CMC of Peptide Formulation for the Treatment of ARDS

用于治疗 ARDS 的肽制剂的 CMC

• 批准号: 10839580
• 负责人: Gerardo M. Castillo
• 金额: $ 96.77万
• 依托单位: PHARMAIN CORPORATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10839580
• 关键词: CMC; Peptide; Formulation; Treatment; ARDS

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.

摘要：没有大流行，例如Covid-19，急性呼吸综合征的患病率（ARDS） 与急性肺损伤（ALI）有关 每年360万日期，死亡率为30-40％。考虑到美国仅占4.23％ 世界人口，ARDS的可能发生率和商业上可寻求的需求将超过400万 患者/年。该应用程序正在寻求用于化学，制造和控制（CMC）的资金 生产新的药物，其中包含非常长的抗炎型Natriaret肽 用于治疗ALI和ARD的衍生物，其特征在于绝大多数肺部炎症。 冠状病毒疾病2019（COVID-19）或严重肺部炎症事件的任何其他触发因素（例如 SARS，MERS，致命的流感，细菌性肺炎或化学/抗原）导致妥协的ARDS 血液氧合。 ARDS需要在医院ICU中的呼吸机，并且由非常传染性引起的ARDS 在ARDS病例中，传染病可能导致升高，并压倒医疗保健系统的能力和 医疗保健提供者被感染或害怕工作可以进一步减少的设备。这 目前的建议，如果成功的话，可以通过提供可以自我自我的安全注射配方来缓解这种情况 由严格家庭隔离的受感染者在家中管理。我们已经完成了证明 我们在小鼠中新型配方的功效。目前的提议将开发一个长架子的公式 通过评估各种赋形剂来稳定。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，并在大流行期间允许现场部署 紧急情况。我们将，建立，验证和验证产品释放所需的所有分析测定法。这 同一组测定将按时间测量稳定性，按照FDA的要求。这些测定将建立质量， 药物制剂及其其他成分的完整性，纯度，效力和不育（QIPP）。 此外，我们将确定a）慢性最大耐受剂量（MTD，大鼠的28天每日sc剂量） 药物及其赋形剂，b）持续升高所需的最低剂量（至少2-- 折叠量为24小时的血液环-GMP水平，用于QD公式，BIW配方为84h，可能为168h，用于168H QW公式和c）体外毒理学筛查潜在的脱靶受体副作用。结果 这将指导我们在执行大鼠和狗的一项完整的GLP-TOX研究中，以提交IND文件。我们将 用定义明确的Qipps制作200G API和足够的受保护的移植共聚物（PGC）赋形剂（在 药品）。我们将在CGMP填充和完成设施中制定药物。这将提供足够的 配方以完成辅助GLP毒理学测试和1阶段临床安全研究。