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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 .

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 .