Phase 2 Proof-of-Concept Efficacy of BT-11 in Crohn's Disease Patients

BT-11 在克罗恩病患者中的 2 期概念验证疗效

• 批准号: 10028917
• 负责人: Simon Lichtiger
• 金额: $ 61.19万
• 依托单位: LANDOS BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10028917
• 关键词: Abdominal Pain; Address; Adverse event; Anti-Inflammatory Agents; Autoimmune Diseases; Benign; Biological Availability; Biological Products; Blood; Blood specimen; C-reactive protein; CD4 Positive T Lymphocytes; Canis familiaris; Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; Clinical; Clinical Chemistry; Clinical Research; Colitis; Colon; Crohn' s disease; Data; Development; Disease; Disease Management; Dose; Double-Blind Method; Down-Regulation; Drug Kinetics; Endoscopy; Epithelial Cells; FOXP3 gene; Family suidae; Feces; Flow Cytometry; Frequencies; Gastrointestinal tract structure; Genetic; Goals; Human; Immune; Immunology; Immunophenotyping; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intercept; Interferon Type II; Interleukin-10; Interleukin-6; Intestinal permeability; Investigational Drugs; Journals; Lactoferrin; Lamina Propria; Lead; Leukocyte L1 Antigen Complex; Ligase; Long-Term Effects; Measures; Modeling; Molecular; Monitor; Mononuclear; No-Observed-Adverse-Effect Level; North America; Oral; Outcome; Participant; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology Study; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Piperazines; Placebos; Plasma; Process; Production; Randomized; Rattus; Regulatory T-Lymphocyte; Safety; Sampling; Signal Transduction; Symptoms; T-Lymphocyte Subsets; TNF gene; Tablets; Technology; Testing; Therapeutic; Toxic effect; Toxicology; Translations; Treatment Efficacy; Ulcerative Colitis; United States; Up-Regulation; Validation; arm; base; clinical investigation; clinical remission; cytokine; design; experimental study; gastrointestinal; healthy volunteer; innovation; lanthionine; microbial; mouse model; new therapeutic target; novel; novel therapeutics; peripheral blood; pharmacodynamic biomarker; placebo controlled study; pre-clinical; preclinical study; programs; public health relevance; randomized placebo controlled study; receptor; research clinical testing; response; secondary outcome; side effect; small molecule; transcriptome sequencing; translational study

Phase 2 Proof-of-Concept Efficacy of BT-11 in Crohn’s Disease Patients Landos Biopharma is a clinical-stage biopharmaceutical company focused on the discovery and development of innovative first-in-class oral therapeutics for patients with autoimmune diseases. Our lead asset, BT-11, is a novel oral, gut-restricted investigational new drug (IND) targeting the Lanthionine Synthetase C-Like 2 (LANCL2) pathway in the gut during inflammatory bowel disease (IBD). An unmet clinical need for safer, more effective IBD drugs remains, as current therapies have limited efficacy and adverse side effects. The Technology & Product. Landos designed BT-11, a new chemical entity, to activate the LANCL2 pathway selectively within the gastrointestinal (GI) tract for the treatment of Crohn’s disease (CD). BT-11 activation of LANCL2 functions through a dual upregulation of regulatory responses and downregulation of inflammatory responses. BT-11 efficacy is proven in 5 mouse models of IBD and translational studies in primary human PBMCs and LPMCs. BT-11 is primarily localized to the GI with a NOAEL of >1,000 mg/kg in 3-month GLP rat and dog toxicity studies. The BT-11 program has 2 open INDs (138071 & 128490), completed Phase I clinical testing in 2018 and initiated a Phase 2 clinical study in mild to moderate UC patients in August of 2019. The Specific Aims for the R01 application are to: (1) Evaluate the blood and fecal PK profiles of BT-11 in CD patients. Blood samples will be collected at 16 timepoints (pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 48 h) on days of the first dose and the seventh dose. Fecal samples will be collected daily. Plasma and feces will be processed and analyzed for systemic and gut BT-11 concentrations. (2) Validate PD biomarkers of BT-11 activity in CD patients. Using samples generated from the 14-d Phase 1b study, we will measure the concentration of C-reactive protein, TNFα, IFNγ, IL-6, and IL-10 in plasma and calprotectin and lactoferrin in feces. (3) Perform a proof-of-concept study to assess efficacy and mechanisms of BT-11 in CD patients. Moderate to severe CD patients will be treated with for 12 wk with oral tablets containing 1,000 mg BT- 11 or placebo (n=20 per arm). Subjects will be monitored at baseline, 2, 6, and 12 wk to assess symptoms and collect blood and feces with endoscopy at baseline and 12 wk. The primary successful outcome will be an induction of clinical remission and endoscopic response. Secondary outcomes will include: >1 mg/g concentration of BT-11 in feces, reduction of plasma CRP and fecal calprotectin by BT-11 treatment, and decrease in inflammatory cytokines in plasma. The long-term goal of Landos’ technology is to develop safer, more effective first-in-class oral therapeutics for IBD that address an unmet clinical need for a market exceeding $10 billion and growing 25% annually.

