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 2 期概念验证疗效 Landos Biopharma 是一家临床阶段的生物制药公司，专注于发现和开发我们的主要资产 BT-11 是一种针对自身免疫性疾病患者的创新型一流口服疗法。新型口服、肠道限制性研究新药 (IND)，靶向羊毛硫氨酸合成酶 C-Like 2 (LANCL2) 炎症性肠病 (IBD) 期间肠道中的通路对更安全、更有效的临床需求尚未得到满足。 IBD 药物仍然存在，因为目前的疗法疗效有限且有不良副作用。 Landos 设计了 BT-11，一种新的化学实体，用于激活 LANCL2 途径。选择性地在胃肠道 (GI) 内治疗克罗恩病 (CD) 的激活。 LANCL2 通过调节反应的双重上调和炎症的下调发挥作用 BT-11 的功效已在 5 个 IBD 小鼠模型和原代人类转化研究中得到证实。 PBMC 和 LPMC 主要定位于胃肠道，3 个月 GLP 大鼠的 NOAEL 大于 1,000 mg/kg。 BT-11项目有2个开放的IND（138071和128490），已完成I期临床。于 2018 年进行测试，并于 2019 年 8 月启动了针对轻至中度 UC 患者的 2 期临床研究。 R01 应用程序的具体目标是： (1) 评估 CD 患者的血液和粪便 BT-11 PK 特征采集血液样本。第一个给药日的 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 小时）每天收集第 1 剂和第 7 剂粪便样本，并处理粪便。并分析全身和肠道 BT-11 浓度。 (2) 使用 14 天生成的样本验证 CD 患者中 BT-11 活性的 PD 生物标志物。 1b期研究，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 患者将接受含有 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 周对受试者进行监测以评估症状。并在基线和 12 周时通过内窥镜检查收集血液和粪便。主要的成功结果将是诱导临床缓解和内镜反应。次要结果包括：粪便中 BT-11 浓度 >1 mg/g、血浆 CRP 和粪便浓度降低 BT-11 治疗可减少钙卫蛋白，并减少血浆中的炎症细胞因子。 Landos 技术的长期目标是开发更安全、更有效的一流口服疗法 IBD 解决了超过 100 亿美元且每年增长 25% 的市场未满足的临床需求。