Restoring Energy Homeostasis to Treat Severe Metabolic Disorders

OrsoBio’s development programs address high unmet medical need in patients with severe metabolic disorders, including type 2 diabetes, severe hypertriglyceridemia, and congenital and acquired lipodystrophies.

Our programs address the root cause of organ dysfunction by modulating fundamental metabolic pathways with four highly targeted and complementary mechanisms:

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Type 2 diabetes patients worldwide

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Risk of pancreatitis in severe hypertriglyceridemia

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Of lipodystrophy patients on approved therapies due to limited efficacy, cost, and/or side effects

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1

Increased fatty acid oxidation in cardiac muscle (ACC2), plus beneficial effects on plasma lipids (LXR, protonophores)

2

Hepatic DNL inhibition (LXR, protonophores), increased fatty acid oxidation (ACC2, protonophores), increased NAD+ synthesis, and improved mitochondrial function (ACMSD)

3

Increased NAD+ synthesis and improved mitochondrial function in kidneys (ACMSD)

4

Increased fatty acid oxidation in skeletal muscle (ACC2)

Each of our programs modulates central aspects of cellular energetics in key, energetically-driven organs

PROGRAM OVERVIEW

ACC2 Inhibitor (TLC-3595)

  • Acetyl-CoA Carboxylase 2 (ACC2) regulates oxidation of fatty acids by controlling their entry into mitochondria
  • TLC-3595 is a potent, oral, selective, allosteric inhibitor of ACC2 that has completed a Phase 1 study
  • In preclinical studies, TLC-3595 increased fatty acid oxidation, reduced ectopic lipid accumulation in muscle, liver and heart, and improved insulin sensitivity, making it an attractive therapeutic option for addressing insulin resistance in patients with type 2 diabetes
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PROGRAM OVERVIEW

LXR Inverse Agonist (TLC-2716)

  • Liver X Receptor (LXR) is the master regulator of cholesterol homeostasis and de novo lipogenesis (DNL)
  • TLC-2716 is a liver-targeted inhibitor of LXR that is currently in Phase 1 development
  • In preclinical studies, TLC-2716 reduced hepatic steatosis and plasma triglycerides and cholesterol, supporting its development as a potential once-daily oral therapy for patients with severe dyslipidemias
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PROGRAM OVERVIEW

Mitochondrial Protonophores (TLC-6740, TLC-1235)

  • By increasing energy expenditure, mitochondrial protonophores have broad metabolic benefits, including AMPK activation, DNL inhibition, and increased fatty acid oxidation and TCA cycle flux
  • TLC-6740 is a novel, liver-targeted mitochondrial protonophore designed to have a wide therapeutic index due to active hepatic uptake and reduced plasma exposure
  • TLC-1235 is a controlled-release mitochondrial protonophore that has an enhanced safety margin
  • In preclinical models, TLC-6740 and TLC-1235 have demonstrated consistent metabolic benefits, including weight loss and improved liver and plasma triglycerides and insulin sensitivity, without evidence of excessive systemic uncoupling
  • Both TLC-6740 and TLC-1235 have potential to treat a broad range of metabolic disorders, including lipodystrophies, diabetes, and obesity
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PROGRAM OVERVIEW

ACMSD Inhibition

  • 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 liver and kidney and NAD+ is reduced in patients with advanced liver and kidney disease
  • In preclinical studies, ACMSD inhibition led to increased NAD+ synthesis, improved mitochondrial function, and protected against liver and kidney injury
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Publications

November 1, 2022

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 (AASLD 2022, Abstract #4210)

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November 1, 2022

Evaluation of the safety and pharmacokinetic effects of the oral, acetyl-CoA carboxylase-2 (ACC2) inhibitor TLC-3595 in healthy volunteers (AASLD 2022, Abstract #3677)

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November 1, 2022

TLC-6740, a potent liver-targeted mitochondrial protonophore, has multiple metabolic benefits in preclinical models (AASLD 2022, Abstract #2551)

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November 1, 2022

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 (AASLD 2022, Abstract #2532)

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November 1, 2022

Enhancement of de novo NAD+ biosynthesis by novel ACMSD inhibitors improves mitochondrial function in iPSC-derived human liver organoid models of steatohepatitis (AASLD 2022, Abstract #2441)

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OrsoBio is developing novel therapies to treat patients with severe metabolic disorders, including diabetes, severe dyslipidemias, lipodystrophies, and more.

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Recent News

OrsoBio team members collaborated with Professor Takebe in his pioneering study in Cell on the first use of en masse human liver organoids to define the genetic basis of metabolic liver disease and potential for tailored therapeutic development.

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