CMC of Peptide Formulation for the Treatment of ARDS

用于治疗 ARDS 的肽制剂的 CMC

基本信息

批准号：
10379771
负责人：
Gerardo M. Castillo
金额：
$ 100万
依托单位：
PHARMAIN CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10379771
关键词：
Accounting Acetates Acute Acute Lung Injury Acute Respiratory Distress Syndrome Animals Anti-Inflammatory Agents Antibodies Antigens Atrial Natriuretic Factor Attenuated Bacterial Pneumonia Biological Assay Blood Blood Pressure C-Type Natriuretic Peptide COVID-19 COVID-19 pandemic Canis familiaris Cells Cessation of life Chemicals Chemistry Chemotactic Factors Chronic Cicatrix Clinical Clinical Trials Communicable Diseases Cyclic GMP Data Development Dose Emergency Situation Equipment Event Excipients FDA approved Fatty Acids Formulation Funding Health Personnel Healthcare Systems Home Hospitals In Vitro Incidence Individual Infection Inflammation Inflammatory Influenza Injectable Interleukin-1 beta Interleukin-6 Length of Stay Life Liquid substance Lung Lung Lavage Fluid Maximum Tolerated Dose Measures Methods Middle East Respiratory Syndrome Mus Orphan Drugs Pathology Pathology Report Patients Peptides Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Polymers Population Prevalence Privatization Production Proteins Pulmonary Inflammation Pulmonary Pathology Pulmonary alveolar structure Quarantine Rattus Regulatory Affairs Safety Savings Secure Self Administration Severe Acute Respiratory Syndrome Small Business Innovation Research Grant Solid Sterility Structure of parenchyma of lung Syndrome System TNF gene Testing Time Tissues Toxicology Up-Regulation Ventilator Work base copolymer cytokine experimental study factor A fibrotic lung improved inhibitor macrophage mortality necrotic tissue neutrophil novel novel therapeutics pandemic disease peptide B peptide drug receptor respiratory safety study screening side effect subcutaneous success

项目摘要

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：如果没有像 COVID-19 这样的大流行，急性呼吸综合征 (ARDS) 的流行据估计，美国每年约有 200-24 万患者与急性肺损伤 (ALI) 相关，其中每年住院 360 万天，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可满足的需求将超过 400 万患者/年。此申请正在寻求化学、制造和控制 (CMC) 资助含有长效抗炎 C 型利尿钠肽的新型药品的生产用于治疗以肺部炎症为主的 ALI 和 ARDS 的衍生物。 2019 年冠状病毒病 (COVID-19) 或任何其他严重肺部炎症事件的触发因素（例如 SARS、MERS、致命流感、细菌性肺炎或化学/抗原）会导致 ARDS，从而危及健康血液氧合。 ARDS 需要在医院 ICU 中使用呼吸机，并且 ARDS 是由传染性极强引起的传染病可能导致急性呼吸窘迫综合征病例激增，并使医疗保健系统不堪重负由于医疗保健提供者被感染或害怕工作，这些设备可能会进一步减少。这目前的提案如果成功，可以通过提供一种可以自行注射的安全注射制剂来缓解这一问题。由感染者在家中进行严格的家庭隔离。我们已经完成证明我们的新配方在小鼠中的功效。本提案将开发一种具有长保质期的配方通过评估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，计划中的 GLP 毒理学研究和临床试验，此外还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定。这根据 FDA 的要求，同一套测定法将测量随时间的稳定性。化验将确定质量，药品配方及其其他成分的完整性、纯度、效力和无菌性 (QIPPS)。此外，我们将确定 a) 慢性最大耐受剂量（MTD，大鼠 28 天每日 SC 给药）药品及其赋形剂，b) 持续升高所需的最小剂量（至少 2- 对于 QD 配方，血液环 GMP 水平持续 24 小时，对于 BIW 配方，持续 84 小时，对于 BIW 配方，可能持续 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。结果这将指导我们在大鼠和狗中执行完整的 GLP-Tox 研究，以提交 IND 文件。我们将制备 200g API 和足够的受保护接枝共聚物 (PGC) 赋形剂以及明确的 QIPPS（在 PharmaIN）。我们将在 cGMP 灌装和加工工厂配制药品。这将提供足够的制剂以完成支持 IND 的 GLP 毒理学测试和 1 期临床安全性研究。