Restoring Energy Homeostasis to Treat Severe Metabolic Disorders

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

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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Prevalence of obesity in
the United States

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Type 2 diabetes patients
worldwide

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Risk of pancreatitis in severe hypertriglyceridemia

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

PROGRAM OVERVIEW

Mitochondrial Protonophores (TLC-6740, TLC-1180, TLC-1235)

Mitochondrial protonophores increase energy expenditure and drive broad metabolic benefits, including enhanced fatty acid and glucose oxidation, TCA cycle flux, AMPK activation, and inhibition of de novo lipogenesis (DNL).
OrsoBio is advancing a portfolio of novel mitochondrial protonophores with differentiated potency, pharmacology, and biodistribution, designed to maximize therapeutic potential while maintaining a wide safety margin in patients with obesity and associated disorders.
TLC-6740, a liver-targeted mitochondrial protonophore designed for active hepatic uptake, which reduces plasma exposure, enabling a favorable therapeutic index. TLC-6740 is currently being evaluated in a Phase 2a clinical trial in obesity, including in combination with a GLP-1 receptor agonist.
TLC-1180, a second-generation, liver-biased protonophore, demonstrates enhanced potency, broader systemic distribution, and a longer half-life, potentially offering additional weight loss and metabolic benefits in obesity-associated comorbidities (e.g., diabetes, heart failure with preserved ejection fraction [HFpEF]).
In preclinical models, both TLC-6740 and TLC-1180 have shown consistent metabolic benefits — including fat-specific weight loss (lean mass preservation), reduced ectopic lipid accumulation, enhanced insulin sensitivity, and improved cardiopulmonary fitness — with no evidence of toxicity due to excessive systemic uncoupling.
OrsoBio’s mitochondrial protonophore program features a pipeline of additional compounds with distinct pharmacologic properties that provide optionality across a broad range of metabolic indications.

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 potent, liver- and gut-restricted, LXR inverse agonist that reduced plasma triglycerides, cholesterol, and hepatic steatosis in preclinical studies.
In a Phase 1 study, TLC-2716 demonstrated a favorable safety and tolerability profile and improvements in atherogenic lipids, including triglycerides, LDL-C, and remnant cholesterol in healthy volunteers.
TLC-2716 is currently being evaluated in a Phase 2a study as a once-daily oral therapy for patients with severe hypertriglyceridemia (SHTG) and metabolic dysfunction-associated steatotic liver disease (MASLD).
OrsoBio aims to advance TLC-2716 in metabolic conditions with high unmet need, including SHTG and residual atherosclerotic cardiovascular risk due to elevated remnant cholesterol, and continues to evaluate its potential in other disorders characterized by dysregulated lipogenesis.

PROGRAM OVERVIEW

ACC2 Inhibitor (TLC-3595)

Acetyl-CoA carboxylase 2 (ACC2) is a central regulator of fatty acid oxidation, controlling the entry of long-chain fatty acids into mitochondria.
TLC-3595 is a potent, oral, selective, small-molecule allosteric inhibitor of ACC2.
In a preclinical model of heart failure characterized by massive cardiac lipid accumulation due to impaired fatty acid utilization (ATGL knockout mouse), TLC-3595 improved cardiac function, locomotor activity, and survival. These findings underscore the potential of ACC2 inhibition to address the metabolic inflexibility which drives cardiac dysfunction in heart failure.
TLC-3595 is currently advancing toward clinical development in heart failure with preserved ejection fraction (HFpEF) and additional potential indications characterized by impaired fatty acid oxidation.

PROGRAM OVERVIEW

ACMSD Inhibition

Aminocarboxymuconate semialdehyde decarboxylase (ACMSD) is a branch-point enzyme in de novo NAD⁺ synthesis, expressed only in the kidney (tubular cells) and liver (hepatocytes and cholangiocytes).
ACMSD plays a key role in regulating cellular stress response pathways—mechanisms central to chronic inflammation, fibrosis, and the progression to end-organ dysfunction or failure.
In dysmetabolic mouse and human liver organoid models, ACMSD inhibition reduced hepatic inflammation and fibrosis by decreasing oxidative stress and DNA damage responses while enhancing mitochondrial function.
By modulating cellular stress responses, ACMSD inhibition offers a novel approach to the management of chronic hepatic and renal diseases driven by maladaptive stress responses.