BCL2A1

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 .

PALO ALTO, Calif.--(BUSINESS WIRE)-- OrsoBio, Inc., a clinical-stage biopharmaceutical company developing treatments for severe metabolic disorders, today announced it has acquired exclusive worldwide rights to an ACC2 inhibitor program from Shionogi & Co., Ltd. The intellectual property includes lead candidate TLC-3595 (formerly S-723595), 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. TLC-3595 also has potential for treating other conditions characterized by impaired FAO, including cirrhosis with sarcopenia and genetic, long-chain FAO disorders. “Increasing fatty acid oxidation via selective ACC2 inhibition without adverse effects of ACC1 inhibition, such as hypertriglyceridemia and thrombocytopenia, offers great promise for improving insulin sensitivity in patients with type 2 diabetes,” said Rob Myers, MD, Chief Medical Officer of OrsoBio. “Our first-in-human study of TLC-3595 and preclinical data showing reduced lipid accumulation in muscle and liver and improved insulin sensitivity, support our plans to initiate a Phase 2a trial in subjects with insulin resistance in the first half of 2023.” OrsoBio will present data from a 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®, November 4-8, 2022, in Washington, D.C. In this Phase 1 single and multiple ascending dose trial, TLC-3595 treatment for up to 14 days was well tolerated, all adverse events were mild, and no serious adverse events were observed. TLC-3595 treatment led to improvements in LDL and total cholesterol, confirming the compound’s pharmacodynamic effects, and its pharmacokinetics support once daily oral administration. “Insulin resistance is the major predisposing factor in the pathogenesis of type 2 diabetes. Previous studies by my group have demonstrated that ACC2 knockout mice manifest increased energy expenditure and improved insulin sensitivity, which is mediated by increased fatty acid oxidation leading to reductions in ectopic lipid content in liver and skeletal muscle. These results strongly support the development of novel pharmacologic ACC2 inhibitors for the treatment of type 2 diabetes,” 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. “Based on its potency and selectivity, and preclinical data to date, I see great potential for TLC-3595 to improve insulin sensitivity in patients with type 2 diabetes, and this mechanism to complement approved therapies.” About TLC-3595 and ACC2 Inhibition ACC2 regulates the oxidation of fatty acids by controlling their entry into mitochondria. In ACC2 knockout mice, and in preclinical models with TLC-3595 treatment, increased fatty acid oxidation (FAO) and reduced lipid accumulation in skeletal muscle, liver, and heart, and improved insulin sensitivity have been observed. Selectively inhibiting ACC2 with TLC-3595 offers promise as a therapy for type 2 diabetes and other disorders characterized by impaired FAO. 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 Shionogi Shionogi & Co., Ltd. is a leading global research-driven pharmaceutical company based in Japan dedicated to bringing benefits to patients based on its corporate philosophy of “supplying the best possible medicine to protect the health and wellbeing of the patients we serve.” Our pipeline is focused on infectious disease, pain, CNS, and new growth areas as society’s needs demand. For more information on Shionogi & Co., Ltd., visit https://www.shionogi.com/global/en/. 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.

