Clinical and pharmacogenetic data confirm the safety and suitability of TLC-6740 for use in conjunction with GLP-1 receptor agonists and proton pump inhibitors across genomic profiles
Preclinical studies demonstrate the potential of TLC-6740 and TLC-1180 to promote weight loss while preserving lean mass, alone and with incretins, in obese mice and monkeys
Phase 1, first-in-human clinical trial initiated for TLC-1180
MENLO PARK, Calif.--(BUSINESS WIRE)--#OW2025--OrsoBio, Inc. (“OrsoBio” or “the Company”), a clinical-stage biopharmaceutical company developing treatments for obesity and related metabolic disorders, today announced the presentation of new clinical and preclinical data at ObesityWeek® 2025, taking place November 4-7, in Atlanta, Ga. The Company’s five abstracts highlight the safety, pharmacokinetics (PK), and efficacy of its portfolio of mitochondrial protonophores. The findings underscore the potential of TLC-6740 and TLC-1180—alone or in combination with glucagon-like peptide-1 (GLP-1) receptor agonists—to induce and sustain weight loss following incretin therapy.
Mitochondrial protonophores promote weight loss by increasing energy expenditure, a validated mechanism that complements incretin-based therapies. OrsoBio is advancing a portfolio of protonophores for obesity, led by the liver-targeted oral agent TLC-6740. At ObesityWeek®, the Company will present Phase 1 data confirming the safety and PK of TLC-6740 when administered with acid suppressants, food, or in individuals with genetic variants that reduce the function of transporters that mediate its hepatic uptake. In a preclinical study, TLC-6740 combined with low-dose semaglutide produced greater weight loss than high-dose semaglutide and maintained metabolic benefits after semaglutide discontinuation in diet-induced obese (DIO) mice.
“We are encouraged by these new data demonstrating the safety and PK of TLC-6740 and the additive benefits observed with coadministration with incretin therapy in preclinical models,” said Mani Subramanian, MD, PhD, Chief Executive Officer of OrsoBio. “These data reinforce our confidence in the potential efficacy of TLC-6740, both as monotherapy and in combination with incretins, in our ongoing clinical study.”
TLC-1180 is a novel, oral, second-generation protonophore with greater potency and systemic distribution than TLC-6740. In prior studies, TLC-1180 increased energy expenditure, reduced body weight, and improved glucose control in DIO mice. At ObesityWeek®, the Company will present two additional preclinical studies evaluating TLC-1180 alone and combined with semaglutide in obese monkeys and mice. Both studies showed comparable or superior reductions in body weight and fat mass with TLC-1180 monotherapy versus semaglutide, and additive benefits from the combination, without worsening lean mass loss. The Company has initiated a first-in-human, Phase 1 clinical trial to evaluate the preliminary safety and PK of this potential therapy for obesity.
“TLC-1180 produced meaningful weight loss and improved insulin sensitivity as monotherapy and with incretin therapy in both rodents and non-human primates,” said Rob Myers, MD, Chief Medical Officer of OrsoBio. “These consistent findings strengthen our confidence in its therapeutic potential. With initiation of a first-in-human Phase 1 study, we’ve reached an important milestone—advancing the second mitochondrial protonophore in our portfolio into clinical development.”
Conference Presentation Details
Oral-013: TLC-1180, a Protonophore, with Semaglutide Enhances Weight Loss and Preserves Lean Mass in DIO Mice
Corporate Orals Session: Tuesday, November 4, 2025 (1:30 – 1:45 p.m.; Rooms A411-A412)
This preclinical study evaluated the effects of TLC-1180 alone and in combination with low-dose semaglutide, compared with high-dose semaglutide, in DIO mice. As monotherapy, TLC-1180 produced body weight and fat mass loss comparable to high-dose semaglutide. In combination with low-dose semaglutide, TLC-1180 achieved greater weight and fat mass reduction with comparable-to-superior metabolic benefits without exacerbating incretin-induced lean mass loss. These findings support a clinical strategy combining a protonophore with a low-dose incretin to minimize adverse effects and improve long-term adherence without compromising efficacy in individuals with obesity.
