Novel first-in-class Therapeutics for Rheumatoid Arthritis

类风湿关节炎的一流新疗法

• 批准号: 10696749
• 负责人: Josep Bassaganya-Riera
• 金额: $ 29.59万
• 依托单位: BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-07 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696749
• 关键词: Acceleration; Adjuvant Arthritis; Advanced Development; Affect; Agonist; American; Animal Model; Animals; Anti-Inflammatory Agents; Antibodies; Benign; Binding; Bioenergetics; Biological Assay; Biological Availability; Biological Response Modifier Therapy; Biotechnology; Cartilage; Cells; Chronic; Clinical; Collagen Arthritis; Computer Models; Development; Disease; Dose; Down-Regulation; Drug Kinetics; Drug or chemical Tissue Distribution; Enzymes; Family; Fibroblasts; Frequencies; Genes; Genus Hippocampus; Glycolysis; Goals; Half-Life; Histopathology; Human; Immune; Immunity; Immunologics; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Integral Membrane Protein; Joints; Lead; Macrophage; Marketing; Metabolic; Metabolism; Methotrexate; Modeling; No-Observed-Adverse-Effect Level; Oral; Oral Administration; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Plasma; Population; Precision Health; Program Development; Property; Rattus; Rheumatoid Arthritis; Safety; Severity of illness; Small Business Innovation Research Grant; Synovitis; Therapeutic; Tissues; Toxic effect; Toxicology; Treatment Efficacy; Up-Regulation; Validation; clinical development; commercial application; commercialization; drug candidate; efficacy study; enzyme activity; experience; immune cell infiltrate; immunoregulation; in vivo; in vivo Model; inflammatory marker; inhibitor; joint inflammation; joint mobilization; metabolic profile; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; plexin; precision medicine; programs; public health relevance; receptor; reduce symptoms; research clinical testing; safety study; side effect; small molecule; small molecule therapeutics; societal costs; success; therapeutic candidate; therapeutically effective; translational study

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.

治疗类风湿性关节炎的一流新药 生物治疗公司(BTI)是一家新兴的生物技术公司，它协同结合了先进的 采用平移实验的计算建模加速新产品的开发 精准医疗与健康。这项SBIR应用将推动新型口腔一流产品的开发 治疗类风湿性关节炎(RA)。 我们的产品：我们已经确定了一系列小分子疗法，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地位 结合激动剂，作为口服治疗类风湿性关节炎的一流药物。 背景：RA是一种致残的慢性炎症性疾病，在美国影响着150万患者， 年社会总成本超过390亿美元。有限的治疗效果和丰富的安全性担忧， 在目前市场上的治疗类别中，导致对发展的临床需求未得到满足 具有新的作用机制的更安全和更有效的类风湿关节炎疗法。我们的新候选药物绑定和 激活一种新发现的具有治疗特性的通路，以改善疾病严重程度和 RA动物模型中的炎症，抑制免疫细胞中的炎症反应并调节 成纤维细胞样滑膜细胞(FLS)激活。这个SBIR第一阶段项目将开发我们的铅结合激动剂 对于RA，验证其治疗效果和安全性，并表征其在FLS激活过程中的作用机制 拉。具体目标是： 目的1.进行药物动力学(PK)和安全性研究，以确定口服生物利用度、组织分布 大鼠的半衰期以及14天的重复给药毒性。 目的2.表征我们的先导化合物对人成纤维样滑膜细胞代谢的影响 并通过代谢谱分析和关键代谢酶活性的评估来激活。 目的3.比较先导化合物与目前批准的RA疗法在 通过两种大鼠模型的临床评分、关节组织病理学、炎症标志物和流式细胞仪分析。 预期结果：证实我们的先导化合物是治疗类风湿关节炎的新候选药物 这：i)抑制RA患者激活的FLS中糖酵解的增加，ii)改善滑膜 3)NOAEL≥1,000 mg/kg具有良好的安全性。 SBIR第二阶段将验证这种新的候选药物在慢性RA模型中的治疗效果 ADME和非靶标分析，并将我们的新药候选推进到IND使能研究。 商业应用：该项目将开发一种新的小分子疗法药物计划， 通过调节多管齐下的作用机制发挥抗炎作用。这种新药 开发计划可能会扰乱RA不断扩大的250亿美元市场。