IND Enabling Studies for a Novel Mas Receptor Agonist for Treatment of Cognitive Impairment in Patients at Risk for Alzheimer's Disease Related Dementia

项目摘要 拟定补充与母公司U 01直接相关，并将提供探索性临床证据 需要一个更大的充分把握度的研究，以确定血液Nfl值是否可以作为预后生物标志物 并作为我们U 01后计划的临床试验中的临床试验富集工具， VCID在高危心力衰竭（HF）患者中的发展。 在我们的U 01 TPP中，我们计划我们的第一个患者人群包括有心脏病风险的VCID人群， 射血分数降低和轻度认知功能障碍证据的II/IV级衰竭患者。我们 我相信NfL可以作为我们计划的1b/2a期临床试验的临床试验富集工具， 有望防止ADRD高危HF患者发生VCID。本研究的时间安排 行政补充将使我们的团队处于一个很好的位置，部署NFL作为生物标志物， 临床试验合格性标准的入组富集，以确定哪些HF患者更有可能 开发VCID/ ADRD。 在临床上，VCID诊断和病情监测一般通过磁共振成像（MRI）实现 扫描和白色高信号（WMH）的存在，通常被解释为 脑小血管病（SVD）。然而，最常见的VCID评估和诊断方法是MRI， 发生在显著的临床测量认知功能障碍的发展之后。神经丝轻蛋白 (NfL)在血液和脑脊髓液中发现的神经丝，已被证明在轴突生长后增加。 损伤和神经退行性变，与认知障碍的增加密切相关， 在患有神经退行性疾病、缺氧性脑损伤和心脏病的受试者中观察到升高 和相关手术。目前还不清楚NfL是否可以用于检测VCID风险个体的神经元损伤 如患有慢性炎症性疾病如冠心病或HF患者。理想情况下，如果我们能 预测心脏病患者神经和认知并发症的存在，我们将能够 以确定那些有风险的VCID患者谁将受益于治疗性治疗。 我们提出的使用背景是NfL可能作为血液中的预后生物标志物，可以帮助预测 早期风险VCID伴II/IV期心力衰竭（HF）的临床进展。我们的最终目标是利用 血液中的Nfl水平作为我们计划的U 01后临床试验的入组富集因子， HF患者更容易发生VCID或ADRD。 具体目的：在有VCID风险的HF患者中建立基线和12个月纵向Nfl值， 确定受试者的Nfl绝对水平与认知功能和MRI测量之间的关联 I/II期和III-IV期HF患者。

PROJECT SUMMARY The proposed supplement is directly related to the parent U01 and will provide the exploratory clinical evidence needed for a larger fully powered study to determine if blood Nfl values might serve as a prognostic biomarker and as a clinical trial enrichment tool in our post U01 planned clinical trials to treat and hopefully prevent the development of VCID in at-risk heart failure (HF) patients. In our U01 TPP, we planned our first patient population to include an at-risk VCID population that include Heart Failure Class II/IV patients with decreased ejection fraction and evidence of mild cognitive impairment. We believe that NfL may serve as a clinical trial enrichment tool in our planned Phase 1b/2a clinical trial to treat and hopefully prevent the development of VCID in ADRD at-risk HF patients. The timing of proposed study in this administrative supplement will position our team in an excellent position to deploy Nfl as a biomarker for enrollment enrichment for clinical trial eligibility criteria to identify which HF patients who are more likely to develop VCID/ ADRD. In the clinic, VCID diagnosis and disease monitoring is generally achieved by magnetic resonance imaging (MRI) scans and the presence of white matter hyperintensities (WMH) that are typically interpreted as a surrogate of cerebral small vessel disease (SVD). However, the assessment and diagnosis of VCID using MRI most often occurs after the development of significant clinically measured cognitive dysfunction. Neurofilament light protein (NfL), a neurofilament found in blood and cerebral spinal fluid, has been shown to increase following axonal damage and neurodegeneration and is tightly correlated with increased cognitive impairment and has been observed to be elevated in subjects with neurodegenerative diseases, hypoxic brain injury, and cardiac disease and related surgeries. It is unclear if NfL can be used to detect neuronal damage in individuals at risk for VCID such as those withs chronic inflammatory disease such as coronary heart disease or HF. Ideally, if we can predict the presence of neurological and cognitive complications in individuals with heart disease, we will be able to identify those at-risk VCID patients who would benefit from therapeutic treatment. Our proposed Context of Use is that NfL might serve as a Prognostic Biomarker in blood that can help predict clinical progression in early at-risk VCID with stage II/IV heart failure (HF). Our ultimate goal will be to use levels of Nfl in blood as an enrollment enrichment factor for our planned post U01 clinical trial to identify individuals with HF who are more likely to develop VCID or ADRD. Specific Aim: Establish a baseline and 12-month longitudinal Nfl values in HF patients at risk for VCID and determine the association between absolute levels of Nfl with measures cognitive function and MRI in subjects with stage I/II and III-IV HF patients.