Pharmacologically Optimized TLR5 Agonist as a Novel Therapy Against Idiopathic Pulmonary Fibrosis
Abstract
This proposal submitted by Genome Protection, Inc. (GPI) describes clinical grade manufacturing and preclinical testing of a novel therapeutic agent against Idiopathic Pulmonary Fibrosis (IPF)/Interstitial Lung Disease (ILD). ILD is the general term for a large group of disorders that cause formation of scar tissue (fibrosis) in the lungs. The scarring causes stiffness that reduces lung capacity and makes it difficult for affected individuals to breathe. Among the many diseases considered types of ILD, one of the more prevalent forms is IPF. IPF is a devastating disease with respiratory failure and death occurring within 3-5 years after diagnosis unless the patient is able to receive a lung transplant. There are currently ~90,000 patients diagnosed with IPF in the United States and ~35,000 new cases are added each year. IPF is most frequently diagnosed after age 50, and is more common in males than females. This, together with association of the disease with smoking and exposure to other types of environmental contaminants, means that IPF is enriched in populations of Veterans of the Armed Forces. Currently, there are no curative treatments available for IPF except for lung transplantation. The only two drugs approved by the Food and Drug Administration (FDA) for this indication, Ninedanib and Pirfenidone, do not prevent or revert the damage caused by the disease, but only slow down its progression. Neither of these drugs has been conclusively proven to reduce the rate of death due to IPF. Therefore, there remains an urgent need for new innovative ILD treatments. The proposed novel therapeutic agent GP532 is a pharmacologically optimized agonist of the human Toll-like receptor 5 (TLR5). GP532 is a second-generation drug that shares many of the key features of the previously developed and well-studied TLR5 agonist from which it was derived (entolimod) but has important improvements as well. Due to the effects of TLR5 agonists on pathways important for protection of cells from various types of damage and for activity of the immune system, these agents are promising therapeutics for a number of indications. Our preliminary studies demonstrating efficacy of GP532 in prevention and treatment of lung fibrosis in mouse models had led us to introduce the novel concept of developing this TLR5 agonist as a new IPF/ILD treatment. GP532 is currently in the stage of advanced preclinical development. This proposal is aimed at completing the final steps needed to bring it to the next stage of filing an Investigational New Drug (IND) application with the FDA, which is necessary to initiate clinical testing in humans. The proposed studies include: (i) manufacturing and characterization of drug product under FDA’s current Good Manufacturing Practice (cGMP) regulations to provide sufficient material for future clinical trials; (ii) performance of IND-enabling toxicology studies in two animal species; and (iii) identification of molecular and cellular mediators of the anti-fibrotic activity of GP532 as potential pharmacodynamical biomarkers for use in clinical trials. Development of GP532 as a novel agent for treatment of IPF (and other types of ILD) is expected to provide a highly significant improvement in clinical outcomes for a disease that currently has no curative treatment and represents a major medical and economic burden.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010761
Entities
People
- Andrei Gudkov
Organizations
- United States Army