ACMSD

ACMSD inhibition offers potential benefit across a broad range of liver and kidney diseases MENLO PARK, Calif.--(BUSINESS WIRE)-- #OrsoBio --OrsoBio, Inc. (“OrsoBio” or “the Company”), a clinical-stage biopharmaceutical company developing treatments for obesity and obesity-associated disorders, together with a team of academic researchers from Europe, Japan, and the United States, published promising preclinical data regarding the potential of ACMSD inhibition in animal and cellular models of metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH). In addition to enhancing synthesis of NAD + , a key co-factor in diverse bodily processes, the researchers discovered that ACMSD inhibition prevents DNA damage and cellular redox stress, leading to significantly reduced inflammation and fibrosis due to MASH. “We see tremendous therapeutic potential in ACMSD inhibitors across a spectrum of metabolic and inflammatory hepatic and renal diseases,” said Mani Subramanian, MD, PhD, Chief Executive Officer of OrsoBio. “The mechanism of action of ACMSD inhibition is highly complementary to our broader portfolio, including mitochondrial protonophores and an ACC2 inhibitor, as they target causal drivers of inflammation and fibrosis. Their potential therapeutic impact extends well beyond the obesity-associated diseases that are the focus of the rest of our pipeline.” The study, published in the Journal of Hepatology , investigates the mechanistic role and therapeutic implications of inhibiting a key enzyme involved in cellular energy metabolism for the potential treatment of MASLD/MASH. Researchers found that inhibition of ACMSD (aminocarboxymuconate semialdehyde decarboxylase), an enzyme restricted to liver and kidney, enhances de novo NAD + synthesis and significantly reduces DNA damage responses in liver, thereby preventing MASLD/MASH progression. 1 These findings were reproduced in mouse models and in a human liver organoid (HLO) model of steatohepatitis. “Enhancing NAD + levels in hepatocytes represents an attractive yet underexplored area for preventing redox stress. We observed that inhibiting ACMSD in human hepatocytes, both ex vivo and in vivo, increases NAD + levels, enhances mitochondrial respiration, and helps maintain genomic stability,” said Takanori Takebe, MD, PhD, Associate Professor at Cincinnati Children’s Hospital Medical Center and a scientific advisor to OrsoBio. “Here, we have reproduced our earlier findings from a study published in Cell that demonstrated the benefits of alternative approaches to cellular NAD + /redox/mitochondrial modulation in a MASH organoid model from human induced pluripotent stem cells (iPSCs). 2 Importantly, ACMSD inhibition alleviated phenotypes found in MASH organoids even from iPSCs of genetically at-risk individuals.” “Prevention and delayed progression of organ injury in the setting of acute and chronic liver and kidney diseases is a major unmet medical need,” said Johan Auwerx, MD, PhD, Professor at the École Polytechnique Fédérale de Lausanne (EFPL), Switzerland, and a scientific advisor to OrsoBio. “This research suggests that pharmacologic ACMSD inhibition could have a role in advanced disease where there is both metabolic and mitochondrial dysfunction leading to cellular redox mediated exacerbation of the DNA damage response, which sustains progressive inflammation and fibrosis. We look forward to continued collaboration with the OrsoBio team to evaluate the benefits of ACMSD inhibition as monotherapy and in combination with other mechanisms to better understand its therapeutic potential.” A range of proprietary compounds within OrsoBio’s ACMSD inhibitor portfolio are 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 in 2025. About ACMSD 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 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 obesity and obesity-associated disorders, including type 2 diabetes, MASH, and severe dyslipidemias. 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 . 1 Liu YJ, et al. J Hepatol 2024 Aug 22:S0168-8278(24)02484-X. doi: 10.1016/j.jhep.2024.08.009. Available: (24)02484-X/fulltext . 2 Kimura M, et al. Cell 2022;185(22):4216-4232.e16. doi: 10.1016/j.cell.2022.09.031. Available: (22)01250-8 . Contacts Media Contact Gwen Gordon Gwen@gwengordonpr.com

