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 www.aasld.org/the-liver-meeting.
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.
