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

基本信息

批准号：
10263351
负责人：
Simon Lichtiger
金额：
$ 61.32万
依托单位：
LANDOS BIOPHARMA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-14 至 2023-12-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10263351
关键词：
Abdominal Pain Address Adverse event Anti-Inflammatory Agents Autoimmune Diseases Benign Biological Availability 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&apos s disease Data Development Disease Disease Management Dose Double-Blind Method Down-Regulation Drug Kinetics Endoscopy Epithelial Cells FOXP3 gene 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 Molecular Monitor Mononuclear No-Observed-Adverse-Effect Level North America Oral Outcome Participant Pathway interactions Patients Peripheral Blood Mononuclear Cell Persons 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 biopharmaceutical industry 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 porcine model 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

项目摘要

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概念概念证明功效 Landos Biopharma是一家临床阶段的生物制药公司，专注于发现和开发自身免疫性疾病患者的创新一流的口服疗法。我们的铅资产BT-11是靶向灯笼合成酶C样2（LANCL2）的新型口服，肠道限制性研究新药（IND）炎症性肠病（IBD）期间肠道中的途径。对更安全，更有效的临床需求未满足 IBD药物仍然存在，因为当前疗法的有效性和不良副作用。技术和产品。 Landos设计的BT-11（一种新的化学实体）激活LANCL2途径在胃肠道（GI）中有选择地治疗克罗恩病（CD）。 BT-11的激活 LANCL2通过对调节反应的双重上调和炎症的下调来发挥作用回答。 BT-11的效率已在5个小鼠IBD模型和初级人类的翻译研究中得到了证明 PBMC和LPMC。 BT-11主要定位于GI，NOAEL在3个月的GLP大鼠中> 1,000 mg/kg 和狗的毒性研究。 BT-11计划有2个开放IND（138071＆128490），完成了I期临床 2018年的测试，并于2019年8月对轻度至中度UC患者进行了2期临床研究。 R01应用程序的具体目的是：（1）评估CD患者BT-11的血液和粪便PK谱。血样将在在第一次的天数，16个时间点（预剂量，0.25、0.75、1.25、1.5、2、3、4、6、6、8、12、18、24、48 h）剂量和第七剂量。每天将收集粪便样品。血浆和粪便将被处理并分析了全身和肠道BT-11浓度。（2）验证CD患者BT-11活性的PD生物标志物。使用14-D生成的样品 1B研究期，我们将测量C反应蛋白TNFα，IFNγ，IL-6和IL-10的浓度粪便中的血浆和钙染色素和乳铁蛋白。（3）进行概念验证研究，以评估CD患者BT-11的效率和机制。中度至重度CD患者将与12周的口服片剂一起治疗，其中包含1,000 mg bt- 11或安慰剂（每臂n = 20）。将在基线，2、6和12周监视受试者以评估症状并在基线和12周时用内窥镜收集血液和粪便。主要的成功结果将是诱导临床缓解和内窥镜反应。次要结果将包括：粪便中BT-11的> 1 mg/g浓度，等离子体CRP和粪便的减少通过BT-11处理，钙特染色素，血浆中炎症细胞因子的降低。 Landos技术的长期目标是开发更安全，更有效的一流的口服疗法 IBD解决了超过100亿美元和每年增长25％的市场未满足的临床需求。