Development of an M1 PAM experimental therapeutic for schizophrenia

开发治疗精神分裂症的 M1 PAM 实验疗法

• 批准号: 9140071
• 负责人: P Jeffrey Conn
• 金额: $ 182.77万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9140071
• 关键词: Adverse effects; Anhedonia; Animal Model; Animals; Architecture; Attention; Behavioral; Biological Markers; Brain Diseases; Chemistry; Clinical; Clinical Research; Cognitive; Data; Delusions; Development; Disease; Dose; Dose-Limiting; Drug Discovery Groups; Electroencephalography; Equilibrium; Evaluation; Funding; Future; Goals; Grant; Guidelines; Hallucinations; Human; Human Volunteers; Impaired cognition; Investigational Drugs; Investigational New Drug Application; Investigational Therapies; Learning; Mediating; Mental disorders; Muscarinic Acetylcholine Receptor; National Institute of Mental Health; Nervous System Physiology; Neuraxis; Paranoia; Patients; Pharmacologic Substance; Phase; Plasma; Property; Rodent; Safety; Schizophrenia; Sleep; Speech; Strategic Planning; Symptoms; Testing; Therapeutic Agents; Toxicokinetics; Withdrawal; associated symptom; clinical biomarkers; cognitive function; cognitive performance; drug candidate; executive function; improved; long term memory; new therapeutic target; nonhuman primate; novel; novel strategies; novel therapeutics; positive allosteric modulator; pre-clinical; preclinical study; programs; public health relevance; research clinical testing; response; safety study; scale up; social; standard of care; symptom cluster; tool; treatment strategy

 DESCRIPTION (provided by applicant): Available treatments for schizophrenia are not effective in treatment of all major symptoms associated with the disease and induce a number of dose-limiting adverse effects. Thus, there is a critical need to develop novel therapeutic agents for treatment of schizophrenia that have broader efficacy and fewer adverse effects. During the initial funding period of the Vanderbilt NCDDG for discovery of novel treatments for schizophrenia, we made tremendous progress in discovery of drug candidates for novel targets and partnering with pharmaceutical companies to advance these agents to clinical development. In addition, we built on previous clinical studies suggesting that selective activators of the M1 muscarinic acetylcholine receptor have potential for treatment of cognitive disturbances and negative symptoms associated with schizophrenia. We optimized novel highly selective M1 positive allosteric modulators (PAMs) and have extensively evaluated these compounds in animal models of cognitive function and in pre-GLP safety studies. We have identified VU0467319 as a highly optimized M1 PAM that possesses an excellent balance of properties required for selection as a clinical development candidate. We now propose continued support of the Vanderbilt NCDDG to advance VU0467319 into first in human studies and to rigorously establish the doses required to achieve activation of M1 in healthy human volunteers. Project 1 will develop and validate a new translational biomarker for M1 PAM activity that can be used as a surrogate for target engagement and dose-finding studies in early clinical development. Project 2 will provide scale-up synthesis of VU0467319 and other compounds and provide backup clinical candidates to respond to findings with VU0467319 during GLP safety assessment. Project 3 will focus on IND-enabling studies to open an IND to allow clinical evaluation of VU0467319. In Project 4, we will perform safety assessments of VU0467319 in healthy human volunteers and employ the biomarker developed in project 1 to establish the doses required to achieve adequate CNS activity in humans. In addition, project 4 will provide a preliminary assessment of effects of VU0467319 on cognitive function in humans. These studies will provide a fully validated clinical research tool for future clinical studies to fully evaluate the efficacy of a highly optimized M1 PAM in schizophrenia patients.

 描述（由申请人提供）：现有的精神分裂症治疗方法不能有效治疗与该疾病相关的所有主要症状，并引起许多剂量限制性不良反应。因此，迫切需要开发具有更广泛功效和更少副作用的用于治疗精神分裂症的新型治疗剂。在范德比尔特NCDDG发现精神分裂症新疗法的最初资助期间，我们在发现新靶点的候选药物以及与制药公司合作将这些药物推向临床开发方面取得了巨大进展。此外，我们建立在以前的临床研究表明，M1毒蕈碱乙酰胆碱受体的选择性激活剂有可能治疗与精神分裂症相关的认知障碍和阴性症状。我们优化了新型高选择性M1正变构调节剂（PAM），并在认知功能的动物模型和GLP前安全性研究中广泛评估了这些化合物。我们已经将VU0467319确定为高度优化的M1 PAM，其具有选择作为临床开发候选物所需的优异性质平衡。我们现在建议继续支持范德比尔特NCDDG将VU 0467319推进为首次人体研究，并严格确定在健康人类志愿者中实现M1激活所需的剂量。项目1将开发和验证M1 PAM活性的新翻译生物标志物，可用作早期临床开发中靶点参与和剂量探索研究的替代物。项目2将提供VU 0467319和其他化合物的放大合成，并提供备用临床候选药物，以应对GLP安全性评估期间VU 0467319的发现。项目3将重点关注IND启动研究，以启动IND，从而对VU 0467319进行临床评价。在项目4中，我们将在健康人类志愿者中进行VU 0467319的安全性评估，并采用项目1中开发的生物标志物来确定在人体中达到足够CNS活性所需的剂量。此外，项目4将提供VU 0467319对人类认知功能影响的初步评估。这些研究将为未来的临床研究提供充分验证的临床研究工具，以充分评价高度优化的M1 PAM在精神分裂症患者中的疗效。