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第二阶段概念验证疗效 兰多斯生物制药是一家专注于发现和开发的临床期生物制药公司 为自身免疫性疾病患者提供一流的创新口腔疗法。我们的主要资产BT-11是一架 针对羊硫氨酸合成酶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)时肠道中的通路。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，因为目前的治疗方法疗效有限，副作用较大。 技术与产品。兰多斯设计了一种新的化学实体BT-11来激活LANCL2途径 选择性地在胃肠道(GI)内用于治疗克罗恩病(CD)。Bt-11的激活 LANCL2通过上调调节反应和下调炎症反应来发挥作用 回应。BT-11在5种IBD小鼠模型和原始人的翻译研究中被证明有效 PBMC和LPMCs。BT-11主要定位于GI，在3月龄GLP大鼠的NOAEL为1,000 mg/kg 和狗的毒性研究。BT-11计划有2个开放的IND(138071和128490)，已完成I期临床 2018年进行了测试，并于2019年8月启动了针对轻中度UC患者的第二阶段临床研究。 R01应用的具体目标是： (1)评价CD患者血和粪便BT-11的PK谱。血液样本将在以下地点采集 第一天的16个时间点(剂量前、0.25、0.5、0.75、1、1.25、1.5、2、3、4、6、8、12、18、24、48小时) 剂量和第七剂。每天都会采集粪便样本。血浆和粪便将被处理 并分析了全身和肠道中Bt-11的浓度。 (2)验证CD患者BT-11活性的PD生物标志物。使用从14-d生成的样本 1b期研究，我们将测定C反应蛋白、肿瘤坏死因子α、干扰素γ、IL-6和IL-10的浓度。 血浆和粪便中的钙保护素和乳铁蛋白。 (3)开展一项概念验证研究，以评估BT-11对CD患者的疗效和机制。 中重度CD患者口服含1,000 mg BT的片剂治疗12wk。 11或安慰剂(n=20)。受试者将在基线、2周、6周和12周进行监测，以评估症状。 并在基线和12周时用内窥镜采集血和粪便。 主要的成功结果将是临床缓解和内窥镜反应的诱导。 次要结果将包括：粪便中Bt-11浓度为1 mg/g，血浆CRP和粪便减少 BT-11可降低血浆中炎症细胞因子的水平。 兰多斯公司技术的长期目标是开发更安全、更有效的一流口腔疗法 IBD解决了一个超过100亿美元且每年增长25%的市场的未得到满足的临床需求。

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.