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

点击翻译按钮获取中文摘要

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.