CMC of Peptide Formulation for the Treatment of ARDS

摘要：如果没有像新冠肺炎这样的大流行，急性呼吸综合征的流行 据估计，在美国，每年约有200-24万患者与急性肺损伤(ALI)有关，占 每年360万住院日，死亡率为30%-40%。考虑到美国只占全球的4.23% 世界人口，ARDS的可能发生率和商业上可满足的需求将超过400万 病人/年。此应用程序正在为以下项目寻求化学、制造和控制(CMC)资金 一种含有超长效抗炎C型利钠肽的新药的制备 用于治疗以肺部炎症为主的ALI和ARDS的衍生物。 冠状病毒病2019(新冠肺炎)或任何其他触发严重肺部炎症事件(例如 SARS、MERS、致命流感、细菌性肺炎或化学/抗原)会导致ARDS 血液氧合作用。ARDS需要在医院ICU使用呼吸机而引起的ARDS具有很强的传染性 传染病可导致ARDS病例激增，并使卫生保健系统的能力不堪重负 如果医疗保健提供者受到感染或不敢工作，设备可能会进一步减少。这个 目前的建议，如果成功，可以通过提供一种安全的注射制剂来缓解这种情况，该制剂可以自我释放 在家中由感染者在严格的家庭隔离下进行管理。我们已经完成了证明 我们的新配方在小鼠身上的疗效。目前的建议将开发一种长货架配方 通过评价各种辅料的稳定性。这将为商业产品提供所需的货架稳定性 计划中的GLP毒理学研究和临床试验，并允许在大流行期间进行现场部署 紧急情况。我们将建立、鉴定和验证产品发布所需的所有分析测试。这个 按照FDA的要求，同一套检测方法将测量随着时间的推移的稳定性。化验结果将确定质量， 药品配方及其其他成分的完整性、纯度、效力和无菌(QIPPs)。 此外，我们将确定a)慢性最大耐受量(MTD，大鼠每日28天SC剂量) 药物产品及其辅料，b)持续升高所需的最小剂量(至少2- 倍)的血液循环-GMP水平，对于QD配方为24小时，对于BIW配方为84小时，并且可能为168小时 QW配方，以及c)体外毒理学筛选潜在的脱靶受体副作用。其结果是 这将指导我们在大鼠和狗身上进行完整的GLP-TOX研究，以提交IND文件。我们会 使200克原料药和足够的保护接枝共聚物(PGC)赋形剂具有明确的QIPPS(在 Pharmain)我们将在cGMP灌装和加工设施中配制药物产品。这将提供足够的 配方以完成启用IND的GLP毒理学测试和第一阶段临床安全性研究。

ABSTRACT: Without a pandemic such as COVID-19, the prevalence of Acute Respiratory Syndrome (ARDS) associated with Acute Lung Injury (ALI) is estimated to be ~200-240K patients/year in the US, accounting for 3.6-million hospital days per year and with 30-40% mortality. Considering that US represent only 4.23 % of world population, the likely incidence of ARDS and commercially addressable needs will be over 4 million patients/year. This application is seeking funding for Chemistry, Manufacturing, and Control (CMC) for production of a novel drug product containing a very long-acting anti-inflammatory C-type natriuretic peptide derivative for use in the treatment of ALI and ARDS characterized by overwhelmingly lung inflammation. Coronavirus disease 2019 (COVID-19) or any other trigger of a severe lung inflammatory event (such as SARS, MERS, deadly influenza, bacterial pneumonia, or chemical/antigen) leads to ARDS that compromises blood oxygenation. ARDS requires a ventilator in a hospital ICU and ARDS caused by very contagious infectious diseases can cause in spike in ARDS cases and overwhelm the health care system capacity and equipment that can further be diminished by healthcare provider becoming infected or scared to work. The present proposal, if successful, can alleviate that by providing a safe injectable formulation that can be self- administered at home by an infected individual under strict home quarantine. We have completed proof of efficacy of our novel formulation in mice. The present proposal will develop a formulation with long shelf stability by evaluating various excipients. This will provide needed shelf stability for commercial product, during a planned GLP toxicology study and clinical trial and additionally allow field deployment during a pandemic emergency. We will, establish, qualify, and validate all the analytical assays needed for product release. The same set of assays will measure stability over time, as required by the FDA. The assays will establish Quality, Integrity, Purity, Potency and Sterility (QIPPS) of the drug product formulation and its other components. Additionally, we will determine a) the chronic maximum tolerated dose (MTD, 28-day daily SC dosing in rats) of the drug product along with its excipients, b) the minimum dose required for sustained elevation (at least 2- fold) of blood cyclic-GMP level for 24h for QD formulation, 84h for BIW formulation, and potentially 168h for QW formulation, and c) in vitro toxicology screening for potential off-target receptor side effects. The result of this will guide us in the execution a full GLP-Tox study in rats and dogs for IND document submission. We will make 200g API and enough protected graft copolymer (PGC) excipient with well-defined QIPPS (at PharmaIN). We will formulate the drug product at a cGMP fill and finish facility. This will provide enough formulation to complete IND-enabling GLP-toxicology testing and Phase 1 clinical safety study.