Developing the required biomarkers that define IL-23R target engagement and effect on downstream signaling for late stage drug development and early clinical proof-of-concept

摘要 开发定义IL-23R靶向参与和对下游影响的所需生物标记物 为后期药物开发和早期临床概念验证提供信号。 炎症性肠病(IBD)影响全球约0.5%的人口。由于发病早，缺乏 如果没有足够的治疗方法，这种疾病需要终生治疗。IBD影响胃肠道(GI)和 表现为两种亚型：克罗恩病(CD)和溃疡性结肠炎(UC)。近年来，抗肿瘤坏死因子生物 药物改变了IBD的治疗方法，但这些都不是理想的药物，需要注射给药， 在某些情况下，因静脉输液而住院。这些药物有很多副作用， 包括增加的感染率；此外，任何地方都有10%-30%的患者要么失去反应(通过 产生中和抗体)或变得不耐受(例如，部位反应)。注射用药物半衰期较长 抗体可导致肿瘤坏死因子持续阻断，可加剧这些问题并使其 很难控制药物暴露，以最大限度地减少安全问题。尽管目前的抗肿瘤坏死因子药物具有类似的模式 作为行动，从一种药物转向另一种药物是一种既定的治疗方法，适用于 反应迟钝或偏执的。Stelara(Ustekinumab)针对IL-12和IL-23途径，是有效的 在对肿瘤坏死因子抵抗患者进行的第三阶段克罗恩病临床试验中。然而，有一些人担心 心血管安全事件，从Briakinumab(也是靶标)市场下架就是例证 IL-12和IL-23)，部分原因是心血管风险增加。IL-23在肠道中局部产生并发挥作用 控制肠黏膜炎症的基础作用。因此，选择性地调节IL-23途径 局部治疗病变组织是首选的治疗策略。这种方法将提供高浓度的药物 并在肠道局部阻断IL-23的功能。在第一阶段SBIR期间，我们开发了一种 高效(2 NM)，口服稳定的IL-23受体(IL-23R)拮抗剂(PN1140)，口服有效 在TNBS诱导的结肠炎模型中传递。PN1140预防体重下降，减轻结肠重量-- 长度比，以及(最重要的)改善结肠的肉眼病理。PN1140主要是 仅限于胃肠道组织，全身暴露最少。此第二阶段SBIR提案的总体目标是 开发表征体内靶向结合的方法，包括药代动力学和药效学 方法鉴定PN1140与IL-23R在不同隔室的结合及其影响 下游生物标志物和疗效。这些生物标志物将用于辅助化合物和剂量的选择，以及 以提供早期临床概念验证。具体目标是：1)开发所需的目标 接合方法使PN1140与IL-23R承载细胞的结合能够量化；2)鉴定 所需的药效学生物标志物，可反映靶向下游的生物变化 参与；以及3)靶向参与和药效学生物标记物与 大鼠结肠炎的TNBS模型。此阶段SBIR计划由在以下项目中有记录的团队提供支持 口服限制性多肽，一种已被证明的将早期研究转化为临床结果的能力， 一组在IBD方面有丰富经验的科学和临床顾问，以及适当的研究 环境。在这个第二阶段的SBIR提案中，我们描述了适当的生物标记物的开发 将通过评估目标建立早期概念验证和有效人体剂量范围 早期人体试验中的参与度和药理活性。这些都是迈向我们 最终目标是在晚期临床试验中证明临床益处。这些生物标志物将允许 评估血液、粪便和/或结肠活检样本中的特定机制和疾病相关参数。

Abstract Developing the required biomarkers that define IL-23R target engagement and effect on downstream signaling for late-stage drug development and early clinical proof-of-concept. Inflammatory bowel disease (IBD) affects about 0.5% of the world's population. Due to its early onset and lack of an adequate cure, this disease requires lifelong treatment. IBD affects the gastrointestinal (GI) tract and manifests as two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). In recent years, anti-TNF biological agents have transformed the treatment of IBD, but these are not ideal drugs, requiring administration by injection, and in some instances hospitalization for intravenous infusion. These agents have numerous side effects, including increased infection rates; additionally, anywhere from 10-30% of patients either lose response (through the production of neutralizing antibodies) or become intolerant (e.g., site reactions). Long half-lives of injected antibodies, which can result in TNF blockade over sustained periods, can exacerbate these issues and make it hard to control drug exposure to minimize safety issues. Although current anti-TNF drugs possess similar modes of action, switching from one agent to another is an established treatment approach for patients who become unresponsive or intolerant. Stelara (ustekinumab) targets both the IL-12 and IL-23 pathways and is efficacious in Phase III Crohn's disease clinical trials in TNF-resistant patients. However, there is some concern about cardiovascular safety events, as illustrated by the removal from the market of briakinumab (which also targets IL-12 and IL-23) due, in part, to increased cardiovascular risk. IL-23 is produced locally in the intestine and plays a fundamental role controlling intestinal mucosal inflammation. Hence, selectively modulating the IL-23 pathway locally in diseased tissue is the preferred strategy. Such an approach would provide high concentrations of drug in diseased tissue and block IL-23 function locally in the intestine. During the Phase I SBIR , we developed a potent (2 nM), orally stable antagonist (PN1140) of the IL-23 receptor (IL-23R) that is efficacious when orally delivered in a TNBS-induced model of colitis. PN1140 prevented body weight loss, reduced the colon weight-to- length ratio, and (most importantly) improved colon macroscopic pathology. PN1140 was predominantly restricted to GI tissue with minimal systemic exposure. The overall objective of this Phase II SBIR proposal is to develop methods for characterizing in vivo target engagement, including pharmacokinetic and pharmacodynamic methods to characterize the binding of PN1140 to IL-23R in various compartments and how binding affects downstream biomarkers and efficacy. These biomarkers will be used to aid compound and dose selections, and to provide early-stage clinical proof-of-concept. The specific objectives are to: 1) Develop the required target engagement methods to enable quantification of binding of PN1140 to IL-23R-bearing cells; 2) Identify the required pharmacodynamics biomarkers that would reflect the downstream biological changes upon target engagement; and 3) Correlate target engagement and pharmacodynamics biomarkers with efficacy readouts in TNBS models of colitis in rats. This Phase 2 SBIR program is supported by a team that has a track record in the oral delivery of constrained peptides, a proven capacity in translating early-stage research to clinical outcomes, a group of scientific and clinical advisors with significant experience in IBD, and the appropriate research environment. In this Phase II SBIR proposal, we describe the development of the appropriate biomarkers that will establish early proof-of-concept and the effective human dose range through an assessment of target engagement and pharmacologic activity in early-stage human trials. These are important steps towards our ultimate objective of demonstrating clinical benefit in late-stage clinical trials. These biomarkers will permit the assessment of mechanism-specific and disease-related parameters in blood, fecal, and/or colon biopsy samples.