Advanced Pre-clinical development of Nox4 inhibitors for Pulmonary Fibrosis - ABSTRACT:
Fibrotic disorders represent a major health problem in the U.S, with a rising incidence (particularly among the
elderly). Idiopathic pulmonary fibrosis (IPF) is a relentless and fatal fibrotic disease, characterized by progressive
scar tissue formation in the lungs, resulting respiratory failure. There are two FDA-approved treatments for IPF,
which slow but do not stop the decline in lung function, and only have a modest survival benefit. Improved
therapies for IPF and other fibrotic diseases are needed to improve patient quality of life and outcomes. We were
the first to identify Nox4 (an oxidant generating enzyme) as a critical mediator of lung fibrosis. Nox4 is now
considered to be a core pathway that mediates fibrosis in various organs (lungs, liver, skin, kidney, blood vessels,
skeletal muscle, and heart). We have also demonstrated that Nox4 becomes dysfunctional in aging, where its
sustained upregulation promotes age-associated persistent/progressive fibrosis – These findings may help to
explain why fibrotic disorders develop are more prevalent among the elderly. Although Nox4 is among the most
promising drug targets for fibrotic disease, selective Nox4 inhibitors have yet to be successfully developed – until
now. This direct to Phase II SBIR application is a collaboration between biotech startup company Fibronox LLC
and Emory University. We have pioneered the development of first-in-class selective Nox4 inhibitor drug
candidates; 10 patents filed. Our Nox4 inhibitors have passed a rigorous screening cascade, including nM
potency in vitro for inhibiting TGFb-induced pro-fibrotic effects and reversing IPF myofibroblast phenotypes.
Importantly, therapeutic treatment with Nox4 inhibitor candidates in vivo led to protection from the development
of fibrosis and promoted the resolution of age-associated established fibrosis. Further, inhaled delivery of Nox4
inhibitors demonstrated efficacy at a dose ~7-fold lower than orally administered and 4-fold increased drug
exposure in the lung. The goal of the proposed studies is to perform side-by-side evaluation of our top 3 most
promising candidates via inhaled delivery in order to identify one development candidate for IND-enabling studies
and subsequent clinical development. Aim 1 will rigorously validate top candidates for selectivity and mode of
action. Aim 2 will de-risk top candidates through advanced screening, including the use of human precision cut
lung slices, single-cell RNAseq, and highly a innovative bioinformatic approach to evaluate Nox4 inhibitors vs.
standard of care. Aim 3 will evaluate specificity and potential for adverse effects. Aim 4 will determine the
therapeutic index and maximum tolerated dose. To date, no therapeutics have been shown to reverse age-
associated established fibrosis, which may represent the holy grail for therapeutic strategies to more effectively
treat IPF. We hypothesize that therapeutic strategies targeting age-associated pathologic mechanisms (ex. age-
dependent sustained Nox4/ROS levels) offer the greatest potential for developing successful IPF treatments.