BT-11在克罗恩病患者中的II期概念验证疗效 Landos Biopharma是一家临床阶段的生物制药公司，专注于发现和开发 为自身免疫性疾病患者提供创新的一流口服疗法。我们的主要资产BT-11是一个 一种新型口服、肠道限制性研究性新药（IND），靶向Lanthivine合成酶C样2（LANCL 2） 炎症性肠病（IBD）期间肠道中的炎症通路。未满足的临床需求，更安全，更有效 IBD药物仍然存在，因为目前的治疗方法疗效有限，而且有不良副作用。 技术与产品。Landos设计了一种新的化学实体BT-11，以激活LANCL 2途径 选择性地在胃肠道（GI）内用于治疗克罗恩病（CD）。BT-11激活 LANCL 2通过双重上调调节反应和下调炎性细胞因子来发挥功能。 应答BT-11的功效在5种IBD小鼠模型和原代人类中的转化研究中得到证实 PBMC和LPMC。在3个月GLP大鼠中，BT-11主要定位于GI，NOAEL> 1，000 mg/kg 和狗毒性研究。BT-11项目有2个开放IND（138071和128490），已完成I期临床 该公司于2018年进行了测试，并于2019年8月在轻度至中度UC患者中启动了2期临床研究。 R 01应用程序的具体目标是： (1)评价CD患者中BT-11的血液和粪便PK特征。血液样本将于 首次给药当天的16个时间点（给药前、0.25、0.5、0.75、1、1.25、1.5、2、3、4、6、8、12、18、24、48 h） 剂量和第七剂量。每天采集粪便样本。将处理血浆和粪便 并分析全身和肠道BT-11浓度。 (2)验证CD患者中BT-11活性的PD生物标志物。使用14-d的样本 1b期研究中，我们将测量C反应蛋白、TNFα、IFNγ、IL-6和IL-10的浓度， 血浆和粪便中的钙卫蛋白和乳铁蛋白。 (3)进行概念验证研究，以评估BT-11在CD患者中的疗效和机制。 中度至重度CD患者将接受含1，000 mg BT的口服片剂治疗12周， 11或安慰剂（每组n=20）。将在基线、第2、6和12周监测受试者，以评估症状 分别于治疗前和治疗12 wk时用内镜采集血和粪便。 主要成功结局将是诱导临床缓解和内镜反应。 次要结果将包括：粪便中BT-11的浓度> lmg/g，血浆CRP和粪便中BT-11的减少。 通过BT-11处理，钙卫蛋白降低，并且血浆中的炎性细胞因子降低。 Landos技术的长期目标是开发更安全，更有效的一流口腔治疗方法， IBD解决了超过100亿美元的市场未满足的临床需求，每年增长25%。