Poster-254: The Protonophore TLC-1180 Drives Weight Loss, Alone and Combined with Semaglutide, in Obese Primates
Poster Session: Wednesday, November 5, 2025 (2:30 - 3:30 p.m.)
This preclinical study evaluated the effects of TLC-1180, alone and in combination with semaglutide, versus semaglutide monotherapy in spontaneously obese non-human primates. As monotherapy, TLC-1180 produced dose-dependent reductions in body weight, fat mass, and plasma insulin while preserving lean mass. After seven weeks, low-dose TLC-1180 and semaglutide achieved similar vehicle-adjusted weight loss (11% and 14%, respectively), while high-dose TLC-1180 achieved greater weight loss (20%). The combination of TLC-1180 and semaglutide produced the most pronounced effects—27% weight loss and a 67% reduction in fat mass—without affecting food intake or lean mass. These results support the evaluation of TLC-1180, alone and with incretins, for the treatment of obesity and related metabolic disorders.
Poster-255: Weight Loss with the Protonophore TLC-6740 Combined with or Post Incretin Withdrawal in DIO Mice
Poster Session: Wednesday, November 5, 2025 (2:30 - 3:30 p.m.)
This preclinical study evaluated TLC-6740 in combination with low-dose semaglutide and as maintenance therapy following semaglutide discontinuation in DIO mice. The combination of TLC-6740 and low-dose semaglutide produced greater reductions in body weight, fat mass, and glycemic parameters than either monotherapy or high-dose semaglutide. Furthermore, TLC-6740 administered after semaglutide withdrawal maintained weight, fat mass, and glycemic improvements, in contrast to vehicle-treated controls. This combination approach is currently under clinical evaluation in a 24-week Phase 2a study of TLC-6740 and the GLP-1/GIP receptor agonist tirzepatide in individuals with obesity (NCT05822544).
Poster-617: Impact of Gastric Acid Suppression and Food on the Pharmacokinetics of the Protonophore TLC-6740
Poster Session: Thursday, November 6, 2025 (2:30 - 3:30 p.m.)
Given TLC-6740’s pH-dependent solubility, this Phase 1 study (NCT05822544) evaluated the effects of gastric acid suppression and food on its PK and safety. Co-administration with a proton pump inhibitor (omeprazole) or a high-fat, high-calorie meal did not meaningfully alter TLC-6740’s PK profile or safety. These results support administration of TLC-6740 without regard to food and with gastric acid suppressants and indicate that co-administration with GLP-1 receptor agonists—which can delay gastric emptying and alter gastric pH—is unlikely to cause clinically meaningful changes in drug exposure.
Poster-618: OATP1B1/1B3 Genetic Variants Do Not Alter PK or Safety of the Liver-Targeted Protonophore TLC-6740
Poster Session: Thursday, November 6, 2025 (2:30 - 3:30 p.m.)
Liver targeting of TLC-6740, which enhances its therapeutic index by limiting systemic exposure, is mediated by the hepatic uptake transporters OATP1B1 and OATP1B3. This clinical pharmacogenetic analysis from a Phase 1/1b study (NCT05822544) assessed the impact of reduced-function variants in these transporters on the PK and safety of TLC-6740. The variants—present in more than 60% of subjects—had no effect on TLC-6740 exposure or safety, supporting broad clinical use regardless of genotype.
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 active hepatic uptake and mitochondrial protonophore activity, TLC-6740 is expected to provide systemic metabolic and cardiovascular benefits, including weight loss, and improved insulin sensitivity, MASH, and dyslipidemia. TLC-6740 is currently being evaluated in a Phase 1b/2a trial as monotherapy and in combination with tirzepatide in individuals with obesity (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 study (ISRCTN21589167).
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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