The global prevalence of chronic kidney disease (CKD) is estimated to be greater than 10%, affecting approximately 500 million people around the world, and due to the global type II diabetes epidemic, incidence is expected to rise. CKD-specific treatments do not currently exist. Clinical management focuses primarily on controlling blood pressure using renin–angiotensin system (RAS) inhibitors, which results in attenuated CKD progression, but it is not curative. Kidney fibrosis (KF) is a pathological hallmark of CKD and a major contributing factor to progression to end-stage renal disease. Therefore, developing a therapy that targets fibrotic processes in the kidney may slow or halt CKD progression, reducing the cost and the quality of life burdens that accompany dialysis and transplantation. Lung Therapeutics’ patented LTI-03 is a 7-mer peptide (FTTFTVT) derived from the 20-mer caveolin-1 scaffolding domain (CSD) of CAV-1 (known as CSP7 in the literature). It attenuates established fibrosis in multiple in vivo pre-clinical models of dermal, cardiac and pulmonary fibrosis (PF) and attenuates multiple pro-fibrotic signaling pathways in vitro. We have developed an inhaled formulation of LTI-03 for the treatment of Idiopathic Pulmonary Fibrosis (IPF), and regulatory approval was received to start a first in human safety trial in 2020. Cav1-/- mice demonstrate increased cell proliferation and collagen synthesis, leading to myocardial hypertrophy and pulmonary hypertension; both are normalized by endothelial cell specific re- expression of Cav-1. Furthermore, Cav1-/- mice exhibited more extensive interstitial fibrosis than WTs following release of a unilateral ureteral obstruction (RUUO). Recently, CSD peptide was found to be efficacious in reducing both heart and kidney fibrosis in an angiotensin model of systemic hypertension. Lung Therapeutics’ patented, soluble and proteolysis resistant peptide, LTI-2355, was even more efficacious than CSD (data unpublished). Furthermore, while both of the FDA-approved (non-curative) IPF drugs Nintedanib and Pirfenidone were efficacious for reducing KF in the UUO model, a new therapeutic, PRM-151, was efficacious in the Alport Syndrome (AS) model of CKD and in a 2019 Ph2 clinical trial for IPF. Based on these findings, we propose to develop both a simple and extended release form of LTI-2355 for subcutaneous (SC) delivery and to generate stability and pharmacokinetic data. Next, after obtaining stability and PK data, leads will be rigorously evaluated in a rapid onset AS model to identify the best lead candidate. The final lead will be assessed in a moderate onset AS model (evaluated both against and with standard of care). Pending efficacious results, a lead candidate will be selected, and a Phase II will be filed to support further clinical development (PK/PD, toxicology specificity of SC formulation, IND-supporting work). This proposal caters to the aggregate strengths of the team including peptide formulation, expertise in the biochemical assessment of organ fibrosis, and animal models of fibrotic kidney disease. Finally, this project has strong potential to yield a novel therapy for the treatment of CKD.
Public Health Relevance Statement: Project Narrative Clinical management of chronic kidney disease (CKD) focuses primarily on controlling blood pressure using renin-angiotensin system (RAS) inhibitors, which results in attenuated CKD progression, but this treatment is not curative. Caveolin-1 scaffolding domain (CSD) peptides have been demonstrated to be anti-fibrotic in cardiac, dermal, pulmonary and kidney fibrosis. This project will develop subcutaneous formulations of patented CSD peptides and evaluate them in Alport Syndrome mice, which model CKD, with the aim of advancing a lead formulation for clinical development for the treatment of CKD.
Project Terms: Affect; Albumins; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animal Model; aqueous; Attenuated; base; Biochemical; Biological Assay; Biological Sciences; Blood Pressure; Blood Urea Nitrogen; Cardiac; caveolin 1; Cell Culture Techniques; Cell Proliferation; Chronic Kidney Failure; clinical development; Clinical Management; Clinical Trials; COL1A1 gene; Collagen; coronary fibrosis; cost; Creatine; Culture Media; Data; Dermal; Development; Dialysis procedure; Disease; Disease Progression; Dose; Drug Kinetics; efficacy study; efficacy testing; End stage renal failure; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Epidemic; Ethics; Exhibits; Extracellular Matrix; FDA approved; Felis catus; Fibroblasts; Fibrosis; first-in-human; Formulation; Freeze Drying; Generations; Glomerular Filtration Rate; Grant; Heart; Hereditary nephritis; Human; Hypertrophy; idiopathic pulmonary fibrosis; In Vitro; in vivo; Incidence; Inhalation; inhibitor/antagonist; Injury; interstitial; Kidney; Kidney Diseases; kidney fibrosis; kidney preservation; Lead; lead candidate; Legal patent; Literature; Lung; Mannitol; Measurement; Measures; Modeling; mouse model; Mus; Myocardial; Non-Insulin-Dependent Diabetes Mellitus; novel therapeutics; Organ; Pathologic; Peptides; Pharmaceutical Preparations; Pharmacodynamics; pharmacokinetics and pharmacodynamics; Phase; Phase II Clinical Trials; Pirfenidone; Plasma; Powder dose form; Pre-Clinical Model; Prevalence; Process; protective effect; Proteins; Proteolysis; Pulmonary Fibrosis; Pulmonary Hypertension; Quality of life; Recombinant Proteins; Renal function; Renin-Angiotensin System; Resistance; Safety; scaffold; Schedule; Seminal; Signal Pathway; Specificity; standard of care; subcutaneous; Systemic hypertension; targeted treatment; Tertiary Protein Structure; Testing; Therapeutic; Therapeutic Intervention; therapy development; Toxicology; Transplantation; Treatment Efficacy; United Kingdom; Ureteral obstruction; Urine; Variant; Withholding Treatment; Work
