— Company to share preclinical data on TLC-065 at The Liver Meeting® —
Palo Alto, Calif. – November 2, 2022 – OrsoBio, Inc., a clinical-stage biopharmaceutical company developing treatments for severe metabolic disorders, today announced its acquisition of an ACMSD inhibitor program from Mitobridge, an Astellas Company. The program includes a range of proprietary compounds being evaluated for their potential to address mitochondrial dysfunction in metabolic and inflammatory liver and kidney disorders.
“The broad biological effects observed with ACMSD inhibition in diseases characterized by mitochondrial dysfunction is impressive and provides a strong scientific rationale for development,” said Mani Subramanian, MD, PhD, Chief Executive Officer of OrsoBio. “Since acquiring this novel program, we have made substantial progress in optimizing chemistry and pharmacology, characterizing the biological effects of these compounds, and exploring complementarity with our other OrsoBio programs.”
ACMSD (aminocarboxymuconate semialdehyde decarboxylase) is a key enzyme involved in the de novo synthesis of NAD+, which is critical to mitochondrial function via maintenance of cellular redox state, sirtuin-mediated signaling, and overall energy homeostasis. ACMSD is highly expressed in the liver and kidneys and NAD+ is reduced in patients with advanced hepatic and renal disease. TLC-065 and other compounds within the ACMSD inhibitor portfolio are being studied for their potential to replenish NAD+ and improve mitochondrial function.
OrsoBio will present preclinical data describing the metabolic benefits of ACMSD inhibition in rodent hepatocytes and human liver organoids (HLOs) in a poster (Abstract #2441) entitled “Enhancement of de novo NAD+ biosynthesis by novel ACMSD inhibitors improves mitochondrial function in iPSC-derived human liver organoid models of steatohepatitis” at AASLD’s The Liver Meeting®, November 4-8, 2022, in Washington, D.C. In this study, ACMSD inhibition with TLC-065 in mouse hepatocytes increased NAD+ synthesis, improved mitochondrial health, enhanced fatty acid oxidation, and decreased de novo lipogenesis, lipotoxicity, and oxidative stress. These benefits, plus reduced steatosis, were recapitulated by TLC-065 treatment in steatotic, induced pluripotent stem cell (iPSC)-derived HLOs, in which ACMSD expression is upregulated.
“The emerging biology around ACSMD inhibition, including translation in human liver organoids, highlight the importance of this pathway and strongly differentiates it from other approaches to NAD+ modulation for improvement of mitochondrial dysfunction,” said Johan Auwerx, MD, PhD, Scientific Founder of Mitobridge, Professor at the École Polytechnique Fédérale de Lausanne (EFPL), Switzerland, and scientific advisor to OrsoBio. “I see tremendous therapeutic potential in OrsoBio’s ACMSD inhibitors across a spectrum of metabolic and inflammatory hepatic and renal diseases.”
About ACMSD and TLC-065
ACMSD (aminocarboxymuconate semialdehyde decarboxylase) is a key enzyme involved in the de novo synthesis of NAD+ from tryptophan. Enhancing NAD+ synthesis by silencing or inhibiting ACMSD improves mitochondrial function, increases the lifespan of C. elegans, and protects against liver and kidney injury in mice. OrsoBio’s preclinical portfolio of ACMSD inhibitors, including TLC-065, is being advanced for the treatment of a range of metabolic and inflammatory liver and kidney disorders.
About OrsoBio, Inc.
OrsoBio, Inc. is a privately held, clinical-stage biopharmaceutical company dedicated to developing therapies to treat severe metabolic disorders, including type 2 diabetes, severe dyslipidemias, lipodystrophies, and nonalcoholic steatohepatitis. The company was co-founded by Mani Subramanian, MD, PhD, former Therapeutic Area Head for Liver Diseases at Gilead Sciences, and Samsara BioCapital. OrsoBio currently has four programs in clinical and preclinical development with first-in-class compounds that address central pathways in energy metabolism. For more information, please visit www.orsobio.com.
About Samsara BioCapital
Samsara BioCapital is a new breed of biotech investment fund focused on translating cutting-edge biology into new therapies to treat patients with unmet medical needs. Founded in 2016 by Srinivas Akkaraju, MD, PhD, our team of scientists, investors and entrepreneurs takes a long-term view to value creation across all stages of public and private life science companies. We believe in a collaborative, hands-on approach, working closely with entrepreneurs to harness exciting scientific advances and build leading companies. Samsara actively manages assets on behalf of endowments, foundations, and family offices. For more information, please visit www.samsaracap.com.