOAEL ≥ 1，000 mg/kg。 SBIR II期将验证这种新型候选药物在慢性RA模型中的治疗效果， ADME和脱靶试验，并将我们的新药候选药物推进IND研究。 商业应用：本项目将开发一个小分子治疗药物的新药项目， 通过调节多方面的作用机制发挥抗炎功能。这种新药 开发计划可能会破坏RA不断扩大的250亿美元的市场。

Novel first-in-class Therapeutics for Rheumatoid Arthritis Biotherapeutics Inc (BTI) is an emerging biotech company that synergistically combines the power of advanced computational modeling with translational experimentation to accelerate the development of novel products for precision medicine and health. This SBIR application will advance the development of a novel oral first-in-class therapeutic for rheumatoid arthritis (RA). Our Product: We have identified a family of small-molecule therapeutics that bind and activate a novel therapeutic target with immunological and metabolic functions. The goal of this project is to develop our lead binding-agonist, as an oral, first-in-class therapeutic for RA. Background: RA is a disabling chronic inflammatory disorder affecting 1.5 million patients in the U.S., with a total annual societal cost exceeding $39 billion. Limited therapeutic efficacy and abundant safety concerns, among the classes of current therapeutics in the market, result in an unmet clinical need for the development of safer and more effective RA therapeutics with novel mechanisms of action. Our novel drug candidate binds and activates a newly identified pathway with therapeutic properties that ameliorates disease severity and inflammation in animal models of RA, suppressing inflammatory responses in immune cells plus modulating fibroblast-like synoviocytes (FLS) activation. This SBIR Phase I project will develop our lead-binding agonist for RA, validate its therapeutic efficacy and safety and characterize its mechanisms on FLS activation during RA. The Specific Aims are to: AIM 1. Conduct pharmacokinetic (PK) and safety studies to determine oral bioavailability, tissue distribution and half-life as well as a 14-day repeat-dose toxicity in rats. AIM 2. Characterize the effects of our lead compound on human fibroblast-like synoviocyte metabolism and activation through analysis of metabolic profile and assessment of key metabolic enzyme activity. AIM 3. Compare the therapeutic efficacy of the lead compound to current approved RA therapeutics in two rat models by clinical scores, joint histopathology, inflammatory markers, and flow cytometric analysis. Expected Outcomes: Validation of our lead compound as a novel therapeutic candidate for the treatment of RA that: i) inhibits the increased glycolytic usage in activated FLS from RA patients, ii) ameliorates synovial inflammation in vivo; and iii) has a benign safety profile with NOAEL ≥ 1,000 mg/kg. SBIR Phase II will validate the therapeutic efficacy of this novel drug candidate in chronic models of RA, perform ADME and off-target assays and advance our novel drug candidate to IND-enabling studies. Commercial Application: This project will develop a new drug program of small molecule therapeutics that exert anti-inflammatory functions through modulation of multi-pronged mechanisms of action. This new drug development program could disrupt the RA expanding market of $25 billion.