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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

MENLO PARK, Calif.--( BUSINESS WIRE )--OrsoBio, Inc. ("OrsoBio” or “the Company”), a clinical-stage biopharmaceutical company developing treatments for obesity and obesity-associated disorders, today announced the close of an oversubscribed $67 million Series B financing. The financing was co-led by new investors Ascenta Capital and Woodline Partners LP, with significant participation from existing investors Samsara Biocapital, Longitude Capital, Enavate Sciences, NuevaBio, and Eli Lilly and Company. In conjunction with the financing, Evan Rachlin, MD, Co-Founder and Managing Partner of Ascenta Capital, has joined the OrsoBio Board of Directors. Proceeds from the financing will be used to accelerate development of the Company’s mitochondrial protonophore portfolio for the treatment of obesity and associated metabolic disorders. Obesity affects more than 40% of U.S. adults and leads to a range of adverse health outcomes including type 2 diabetes, cardiovascular disease, and metabolic dysfunction-associated steatohepatitis (MASH). Obesity is caused by an imbalance between energy intake and energy expenditure that leads to excess adiposity. Although glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revolutionized weight management by reducing caloric intake, they may cause loss of lean mass and metabolic adaptations that reduce energy expenditure. Mitochondrial protonophores directly increase energy expenditure and may represent the ideal means to complement the metabolic benefits of GLP-1 RAs. In preclinical studies, mitochondrial protonophores developed by OrsoBio led to weight loss, preserved lean mass, and improved insulin sensitivity. Further, when these potential therapies were used in combination with a GLP-1 RA, additional weight and fat mass loss were observed, without significant effects on lean mass. These benefits were sustained with continued protonophore therapy following GLP-1 RA discontinuation. 1 TLC-6740 is a novel, oral, liver-targeted mitochondrial protonophore under evaluation in a 12-week, Phase 1b clinical trial in patients living with obesity ( NCT05822544 ). In a prior Phase 1 study in healthy subjects, TLC-6740 was safe, well tolerated, and caused dose-dependent increases in energy expenditure and improvements in lipids and markers of insulin resistance. Additional Phase 1b and Phase 2a studies of TLC-6740 in patients with obesity and type 2 diabetes, including those on a GLP-1 RA, will initiate in the coming months. IND-enabling studies for two additional novel protonophores (TLC-1180 and TLC-1235) with unique attributes compared to TLC-6740, including greater systemic distribution, are expected to be completed in 2025. TLC-1180 is a potent, long-acting mitochondrial protonophore that is suitable for weekly oral or subcutaneous administration. TLC-1235 is a controlled-release mitochondrial protonophore (CRMP) that has shown metabolic benefits across a range of models and species. 2 "We welcome Ascenta Capital and Woodline Partners to OrsoBio and appreciate their support and that of our existing investors. These resources enable us to continue advancing our portfolio of mitochondrial protonophores and other potential therapies to address the burden of obesity and obesity-associated diseases,” said Mani Subramanian, MD, PhD, CEO and Founder of OrsoBio. “We believe that the future of obesity treatment will include GLP-1 RA-based combinations; this financing will enable us to build the scientific and clinical foundations to support our protonophores as components of these regimens.” "OrsoBio’s novel mechanisms hold promise to enhance weight loss, improve metabolic function, and preserve lean muscle mass,” said Evan Rachlin, MD, Co-Founder and Managing Partner of Ascenta Capital. “These medicines could one day complement GLP-1 RA-based approaches and expand the long-term health benefits of these treatments. We look forward to partnering with the world-class team at OrsoBio to help bring these extraordinary medicines to patients.” OrsoBio’s portfolio of compounds in clinical development also includes TLC-3595, an ACC2 inhibitor, currently in a Phase 2a study for the treatment of type 2 diabetes, and TLC-2716, a liver X receptor (LXR) inverse agonist currently in a Phase 2a study for severe hypertriglyceridemia and MASH. 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 www.orsobio.com . ____________________________ 1 Data accepted for presentation at ObesityWeek® 2024. 2 Perry RJ, et al. Science 2015 ( PMID: 25721504 ); Goedeke L, et al. Mol Metab 2021 ( PMID: 33545391 ).

