FIBROTHERAPEUTICS INC — Department of Health and Human Services STTR Phase I: NHLBI

Description

Abstract Our long-term goal is to improve on the limited choices for treating the many devastating diseases that together constitute the Interstitial Lung Diseases (ILD), the most prevalent of which are scleroderma and Idiopathic Pulmonary Fibrosis. As ILD affects those in late middle age trying to remain active, the market for a treatment will grow rapidly. Caveolin-1 is a promising therapeutic target in fibrotic diseases. The profibrotic effects of caveolin-1 deficiency in cells and in mouse models is suppressed by a peptide equivalent to its active site (caveolin-1 scaffolding domain, CSD). However, CSD lacks suitable pharmacologic properties for drug development. To overcome this problem, we developed novel, modified versions of CSD. We first divided CSD into three subregions and found they all suppressed bleomycin-induced lung fibrosis. To improve the pharma- cological properties, we then modified CSD and each subregion to be water soluble and protected from proteo- lysis. This modification enhanced the uptake by cells of all four modified peptides and increased their ability to inhibit several purified kinases in vitro. We have so far tested only one of the four modified peptides in vivo and it was outstandingly active in inhibiting bleomycin-induced lung fibrosis. These initial studies justify and strongly support our proposal to identify a Lead Compound from among the four candidates, then evaluate its Thera- peutic Index (ratio between toxic and beneficial doses). Our studies and the literature also suggest that our peptides will be more effective and have fewer side effects than the FDA-approved blockbuster drug nintedanib (brand name Ofev). In summary, to proceed with drug development we must identify a Lead Compound. Due to their distinct pharmacological and functional features, we must do a side-by-side comparison of our four modified peptides. 1) Select a Lead Compound using two model systems: Systemic Bleomycin Treatment and Fluorescein Isothiocyanate (FITC) Treatment. We will choose a Lead Compound, then demonstrate its specificity and activity by comparing it to a control peptide (scrambled Lead), nintedanib, and pirfenidone (brand name Esbriet, an FDA-approved drug for ILD reported to affect caveolin-1 levels). Peptides will be delivered s.c. in a Therapeutic Protocol, beginning 7 days after fibrosis is induced. Primary Readouts will be lung function and quantification of fibrosis markers, microvascular leakage, and tissue morphology. Success will be defined as the suppression by the Lead Compound of andgt;50% of the deleterious effect on lung function and andgt;75% of the deleterious effect on fibrosis and microvascular leakage. 2) Determine the Therapeutic Index of the Lead Compound. The dose-dependence of the Lead Compound’s beneficial effects will be determined using doses above and below our current standard dose. Its toxicity will be evaluated in a Single-Treatment Maximum Tolerated Dose Experiment using 1X, 5X, 25X, and 125X our current standard dose. We will consider these studies to be a success if the Therapeutic Index is andgt;50. In summary, these studies will provide a novel Lead Compound that meets our Criteria for Success, both in terms of suppression of ILD and of safety.Narrative Fibrosis (the stiffening of tissues due to collagen overproduction/deposition) and blood vessel leakage are major contributors to the deficits in lung function that occur in the group of devastating diseases known as the Interstitial Lung Diseases (ILD). We have been working on novel, modified versions suitable for drug development of a biologic peptide (called CSD) that we have already shown to suppress fibrosis and blood vessel leakage in multiple model systems. In this proposal, based on its beneficial effects in two model systems for ILD, we will select a Lead Compound for further development from among four candidates that we have designed and, additionally, we will evaluate the potential toxicity of this Lead Compound in a Maximum Tolerated Dose experiment.