CMC of Peptide Formulation for the Treatment of 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.