CN-105 Improves Functional Outcome After Intracranial Hemorrhage

CN-105 改善颅内出血后的功能结果

• 批准号: 10765063
• 负责人: Ellen Bennett
• 金额: $ 56.23万
• 依托单位: AEGISCN, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10765063
• 关键词: Acute; Age; Algorithms; Amino Acids; Anti-Inflammatory Agents; Apolipoprotein E; Binding; Blood Proteins; Brain imaging; CCL2 gene; Cell surface; Cerebral hemisphere hemorrhage; Clinical; Clinical Research; Clinical Trials; Cognitive; Collaborations; Consultations; Coupling; Data; Development; Dose; Drug Kinetics; Edema; Elements; Evolution; Face; Funding; Gelatinase B; Half-Life; Histologic; IL17 gene; IL8 gene; Individual; Interleukin-1 beta; Interleukin-10; Intracranial Hemorrhages; Low-Density Lipoproteins; Manuals; Measurement; Measures; Monitor; Neurons; Orphan Drugs; Outcome; Participant; Patient Selection; Patients; Penetration; Peptides; Phase; Phase III Clinical Trials; Placebos; Privatization; Procedures; Proteins; Protocols documentation; Publishing; Randomized; Recovery; Regimen; Research; Research Institute; Safety; Serology; Singapore; Site; Small Business Technology Transfer Research; Statistical Data Interpretation; Stroke; Supratentorial; Surface; Testing; Therapeutic; Time; Translations; Treatment Efficacy; VWF gene; Work; anakinra; clinical efficacy; clinical translation; cohort; comorbidity; data management; data tools; design; excitotoxicity; functional improvement; functional outcomes; glial activation; hypertensive; improved; insight; interleukin-23; mortality; neuroinflammation; neuroprotection; open label; pharmacologic; phase I trial; pre-clinical; preclinical efficacy; radiological imaging; randomized placebo-controlled clinical trial; rational design; receptor; receptor binding; response; safety study; screening; sex; translational model; treatment response; trial comparing

Annually, approximately 100,000 patients in the USA suffer from intracerebral hemorrhage (ICH), which is associated with high mortality rates and poor long-term cognitive and physical recovery. At present, no pharmacological therapies have been demonstrated to improve functional outcomes after ICH. However, we have successfully demonstrated that CN-105, a pentapeptide derived from the receptor binding surface of the apolipoprotein E (apoE), is a highly promising therapy for improving recovery after ICH. CN-105 was rationally designed to mimic the LRP-1 receptor binding face of the apoE holoprotein, which binds the cell surface low density lipoprotein-related (LRP1) receptor, reducing microglial activation, neuroinflammation, and neuronal excitotoxicity. We demonstrated that CN-105 has excellent CNS penetration, is well tolerated, and retains the anti-inflammatory and neuroprotective effects of endogenous apoE holoprotein. In the Phase 1 of this STTR, we demonstrated CN-105's preclinical efficacy across species, sex, age, and hypertensive comorbidity, as evidence to support efficacy phase clinical trials. Our preclinical work with CN-105 has led to the successful completion of an IND and translation to a Phase 1 single- and multiple-escalating dose study (NCT02670824), where CN-105 demonstrated excellent clinical safety profile and linear pharmacokinetics. Based on the successful completion of the Phase 1 trial and after consultation with and funding from the FDA, we completed and recently published the CN-105 in participants from the Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial, a multisite open-label safety study in patients with acute ICH (NCT03168581)1, which demonstrated early efficacy, and completed a parallel randomized placebo-controlled clinical trial in patients with ICH in Singapore (S-CATCH; NCT03711903). Together the CATCH and S-CATCH trials will allow insight into target engagement and therapeutic efficacy of CN-105 via analyses of serologic proteins and radiographic surrogates. Given the orphan drug status of CN- 105, our preliminary data are critical to rationally inform the development of a larger and definitive ICH study. In the current proposal, we will design an adaptive Phase 2b/3 clinical trial to evaluate CN-105 efficacy, in collaboration with StrokeNet and the Duke Clinical Research Institute (DCRI) (Milestone 1). To form the basis for trial adaptation, we will utilize radiographic and serologic data already collected in the completed CATCH and S-CATCH trials to characterize an algorithm for screening treatment response to CN-105 (Milestone 2).

每年，美国约有100，000名患者患有脑出血（ICH）， 与高死亡率和长期认知和身体恢复不良有关。目前没有 药物治疗已被证明可改善ICH后的功能结局。但我们 已经成功地证明CN-105，一种来源于受体结合表面的五肽， 载脂蛋白E（apoE）是一种非常有前途的改善ICH后恢复的疗法。CN-105是合理的 设计为模拟apoE全蛋白的LRP-1受体结合面，其结合细胞表面低 密度脂蛋白相关（LRP 1）受体，减少小胶质细胞活化，神经炎症和神经元 兴奋性毒性我们证明CN-105具有良好的CNS渗透性，耐受性良好，并保留了 内源性apoE全蛋白的抗炎和神经保护作用。 在该STTR的第1阶段，我们证明了CN-105在不同物种、性别、年龄和性别的临床前疗效。 高血压合并症，作为支持疗效阶段临床试验的证据。我们对CN-105的临床前研究 已成功完成IND并转化为I期单次和多次递增剂量 研究（NCT 02670824），其中CN-105表现出优异的临床安全性特征和线性药代动力学。 基于第一阶段试验的成功完成，在与FDA协商并获得FDA资助后， 我们完成并于最近发表了CN-105在参与者从急性幕上 脑出血（CATCH）试验，一项在急性ICH患者中进行的多中心开放标签安全性研究 （NCT 03168581）1，显示了早期疗效，并完成了一项平行随机安慰剂对照研究。 新加坡ICH患者的临床试验（S-CATCH; NCT 03711903）。 CATCH和S-CATCH试验将一起允许深入了解靶向参与和治疗效果。 CN-105通过血清学蛋白和放射学替代物分析。鉴于CN的孤儿药地位- 105，我们的初步数据是至关重要的，合理地通知一个更大的和明确的ICH研究的发展。在 根据目前的提议，我们将设计一项适应性2b/3期临床试验，以评估CN-105的疗效， 与StrokeNet和杜克临床研究所（DCRI）合作（里程碑1）。奠定基础 为了适应试验，我们将利用已完成的CATCH中收集的放射学和血清学数据， S-CATCH试验，用于表征筛选CN-105治疗反应的算法（里程碑2）。