OrsoBio Announces Positive Topline Phase 1b/2a Clinical Data for its Oral Mitochondrial Protonophore TLC-6740 in Combination with Tirzepatide

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MENLO PARK, Calif.--(BUSINESS WIRE)--Dec 16, 2025--

OrsoBio, Inc. (“OrsoBio” or “the Company”), a clinical-stage biopharmaceutical company developing treatments for obesity and related metabolic disorders, today announced positive topline data from a 24-week Phase 1b/2a trial evaluating its oral, liver-targeted mitochondrial protonophore TLC-6740 in combination with the GLP-1/GIP receptor agonist tirzepatide. The combination met the study’s primary and key exploratory endpoints for safety, tolerability, and weight loss compared with tirzepatide monotherapy.

The randomized, double-blind, placebo-controlled study enrolled 55 adults with obesity (BMI ≥30 kg/m 2 ) without diabetes. Participants (mean baseline weight 109.2 kg; BMI 37.5 kg/m 2 ) received tirzepatide 5 mg by weekly subcutaneous injection 1 plus either TLC-6740 180 mg (N=33) or placebo (N=22) administered orally once daily for 24 weeks.

At week 24, participants receiving TLC-6740 plus tirzepatide achieved mean weight loss of 13.3%, compared with 8.8% with tirzepatide alone. The 4.5% mean incremental weight loss with the combination—representing approximately 5.1 kg or a 51% relative increase versus tirzepatide monotherapy—was statistically significant (p=0.018, intention-to-treat). While weight loss in the tirzepatide monotherapy arm plateaued at 24 weeks, the combination arm showed continued linear decline.

TLC-6740 was safe and well tolerated in combination with tirzepatide. Adverse event rates, including gastrointestinal events typical of incretin therapy, were similar between groups. No Grade 3 or severe adverse events, treatment discontinuations, or signs of excessive systemic uncoupling (e.g., fevers) were observed in participants receiving TLC-6740.

“Our results demonstrate that TLC-6740 can safely enhance weight loss when added to incretin therapy,” said Rob Myers, MD, Chief Medical Officer and Head of Development at OrsoBio. “The weight loss achieved with TLC-6740 plus low-dose tirzepatide is comparable to that seen with higher-dose tirzepatide in the registrational program, 2 supporting the potential to improve efficacy while maintaining tolerability. We believe TLC-6740 could broadly enhance therapies that reduce food intake, including GLP-1 receptor agonists and amylin analogs, given its complementary mechanism to increase energy expenditure.”

Across additional endpoints, the combination produced significant improvements in insulin sensitivity, liver biochemistry, adiponectin, and hsCRP. An MRI substudy demonstrated meaningful reductions in liver fat and total, visceral, and skeletal muscle adiposity, with no adverse impact on lean mass.

OrsoBio plans to present these findings at a scientific conference and pursue peer-reviewed publication in 2026.

OrsoBio Continues Development of Mitochondrial Protonophore Portfolio

TLC-6740 is part of OrsoBio’s portfolio of mitochondrial protonophores being developed as potential treatments for obesity and obesity-associated disorders, including type 2 diabetes and MASH.

With TLC-6740 continuing to demonstrate safety and potential efficacy, and with more than 300 patients dosed for up to 24 weeks across multiple studies, OrsoBio plans to initiate a larger, longer Phase 2b clinical trial evaluating TLC-6740 in combination with an incretin in 2026.

In addition, OrsoBio is enrolling patients in an ongoing, first-in-human clinical trial of TLC-1180, its second-generation mitochondrial protonophore ( ISRCTN21589167 ). Dosing has been completed in the first two single-dose cohorts, with favorable preliminary safety and tolerability. OrsoBio previously presented preclinical data at ObesityWeek® 2025 demonstrating robust weight loss with TLC-1180 administered as monotherapy and in combination with semaglutide in obese mice and non-human primates.

“Emerging evidence indicates that our protonophore portfolio, as monotherapy or combined with incretins, may address unmet needs in obesity treatment, including greater weight loss with lean mass preservation, improved tolerability, insulin sensitivity, and liver health,” said Mani Subramanian, MD, PhD, Chief Executive Officer of OrsoBio. “With TLC-6740 and TLC-1180 advancing through clinical development and oral incretins on the horizon, our protonophores are well positioned for use in next-generation treatment regimens, including oral fixed-dose combinations.”

About TLC-6740

TLC-6740 is a novel, oral, liver-targeted mitochondrial protonophore in development for obesity and related metabolic diseases, including diabetes and MASH. By increasing energy expenditure through targeted hepatic activity, TLC-6740 is designed to drive weight loss and improve metabolic health, including insulin sensitivity and lipid metabolism. In a Phase 1b/2a trial in individuals with obesity, TLC-6740 combined with tirzepatide resulted in an average of 4.5% greater weight loss compared with tirzepatide alone, with no additional safety concerns, discontinuations, or weight loss plateau at 24 weeks, and improvements across multiple metabolic measures ( NCT05822544 ).

About TLC-1180

TLC-1180 is a novel, potent, oral, mitochondrial protonophore with liver-biased distribution that increases energy expenditure and promotes fat-selective weight loss. In preclinical studies of obese mice and non-human primates, TLC-1180 reduced fat mass, improved glucose control, and enhanced the efficacy of GLP-1 receptor agonists. TLC-1180 is currently being evaluated in a first-in-human, Phase 1 dose escalation study ( ISRCTN21589167 ).

About OrsoBio, Inc.

OrsoBio, Inc. is a privately held, clinical-stage biopharmaceutical company dedicated to developing therapies for 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 targeting central pathways in energy metabolism. For more information, visit www.orsobio.com.

1 Study participants received tirzepatide 2.5 mg by weekly subcutaneous injection for the first 4 weeks, followed by 5 mg weekly for the remaining 20 weeks. Participants were advised to continue pre-trial diet and exercise regimens without modification.

2 Jastreboff AM, et al. N Engl J Med 2022;387(3):205-216 (SURMOUNT-1trial).

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KEYWORD: CALIFORNIA UNITED STATES NORTH AMERICA

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SOURCE: OrsoBio, Inc.

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PUB: 12/16/2025 08:00 AM/DISC: 12/16/2025 08:00 AM

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