Novel oral small molecules for progressive pulmonary fibrosis

Abstract The overall goal of this program is the development and commercialization of a novel, safer, and more effective, therapy for the treatment of idiopathic pulmonary fibrosis (IPF). IPF is a progressive and generally fatal disease for which there is no cure. IPF has a median survival rate of 3-5 years, which is less than most cancers. There are approximately 100,000 people in the US with IPF with 30,000 – 40,000 new cases per year. As many as 40,000 Americans die each year from IPF. The two FDA approved drugs for IPF, pirfenidone and nintedanib, only slow disease progression, have side effects which limit their use, and do not improve mortality. Clearly, there is a significant need for therapies to treat this devastating disease. Additionally, there are several other causes of progressive pulmonary fibrosis including connective tissue-associated interstitial lung disease (ILD), fibrotic hypersensitivity pneumonitis and sarcoidosis for which new antifibrotics are required. IPF is characterized by excessive collagen deposition by activated myofibroblasts in the lung. NovoMedix has developed a novel series of small molecules that inhibit myofibroblast activation and differentiation and can also convert activated fibroblasts back to their quiescent state, potentially reversing fibrotic damage. NM novel compounds inhibit IL-11 secretion by activated fibroblasts and epithelial cells and act as allosteric AMP Kinase (AMPK) agonists. NovoMedix drug candidates decrease fibrosis and inflammation in two different bleomycin models of pulmonary fibrosis. They also decrease fibrosis and inflammation in a liver fibrosis model; prevent heart failure in mouse transverse aortic constriction (TAC) models; and prevent doxorubicin-induced cardiomyopathy in mouse cancer models. IL-11 and AMPK play key roles in fibrosis and inflammation, and activation of AMPK has been shown to be cardioprotective. However, the role of inflammation in IPF is unclear, and there is widespread agreement that the bleomycin mode of lung fibrosis in mice has limitations as a translational model. We have also identified new NM compounds that lower IC50s and better oral availability, which we believe will be superior drug development candidates. Our hypothesis is that one or more of these compounds will reduce lung fibrosis and block pro-fibrotic feedforward loops, reducing disease progression and improving outcomes. We propose the following specific aims: 1) Confirm efficacy in novel cell assays including physiologically relevant stretch and 3D models, and select lead candidates, 2) Scale-up production of lead candidates for animal studies, and 3) Demonstrate efficacy in the TGF- model of progressive pulmonary fibrosis, which has some key advantages over the bleomycin model. These studies will pave the way for trials in lung fibrosis patients.