-- Company to share clinical and preclinical data on ACC2, LXR, mitochondrial protonophore, and ACMSD programs -- PALO ALTO, Calif.--(BUSINESS WIRE)-- OrsoBio, Inc., a clinical-stage biopharmaceutical company developing treatments for severe metabolic disorders, today announced the presentation of five abstracts from the company’s programs at AASLD’s The Liver Meeting® from November 4-8. OrsoBio recently announced that it has acquired novel compounds and intellectual property for four programs addressing fundamental aspects of energy metabolism, including inhibitors of acetyl-CoA carboxylase-2 (ACC2), liver X receptor (LXR), and aminocarboxymuconate semialdehyde decarboxylase (ACMSD), as well as a portfolio of mitochondrial protonophores. These compounds have potential for the treatment of a range of metabolic diseases, including type 2 diabetes, severe dyslipidemias, lipodystrophies, and nonalcoholic steatohepatitis (NASH). “There remains tremendous unmet medical need for patients with severe metabolic disorders,” said Mani Subramanian, MD, PhD, Chief Executive Officer of OrsoBio. “We believe that our portfolio of first-in-class compounds targeting central pathways in energy metabolism holds great promise to address both common and rare metabolic diseases. The breadth of our preclinical and clinical research being presented at The Liver Meeting® highlights the potential of these programs, as well as the strength of the OrsoBio research and development team and our scientific collaborations.” “Advances in organoid medicine, including our recent publication describing en masse population-based analysis of human liver organoids (HLOs) for understanding disease genetics and drug response in NASH, highlights the feasibility of a precision therapeutic approach for severe metabolic liver disease,” said Takanori Takebe, MD, PhD, Director of Commercial Innovation at Center for Stem Cell and Organoid Medicine (CuSTOM), Endowed Chair and Associate Professor of Pediatrics at Cincinnati Children’s Hospital Medical Center, and co-author on two of OrsoBio’s presentations (Abstracts #2441, #4210). “I am truly excited about translating the data on OrsoBio’s compounds in HLOs derived from genetic subsets of patients to clinical studies in patients with severe metabolic disorders.” The following abstracts will be presented as poster presentations at The Liver Meeting®, in Washington, D.C., November 4-8, 2022. Abstract #2441: Enhancement of de novo NAD+ biosynthesis by novel ACMSD inhibitors improves mitochondrial function in iPSC-derived human liver organoid models of steatohepatitis Poster Session, Saturday, November 05, 2022 (1:00-2:00 pm) This study evaluated the effect of treatment with ACMSD-inhibiting therapy TLC-065 on mouse hepatocytes and induced pluripotent stem cell (iPSC)-derived HLOs to understand whether the compound could help boost de novo NAD+ synthesis from tryptophan. The study showed multiple benefits of ACMSD-inhibition in rodents, including improved mitochondrial health, enhanced fatty acid oxidation, and decreased de novo lipogenesis, lipotoxicity, and oxidative stress. In iPSC-derived HLOs in which ACMSD expression is upregulated, ACMSD-inhibition elicited similar metabolic benefits as observed in rodent models. Abstract #2532: TLC-2716, a potent, liver-targeted, inverse agonist of the liver X receptor (LXR), demonstrates profound reductions in hepatic and plasma lipids in dysmetabolic rodent models Poster Session, Saturday, November 05, 2022 (1:00-2:00 pm) This study evaluated the effects of TLC-2716 on lipid metabolism in multiple preclinical models. In dysmetabolic rodents, TLC-2716 led to profound improvements in plasma and liver triglycerides, plasma cholesterol, and glucose tolerance. Additionally, in humanized chimeric liver (PXB®) mice, TLC-2716 suppressed the hepatic expression of genes involved in triglyceride and cholesterol metabolism. Due to high hepatic extraction, no impact on expression of genes involved in reverse cholesterol transport (ABCA1, ABCG1) in the circulation were observed with TLC-2716 treatment. Abstract #2551: TLC-6740, a potent liver-targeted mitochondrial protonophore, has multiple metabolic benefits in preclinical models Poster Session, Saturday, November 05, 2022 (1:00-2:00 pm) This study evaluated TLC-6740 in vitro, in nonhuman primates, and in multiple dysmetabolic rodent models. In vitro, mild hepatic mitochondrial uncoupling with TLC-6740 was associated with metabolic benefits in multiple cell types, including AMPK activation, increased TCA cycle flux, and inhibition of de novo lipogenesis. In rodent models of NASH and insulin resistance, TLC-6740 led to weight loss, reduced liver and plasma triglycerides, and improved insulin sensitivity, without evidence of excessive systemic mitochondrial uncoupling, which can be attributed to its selective liver loading (~40x liver:plasma ratio in nonhuman primates). Abstract #3677: Evaluation of the safety and pharmacokinetic effects of the oral, acetyl-CoA carboxylase-2 (ACC2) inhibitor TLC-3595 in healthy volunteers Poster Session, Sunday, November 6, 2022 (1:00-2:00 pm) This Phase 1, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of TLC-3595 in healthy volunteers. In this single and multiple ascending dose trial, TLC-3595 treatment for up to 14 days was well-tolerated and all adverse events were non-serious and mild. TLC-3595 treatment led to improvements in LDL and total cholesterol, confirming the compound’s pharmacodynamic effects, and its pharmacokinetic properties support once daily oral administration. Abstract #4210: Enhanced lipogenesis associated with a high-risk GCKR variant (rs1260326) is effectively suppressed by TLC-2716, a novel, liver-targeted LXR inverse agonist in steatotic human liver organoids Poster Session, Monday, November 7, 2022 (1:00-2:00 pm) This study utilized induced pluripotent stem cell (iPSC)-derived HLOs to evaluate the relevance of the LXR pathway in NASH, and to assess the effects of TLC-2716 on NASH-related phenotypes in HLOs from subjects with and without the glucokinase regulatory protein (GCKR) missense variant rs1260326:C>T (TT). This variant leads to increased DNL and has been associated with NASH in genome-wide association studies. The study showed upregulation of LXR expression in steatotic HLOs, and that TLC-2716 reduced the expression of lipogenic genes and lipid accumulation in HLOs from patients with and without the GCKR variant rs1260326. The data support the evaluation of TLC-2716 in NASH patients with this GCKR variant in a precision medicine approach. Further information about The Liver Meeting® 2022, hosted by AASLD, can be found at . 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 . 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 .