Co-led by Longitude Capital and Enavate Sciences, with Significant Participation by Existing Investors Samsara BioCapital and NuevaBio MENLO PARK, Calif.--(BUSINESS WIRE)-- OrsoBio, Inc. ("OrsoBio” or “the Company”), a clinical-stage biopharmaceutical company developing treatments for severe metabolic disorders, today announced the successful completion of a $60 million Series A financing, bringing the total capital raised by the Company to $97 million. The financing, which will support the advancement of OrsoBio’s obesity-focused portfolio, was co-led by Longitude Capital and Enavate Sciences. Existing investors Samsara BioCapital (“Samsara”) and NuevaBio, an affiliate of the founders, and new investor Eli Lilly and Company (NYSE: LLY) also participated in the round. Matthew Young of Longitude Capital and Edd Fleming, MD, of Enavate Sciences will join the OrsoBio Board of Directors, which includes Samsara representatives Srini Akkaraju, MD, PhD, and Cory Freedland, PhD. Obesity is a global health crisis that affects over 40% of U.S. adults, resulting in a range of complications, including diabetes, NASH, cardiovascular diseases, and some cancers. OrsoBio will utilize the Series A funding to advance the development of its innovative portfolio of four programs focused on obesity and associated metabolic disorders. Mitochondrial protonophore portfolio: Clinical development of the liver-targeted protonophore TLC-6740 through a Phase 1b study to establish proof of concept and initiation of a Phase 2a study in patients living with obesity, and advancement of IND-enabling activities for TLC-1235, a controlled-release mitochondrial protonophore. TLC-3595 (ACC2 inhibitor): Completion of a Phase 2a study in patients with insulin resistance/diabetes (NCT05665751) and preparations for a Phase 2b study. TLC-2716 (LXR inverse agonist): Completion of a Phase 2a study in patients with severe hypertriglyceridemia (SHTG)/nonalcoholic steatohepatitis (NASH) and groundwork for a Phase 2b program. ACMSD inhibitor (aminocarboxymuconate semialdehyde decarboxylase inhibitor): Selection of a development candidate for potential treatment of metabolic and inflammatory liver and kidney disorders and advancement of IND-enabling activities. “We are thrilled to welcome our new investors and for the continued support from our existing investors,” said Mani Subramanian, MD, PhD, CEO and Founder of OrsoBio. “We are grateful for the continued trust in our team and commitment to our mission to improve clinical outcomes in patients with obesity and associated metabolic disorders. This financing is an important milestone for OrsoBio that will enable us to progress our portfolio of first-in-class compounds targeting fundamental aspects of energy metabolism towards key clinical milestones.” “We have high conviction in the OrsoBio team, the Company’s differentiated portfolio, and its strategy to pursue complementary approaches to meaningfully impact the burden of a range of metabolic conditions that affect substantial patient populations,” said Matthew Young, Managing Director at Longitude Capital. “OrsoBio’s commitment to addressing unmet needs in obesity, diabetes, and associated diseases aligns with our vision for transformative healthcare,” said Edd Fleming, MD, Executive Vice President, Commercialization at Enavate Sciences. “While we’ve witnessed remarkable breakthroughs in the treatment of obesity and diabetes, notably with GLP-1 receptor agonists, there remains a high unmet need for effective and safe oral therapies that are complementary to, and can be used in combination with, these agents.” “We have worked closely with the experienced development team at OrsoBio since helping found the Company in 2020 and are proud of its track record of success and of the tremendous progress it has realized since emerging from stealth last year,” said Srini Akkaraju, MD, PhD, Founder and Managing Partner of Samsara BioCapital and founding OrsoBio board member. “I look forward to continuing to partner with the executive leadership team and new members of the Board to accelerate the evolution and advancement of the Company’s novel pipeline to improve the care of patients living with metabolic diseases.” About OrsoBio, Inc. OrsoBio, Inc. is a privately held, clinical-stage biopharmaceutical company dedicated to developing therapies to treat obesity and other severe metabolic disorders, including type 2 diabetes, NASH, and severe dyslipidemias. 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 . About Longitude Capital Longitude Capital is a leading healthcare venture capital firm that invests in transformative biotechnology, medical technology, and health solutions companies seeking to improve clinical outcomes, enhance patient quality of life, and drive efficiency of healthcare delivery. Founded in 2006, Longitude Capital invests in both privately held and publicly traded companies through a variety of investment approaches. Longitude Capital has offices in Menlo Park, CA, Greenwich, CT, and Boston, MA. For more information, please visit or LinkedIn. About Enavate Sciences Enavate Sciences is a platform created by Patient Square Capital dedicated to supporting therapeutic companies advancing medicines and enabling technologies with transformative potential to address patient need. Through the application of capital support and operational experience, Enavate strives to enable and empower a diverse portfolio of therapeutics companies to accelerate innovation. To learn more about Enavate, please visit . About Samsara BioCapital Founded in 2017, Samsara BioCapital is a leading biotech investment firm focused on identifying opportunities across public and private markets. Samsara invests across the full spectrum of biotech opportunities from early-stage start-up to late-stage clinical assets. Our primary goal is to focus on finding and advising companies that will have significant impact on patients and address high unmet medical needs. Samsara works with entrepreneurs and top tier management teams that they believe will have meaningful impact on innovative therapeutics. The Samsara team has deep expertise in biotech with significant experience working together prior to founding the firm. The team is led by Srini Akkaraju who has over twenty-two years of industry experience and an MD, PhD in Immunology from Stanford University. For more information, please visit .

PALO ALTO, Calif.--(BUSINESS WIRE)-- 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.