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OrsoBio to Present Phase 1 and Preclinical Data for Liver-Targeted Mitochondrial Protonophore TLC-6740 at the American Diabetes Association's 84th Scientific Sessions

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 profile of 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 www.orsobio.com.

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