CMC of Peptide Formulation for the Treatment of ARDS

摘要：如果没有像COVID-19这样的大流行，急性呼吸综合征（ARDS）的患病率 据估计，美国每年约有20 - 24万例患者与急性肺损伤（ALI）相关， 3.6-每年有100万个住院日，死亡率为30-40%。考虑到美国仅占4.23%， 世界人口中，ARDS的可能发病率和商业上可解决的需求将超过400万 患者/年该申请正在寻求化学，制造和控制（CMC）的资金， 含有非常长效的抗炎C型利钠肽的新药物产品的生产 本发明提供了用于治疗以压倒性的肺部炎症为特征的ALI和ARDS的衍生物。 2019冠状病毒病（COVID-19）或任何其他严重肺部炎症事件的触发因素（如 SARS、MERS、致命性流感、细菌性肺炎或化学/抗原）导致ARDS， 血液氧合ARDS需要在医院ICU使用呼吸机，而ARDS是由非常具有传染性的 传染病可导致ARDS病例激增，并使卫生保健系统不堪重负， 设备，可以进一步减少医疗保健提供者被感染或害怕工作。的 本发明的建议如果成功的话，可以通过提供一种安全的可注射制剂来缓解这种情况， 在严格的家庭隔离下由受感染的个人在家中施用。我们已经完成了 我们的新制剂在小鼠中的功效。本提案将开发一种具有长货架期的制剂 通过评价各种赋形剂的稳定性。这将为商业产品提供所需的货架稳定性， 计划的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、鉴定和验证产品放行所需的所有分析测定。的 根据FDA的要求，同一组试验将测量随时间推移的稳定性。试验将确定质量， 制剂处方及其其他组分的完整性、纯度、效价和无菌性（QIPPS）。 此外，我们将确定a）以下的慢性最大耐受剂量（MTD，大鼠中28天每日SC给药）： 药物产品沿着其赋形剂，B）持续升高所需的最小剂量（至少2- QD制剂的血液循环GMP水平为24小时，BIW制剂为84小时， QW制剂，和c）潜在脱靶受体副作用的体外毒理学筛选。的结果 这将指导我们在大鼠和犬中进行完整的GLP-Tox研究，以提交IND文件。我们将 制备200 g API和足够的具有明确定义的QIPPS的受保护的接枝共聚物（PGC）赋形剂（在 PharmaIN）。我们将在cGMP灌装和成品设施中配制制剂。这将提供足够的 完成IND使能GLP毒理学试验和I期临床安全性研究。

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.