Supplemental Grant Request to existing 5U01AG053247 - 03 - TK/PK Assay Analysis and Development

对现有 5U01AG053247 - 03 - TK/PK 测定分析和开发的补充拨款请求

• 批准号: 10083278
• 负责人: Eric Siemers
• 金额: $ 26.25万
• 依托单位: ACUMEN PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10083278
• 关键词: Acute; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Antibodies; Biological Assay; Clinical Trials; Contracts; Detection; Development; Development Plans; Diagnostic; Disease Progression; Dose; Failure; Feedback; Funding; Grant; Human; Immunoassay; Immunoglobulins; Immunotherapy; Investigational Drugs; Macaca fascicularis; Measurement; Memory; Methods; Minor; Monkeys; Neurons; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Plasma; Protocols documentation; Rattus; Research Design; Risk; Sample Size; Schedule; Senile Plaques; Series; Serum; Sprague-Dawley Rats; Time; Toxicokinetics; Toxicology; United States Food and Drug Administration; Validation; Visit; Work; abeta oligomer; analytical method; cost; experimental study; meetings; monomer; phase 1 designs; prevent

5U01AG053247-3 Supplemental Request Summary The development of ACU-193 for Alzheimer’s disease is now reaching the final IND-enabling portions of the non-clinical research, including first non-GLP followed by GLP toxicology studies. Following completion of the toxicology studies, the current plan is to finalize and submit an IND to FDA. The design of the Phase 1 protocol has been agreed on and the protocol will be written early in 2020. Additionally, a Type C interaction with FDA occurred with a meeting request made in December 2018. The FDA did not feel that a meeting was required but provided written feedback in February 2019 to 3 questions posed in the Briefing Document. The FDA made relatively minor requests for additional non-clinical data in the IND, which will be provided. FDA agreed in principle to the study design as described in the Briefing Document, although they did ask for a small increase in sample size in the single dose portion of the study which will be done. First patient visit for the study is planned for 4Q2020. In support of non-GLP toxicokinetic (TK/PK) dose-ranging studies, a basic electrochemiluminescent immunoassay (ECLIA) method was developed and readily qualified for measurement of ACU-193 in Cynomologous monkey plasma. In contrast, the same basic method proved unacceptable when applied to plasma from Sprague Dawley rats. Specifically, excessive imprecision was noted at the upper end of the assay dynamic range. This precluded reliable quantification of the high ACU-193 concentrations anticipated in the planned dose- ranging studies. A series of additional experiments revealed that interfering substances were present in some but not all rats. Parallel development of a bridging ECLIA for detection and characterization of Anti-Drug Antibodies (ADA) in serum from Cynomologous monkey and Sprague Dawley rat revealed reactivity, sometimes quite high reactivity, in selected drug naïve rats. No such reactivity was observed in sera obtained from Cynomolgus monkeys. The interfering substances in the rat PK/TK assay and reactivity in the rat ADA assay were ultimately determined to be rat anti-human immunoglobulin antibodies. When present, these antibodies interfered with the measurement ACU-193 in rat plasma and behaved like ADAs in the serum of treatment naïve rats. Unfortunately, funds originally intended to cover an anticipated, straightforward development and qualification of the rat TK and rat ADA assays had to be spent to define the cause of the problem and modify basic assay formats to resolve that underlying issue. Supplemental funding is now being requested to cover the costs for completing the initially planned development and qualification work. With this additional funding, we believe that first patient visit for the clinical trial can begin without a delay. Acumen Pharmaceuticals is thus requesting a $250,000 Supplemental Grant to the existing Grant 5U01AG053247 - 03 to complete the development of the rat TK/PK and ADA assays. The technical challenges as described above are requiring additional contracted time with the CRO to produce qualified methods to support non-GLP dose ranging studies and subsequently fully validate these analytical methods so that they might support the planned GLP Toxicology studies. These assays are critical as part of the IND application which is currently scheduled for September 2020. The requested additional funding will allow additional work to be performed immediately and will reduce the risk that the IND would need to be submitted at a later date. The estimated additional diagnostic activities and validation work for the TK/PK assays is estimated to be approximately $70,000, and additional development work on the ADA assay is estimated to be approximately $180,000.

5U01AG053247-3 补充请求摘要 用于治疗阿尔茨海默病的 ACU-193 的开发现已达到最终 IND 批准阶段 部分非临床研究，包括首先是非 GLP，然后是 GLP 毒理学 研究。毒理学研究完成后，目前的计划是最终确定和 向 FDA 提交 IND。第一阶段协议的设计已经达成一致，协议 将于 2020 年初编写。此外，与 FDA 的 C 类互动发生在 2018 年 12 月提出的会议请求。 FDA 认为不需要召开会议，但 于 2019 年 2 月对简报文件中提出的 3 个问题提供了书面反馈。这 FDA 对 IND 中额外的非临床数据提出了相对较小的要求，这将是 假如。 FDA 原则上同意简报文件中描述的研究设计， 尽管他们确实要求在研究的单剂量部分中小幅增加样本量 这将会完成。该研究的首次患者访视计划于 2020 年第四季度进行。 为了支持非 GLP 毒代动力学 (TK/PK) 剂量范围研究，基本 开发了电化学发光免疫分析 (ECLIA) 方法，并且易于验证 食蟹猴血浆中 ACU-193 的测量。相比之下，同样的基本 当应用于斯普拉格道利大鼠的血浆时，该方法被证明是不可接受的。具体来说， 在检测动态范围的上限处注意到过度的不精确性。这排除了 对计划剂量中预期的高 ACU-193 浓度进行可靠的定量 范围研究。一系列额外的实验表明，干扰物质 存在于一些但不是所有大鼠中。用于检测和检测的桥接 ECLIA 的并行开发 食蟹猴血清中抗药物抗体 (ADA) 的表征 斯普拉格道利大鼠在选定的药物天真中显示出反应性，有时反应性相当高 老鼠。在从食蟹猴获得的血清中没有观察到这种反应性。这 大鼠 PK/TK 测定中的干扰物质和大鼠 ADA 测定中的反应性最终得到 经鉴定为大鼠抗人免疫球蛋白抗体。当存在时，这些抗体 干扰大鼠血浆中 ACU-193 的测量，并且在大鼠血清中表现得与 ADA 相似 治疗幼稚大鼠。不幸的是，资金最初是用于支付预期的， 必须花费直接开发和鉴定大鼠 TK 和大鼠 ADA 测定的费用 确定问题的原因并修改基本检测格式以解决根本问题 问题。现在正在请求补充资金来支付完成该项目的费用 初步计划的开发和资格认证工作。有了这笔额外资金，我们相信 临床试验的首次患者就诊可以立即开始。 因此，Acumen Pharmaceuticals 请求在现有拨款的基础上追加 250,000 美元 5U01AG053247 - 03 完成大鼠 TK/PK 和 ADA 测定的开发。这 上述技术挑战需要与 CRO 签订额外的合同时间来 制定合格的方法来支持非 GLP 剂量范围研究，并随后全面 验证这些分析方法，以便它们支持计划的 GLP 毒理学 研究。这些检测作为目前计划进行的 IND 申请的一部分至关重要 2020 年 9 月。请求的额外资金将允许开展额外的工作 立即，并将降低需要稍后提交 IND 的风险。 预计 TK/PK 检测的额外诊断活动和验证工作为 估计约为 70,000 美元，并且 ADA 检测的额外开发工作 估计约为180,000美元。