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.

类风湿关节炎的一流新疗法 Biotherapeutics Inc (BTI) 是一家新兴的生物技术公司，协同结合了先进技术的力量 计算建模与转化实验加速新产品的开发 该 SBIR 应用将推动新型口服一流药物的开发。 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型药物 该项目的目标是开发我们的领先药物。 结合激动剂，作为 RA 的口服一流治疗剂。 背景：RA 是一种致残性慢性炎症性疾病，影响美国 150 万患者， 每年的社会总成本超过 390 亿美元。有限的治疗效果和大量的安全问题， 在市场上现有的治疗方法中，导致开发的临床需求未得到满足 我们的新型候选药物具有新的作用机制，更安全、更有效。 激活新发现的具有治疗特性的途径，可减轻疾病的严重程度和 RA 动物模型中的炎症，抑制免疫细胞的炎症反应并调节 该 SBIR 第一阶段项目将开发我们的先导结合激动剂。 对于 RA，验证其治疗功效和安全性，并表征其在治疗期间 FLS 激活的机制 RA的具体目标是： 目的 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 大鼠体内的半衰期以及 14 天重复剂量毒性。 目标 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酶代谢活性来激活。 目标 3. 比较先导化合物与目前批准的 RA 治疗药物的治疗效果 通过临床评分、关节组织病理学、炎症标记物和流式细胞术分析来建立两种大鼠模型。 预期结果：验证我们的先导化合物作为治疗 RA 的新型候选药物 i) 抑制 RA 患者激活的 FLS 中糖酵解的使用增加，ii) 改善滑膜 体内炎症；和 iii) 具有良好的安全性，NOAEL ≥ 1,000 mg/kg。 SBIR II 期将验证这种新候选药物在 RA 慢性模型中的治疗效果，执行 ADME 和脱靶检测，并将我们的新候选药物推进 IND 研究。 商业应用：该项目将开发一种小分子疗法的新药物方案， 这种新药通过调节多管齐下的作用机制发挥抗炎功能。 开发计划可能会扰乱 RA 250 亿美元的不断扩大的市场。