Phase 1 data confirm the safety of TLC-6740, dose-dependent increases in energy expenditure, and improvements in plasma lipids and markers of insulin resistance Preclinical data confirm increased energy expenditure and weight loss with TLC-6740, and the potential of combination treatment with GLP-1 receptor agonists and the company’s ACC2 inhibitor TLC-3595 MENLO PARK, Calif.--(BUSINESS WIRE)-- OrsoBio, Inc., a clinical-stage biopharmaceutical company developing treatments for obesity and obesity-associated disorders, today announced new data for liver-targeted mitochondrial protonophore TLC-6740 being presented at the 84th Scientific Sessions of the American Diabetes Association being held June 21-24, 2024, in Orlando, Fla. The company will present three abstracts sharing new data demonstrating the safety and preliminary efficacy of its mitochondrial protonophore, TLC-6740, in healthy humans, and preclinical data highlighting weight loss driven by increased energy expenditure and improved glycemic control in mouse models following monotherapy and combinations with the selective ACC2 inhibitor, TLC-3595, and a GLP-1 receptor agonist. “Our Phase 1 data illustrate the potential of our liver-targeted mitochondrial protonophore, TLC-6740, to enable safe increases in energy expenditure, metabolic benefits, and to promote weight loss in people living with obesity,” said Rob Myers, MD, Chief Medical Officer of OrsoBio. “In light of our new clinical and preclinical data, we look forward to advancing TLC-6740 to treat obesity and its comorbidities, including in combination with GLP-1 receptor agonists.” Increasing cellular energy expenditure by mitochondrial uncoupling is a validated approach to weight loss. By targeting the liver—a key organ governing whole-body energy metabolism—TLC-6740 has demonstrated substantial weight loss in rodents driven by increased energy expenditure and fat oxidation. These new Phase 1 data confirm the safety of TLC-6740 in humans and demonstrate clinically relevant increases in energy expenditure, utilization of fat for energy, and multiple metabolic benefits, including improvements in LDL cholesterol, total cholesterol, markers of insulin resistance, and liver biochemistry. Further, data from preclinical models of diabetes suggest that combining TLC-6740 and drugs with complementary mechanisms, including the ACC2 inhibitor, TLC-3595, and the GLP-1 receptor agonist, semaglutide, can have additive benefits on insulin resistance. “With the growing burden of obesity-related disorders, it’s critical that new, safe, effective therapies be developed to complement existing medications, such as GLP-1 receptor agonists,” 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. “These human and preclinical data highlight the promise of TLC-6740 to promote healthy weight loss by driving increased energy expenditure and fat oxidation, and directly address the root cause of insulin resistance, which drives many of the complications of obesity.” ADA Presentation Details Abstract #1186-LB: Safety, PK and preliminary efficacy of the liver-targeted mitochondrial protonophore TLC-6740: A Phase 1 study Late-Breaking Poster Session: Saturday, June 22, 2024 (12:30 – 1:30 p.m.) This randomized, double-blind Phase 1 trial (NCT05822544) was designed to evaluate the safety, tolerability, PK, and pharmacodynamics of single and multiple ascending doses of TLC-6740 (3-120 mg) in healthy subjects. OrsoBio previously presented data from the SAD cohorts at ObesityWeek® 2023, and new data from MAD cohorts confirmed the safety of TLC-6740 administered for 10 days. All TLC-6740-related adverse events were mild, and there were no drug-related discontinuations, lab abnormalities, or temperature increases. The PK pro TLC-6740 includes a prolonged half-life (18 to 33 hours), supporting once-daily, oral dosing. In addition, indirect calorimetry demonstrated significant, dose-dependent increases in resting energy expenditure and reductions in respiratory quotient (RQ), indicating a preference for oxidation of fat for energy, with TLC-6740 treatment. Finally, TLC-6740 caused dose-dependent improvements in serum total and LDL cholesterol, markers of insulin resistance, and liver biochemistry. Abstract #899-P: Combinations of the mitochondrial protonophore TLC-6740 and/or the ACC2 inhibitor TLC-3595 provide additive glycemic benefits to semaglutide (SEMA) in db/db mice Poster Session: Sunday, June 23, 2024 (12:30 – 1:30 p.m.) This preclinical study assessed the effects of TLC-6740, TLC-3595, and semaglutide in the db/db mouse model of diabetes. Mice were treated with these compounds as monotherapy, or a combination of either two or three of these agents, and fasting blood glucose (FBG), HbA1c, and glucose during an oral glucose tolerance test were measured. All groups saw reductions in FBG and HbA1c; the greatest reductions were observed in groups treated with combination therapy. Both TLC-6740 and TLC-3595 improved glycemic parameters as monotherapy and had additive benefits when combined with each other and semaglutide. These data provide evidence to support the continued evaluation of TLC-6740 and TLC-3595 as monotherapy and in combination with GLP-1 receptor agonists as potential treatments for type 2 diabetes. Abstract #1637-P: TLC-6740, a liver-targeted mitochondrial protonophore, increases energy expenditure and lipid utilization in obese mice Poster Session: Monday, June 24, 2024 (12:30 – 1:30 p.m.) This preclinical study evaluated mechanisms of weight loss with TLC-6740 treatment in diet-induced obese (DIO) mice. Body weight and energy (food) intake were monitored, and energy expenditure was measured by indirect calorimetry. The data showed that TLC-6740 increased energy expenditure by ~20%, without altering food intake, thereby inducing a negative energy balance, and causing weight loss. In addition, TLC-6740 decreased RQ, indicating increased fat oxidation, consistent with data observed in the Phase 1 human study, and supporting continued development of TLC-6740 for the treatment of obesity. About TLC-6740 TLC-6740 is a novel, oral, liver-targeted mitochondrial protonophore in development for the treatment of obesity and obesity-associated diseases, including diabetes and MASH. Based on active hepatic uptake and mitochondrial protonophore activity, TLC-6740 increases energy expenditure in hepatocytes, and is expected to have broad, systemic metabolic and cardiovascular benefits, including weight loss, and improved insulin sensitivity, MASH, and dyslipidemia. TLC-6740 is currently being evaluated in a 12-week, Phase 1b clinical trial in patients living with obesity (NCT05822544). About TLC-3595 and ACC2 Inhibition TLC-3595 is a novel and selective ACC2 inhibitor designed to treat type 2 diabetes by increasing fatty acid oxidation (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 MASH. TLC-3595 is currently being evaluated in a 12-week, Phase 2a clinical trial in patients with insulin resistance and type 2 diabetes (NCT05665751). 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 .