Nonalcoholic steatohepatitis (NASH) occurs when excessive amounts of fat build up in the liver, damaginghepatocytes and causing inflammation. The progression of the disease further leads to fibrosis, hepatocellularcarcinoma, and liver failure. After numerous failures in clinical trials with single-agent therapies, the therapeuticapproach has gradually shifted toward using combination therapies that involve both a metabolic modifier andan anti-fibrotic agent. However, limited progress has been made so far. We recently discovered that not onlylipid metabolism but also amino acid metabolism is disrupted in NASH, leading to the development of fatty acid-amino acid conjugates (NAAs) intersecting both metabolic pathways for the treatment of NASH. Mice withestablished NASH that were treated with endogenous NAAs exhibited reduced steatohepatitis and fibrosis. Usinga medicinal chemistry approach, we designed, synthesized, tested, and optimized a series of novel NAAs. Ourcurrent lead compound, FAL-113, obtained superior physicochemical properties, oral bioavailability, and efficacyin preliminary cellular and animal models. It is hypothesized that FAL-113 could reduce lipotoxicity bysimultaneously increasing fatty acid oxidation and decreasing its biosynthesis while providing the anti-fibrosisseen with the endogenous NAAs. In addition, the novel structural modification improved the compound's oralbioavailability and half-life, enabling an otherwise impossible oral administration. The metabolism of FAL-113also releases a secondary bioactive fatty acid that improves energy homeostasis through metabolicreprogramming, which subsequently benefits the comorbidities commonly associated with NASH. The greatlyimproved pharmacokinetics and efficacy of novel NAAs led us to hypothesize that FAL-113 could tackle NASHthrough a multiplexed mechanism - synergizing the benefits of metabolic modification and anti-inflammatory/fibrotic properties. This hypothesis will be tested by pursuing the following Specific Aims:Aim 1: Determine the mechanisms of action of FAL-113 using bioorthogonal chemistry.Aim 2: Establish the pharmacokinetics of FAL-113 in rodents.Aim 3: Define the pharmacology of FAL-113 in a NASH mouse model.The multidisciplinary approach involved in the project, including bioorthogonal chemistry, mass spectrometer-based analytics, and animal pharmacokinetics and pharmacology, will definitively reveal the ADME, validate theprotection against NASH and characterize the modes of action of the lead compound FAL-113. The successfuloutcomes of this project will result in a solid preclinical candidate ready for IND-enabling studies and greatlyaccelerate its translation to real clinical value for NASH patients.The team leading this effort has experienced and participated in several preclinical and clinical studies in relateddisease areas. In addition, the team is supported by experienced collaborators and consultants to execute theproposed research plan successfully.
Public Health Relevance Statement: Project Narrative
Non-alcoholic steatohepatitis (NASH), a severe form of non-alcoholic fatty liver disease (NAFLD) inflicting nearly
one-third of the global population, currently has no FDA-approved therapy. We propose to advance novel fatty
acid-amino acid drugs to manage 1) hepatic lipotoxicity, 2) inflammation and fibrosis, and 3) NASH-related
comorbidities. The successful development of this novel drug class would greatly benefit a large group of
underserved patients who currently have NASH or are at significant risk of developing NASH.
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