OrsoBio Publishes Preclinical Data on New Method for Metabolic Regulation and Reducing Inflammation

OrsoBio, Inc., a clinical-stage biopharmaceutical company focused on treatments for obesity and associated disorders, alongside an international team of researchers, has shared promising preclinical data on the potential of ACMSD inhibition for metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). The findings, published in the Journal of Hepatology, demonstrate that ACMSD inhibition can enhance NAD+ synthesis, a crucial co-factor in numerous bodily processes, and significantly reduce DNA damage and cellular redox stress, resulting in decreased inflammation and fibrosis associated with MASH.

Mani Subramanian, MD, PhD, CEO of OrsoBio, emphasized the therapeutic potential of ACMSD inhibitors across a range of metabolic and inflammatory liver and kidney diseases. He noted the complementary mechanism of action of ACMSD inhibitors with OrsoBio's broader portfolio, including mitochondrial protonophores and an ACC2 inhibitor, which target key drivers of inflammation and fibrosis, extending beyond obesity-related diseases.

The study investigated the therapeutic implications of inhibiting ACMSD, an enzyme involved in cellular energy metabolism and found mainly in the liver and kidney, for treating MASLD/MASH. Researchers discovered that inhibiting ACMSD enhances NAD+ synthesis and reduces DNA damage responses in the liver, thus preventing the progression of MASLD/MASH. These findings were confirmed in both mouse models and human liver organoid models of steatohepatitis.

Takanori Takebe, MD, PhD, Associate Professor at Cincinnati Children’s Hospital Medical Center and a scientific advisor to OrsoBio, highlighted the promise of enhancing NAD+ levels in hepatocytes to prevent redox stress. The research showed that ACMSD inhibition in human hepatocytes, both ex vivo and in vivo, increases NAD+ levels, enhances mitochondrial respiration, and maintains genomic stability. These findings build on previous studies demonstrating the benefits of cellular NAD+/redox/mitochondrial modulation in MASH organoid models from human induced pluripotent stem cells (iPSCs). ACMSD inhibition was also effective in alleviating phenotypes in MASH organoids derived from iPSCs of genetically at-risk individuals.

Johan Auwerx, MD, PhD, Professor at the École Polytechnique Fédérale de Lausanne (EPFL) and a scientific advisor to OrsoBio, noted the critical need for therapies that prevent and delay organ injury in acute and chronic liver and kidney diseases. The research suggests that pharmacologic ACMSD inhibition could play a role in advanced diseases characterized by metabolic and mitochondrial dysfunction, leading to cellular redox-mediated DNA damage response, progressive inflammation, and fibrosis. Continued collaboration with OrsoBio aims to further evaluate the benefits of ACMSD inhibition, both as a monotherapy and in combination with other mechanisms, to better understand its therapeutic potential.

OrsoBio's portfolio includes a range of proprietary ACMSD inhibitors currently being evaluated for their potential to replenish NAD+ and improve mitochondrial function in metabolic and inflammatory liver and kidney disorders. The company plans to complete lead optimization and IND-enabling activities by 2025.

ACMSD, or aminocarboxymuconate semialdehyde decarboxylase, is a key enzyme in the de novo synthesis of NAD+ from tryptophan. Enhancing NAD+ synthesis by inhibiting ACMSD has been shown to improve mitochondrial function, increase the lifespan of organisms like C. elegans, and protect against liver and kidney injury in mice. OrsoBio is advancing its preclinical portfolio of ACMSD inhibitors for treating a range of metabolic and inflammatory liver and kidney disorders.

OrsoBio, Inc. is dedicated to developing therapies for obesity and related disorders, including type 2 diabetes, MASH, and severe dyslipidemias. The company currently has four programs in clinical and preclinical development, focusing on first-in-class compounds that address central pathways in energy metabolism.