ACC2

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 .

-- Trial will evaluate the insulin-sensitizing effects of TLC-3595, alone and in combination with approved diabetes therapies -- PALO ALTO, Calif.--(BUSINESS WIRE)-- OrsoBio, Inc., a clinical-stage biopharmaceutical company developing treatments for severe metabolic disorders, today announced that the first patient has been dosed in a Phase 2a clinical trial evaluating TLC-3595, a selective inhibitor of acetyl-CoA carboxylase 2 (ACC2). The trial aims to demonstrate the safety and insulin-sensitizing effects of TLC-3595 in patients with insulin resistance, including those with type 2 diabetes on approved glucose-lowering therapies. Proof-of-concept data supporting the safety and efficacy of TLC-3595 will be available by the end of 2023. Today, 537 million adults are living with diabetes, a number projected to grow to over 640 million by 2030 and approximately 780 million by 2045.1 Insulin resistance is pathogenic across the spectrum of diabetes—from patients with prediabetes to advanced diabetes requiring insulin—and drives a range of complications, including cardiovascular disease, renal disease, and cancer. “With the growing global burden of type 2 diabetes, the need for novel, well-tolerated therapies that enhance insulin sensitivity has never been greater,” said Rob Myers, MD, Chief Medical Officer of OrsoBio. “Dosing our first patient in this Phase 2a trial is an important milestone for OrsoBio as we continue to advance our four programs to address unmet needs in patients with severe metabolic disorders, including diabetes, obesity, nonalcoholic steatohepatitis (NASH), and dyslipidemias.” The Phase 2a, multicenter, randomized, double-blind, placebo-controlled trial (NCT05665751) is designed to evaluate the safety, tolerability, and efficacy of two doses of TLC-3595 in patients with insulin resistance. The study will enroll 50 overweight or obese subjects with insulin resistance, including type 2 diabetes treated with glucose-lowering therapies. The trial’s primary endpoint is improvement in insulin sensitivity based on results from an oral glucose tolerance test (OGTT) after 4 weeks of therapy. Additional exploratory endpoints include biomarkers of glycemic control (e.g., HbA1c, glucose, glycated albumin), fatty acid oxidation (FAO), lipids, and MRI/magnetic resonance spectroscopy (MRS)-based assessments of muscle and liver fat, key drivers of insulin resistance. “ACC2 inhibition is a novel mechanism of action that holds great potential to address insulin resistance in patients with type 2 diabetes, including those being treated with other complementary therapies,” said Gerald Shulman, MD, PhD, MACP, MACE, FRCP, the George R. Cowgill Professor of Medicine and Professor of Cellular and Molecular Physiology at Yale School of Medicine, Co-Director of the Yale Diabetes Research Center, and scientific advisor to OrsoBio. “It’s critical that we identify novel therapies that are safe, well tolerated, and effective in improving insulin sensitivity, both as standalone medicines and to enhance the effectiveness of existing treatments for diabetes.” OrsoBio previously presented data from a successful Phase 1 trial of TLC-3595 in a poster (Abstract #3677) entitled “Evaluation of the safety and pharmacokinetic effects of the oral, acetyl-CoA carboxylase-2 (ACC2) inhibitor TLC-3595 in healthy volunteers” at AASLD’s The Liver Meeting® in November 2022. This single and 14-day, multiple ascending dose trial showed that TLC-3595 was well tolerated, led to improvements in LDL and total cholesterol, and had pharmacokinetic parameters supporting once daily oral administration. About TLC-3595 and ACC2 Inhibition TLC-3595 is a novel and selective ACC2 inhibitor designed to treat type 2 diabetes by increasing FAO, reducing ectopic lipid accumulation, and improving insulin sensitivity in skeletal muscle and liver. The compound may also have potential as a treatment for other conditions characterized by impaired FAO, including cirrhosis with myosteatosis-associated sarcopenia and NASH. In 2022, OrsoBio acquired exclusive worldwide rights to an ACC2 inhibitor program with lead compound TLC-3595 (formerly S-723595) from Shionogi & Co., Ltd. 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, obesity, nonalcoholic steatohepatitis, severe dyslipidemias, and lipodystrophies. 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 . 1 International Diabetes Federation Diabetes Atlas 2022. Available: .