ACMSD

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.

-- 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 .