TLC-6740 / OrsoBio - LARVOL DELTA

Phase 1/1b Study of TLC-6740 in Healthy Subjects and Subjects With Obesity, With or Without Diabetes (clinicaltrials.gov) - P1 | N=564 | Active, not recruiting | Sponsor: OrsoBio, Inc | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2026 ➔ Jan 2027 | Trial primary completion date: Feb 2026 ➔ Sep 2026

Enrollment closed • Trial completion date • Trial primary completion date • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Increasing Energy Expenditure with the Liver-Targeted Mitochondrial Protonophore TLC-6740 Enhances Weight Loss and Metabolic Benefits in Combination with Tirzepatide in Obesity: A Phase 2a Study (ADA 2026) - P1 | "The liver-targeted mitochondrial protonophore TLC-6740 combined with TZP was well tolerated and produced greater weight loss and metabolic benefits than TZP alone. These findings support combining incretins with therapies that increase energy expenditure to improve weight loss and metabolic outcomes in obesity."

Combination therapy • Late-breaking abstract • P2a data • Diabetes • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • CRP

Clinical data for TLC-6740 demonstrate additive metabolic benefits in combination with tirzepatide (Businesswire) - "At week 24, participants receiving TLC-6740 plus tirzepatide achieved an additional 4.5% mean weight loss compared to those treated with tirzepatide alone, and showed significant improvements in insulin sensitivity, liver health, and body composition. 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, and 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."

P1 data • Obesity

Phase 1/1b Study of TLC-6740 in Healthy Subjects and Subjects With Obesity, With or Without Diabetes (clinicaltrials.gov) - P1 | N=564 | Recruiting | Sponsor: OrsoBio, Inc | Trial completion date: Dec 2025 ➔ Jun 2026 | Trial primary completion date: Oct 2025 ➔ Feb 2026

Trial completion date • Trial primary completion date • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

OrsoBio Continues Development of Mitochondrial Protonophore Portfolio (Businesswire) - "...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."

New P2b trial • Trial status • Obesity

OrsoBio Announces Positive Topline Phase 1b/2a Clinical Data for its Oral Mitochondrial Protonophore TLC-6740 in Combination with Tirzepatide (Businesswire) - "The combination met the study’s primary and key exploratory endpoints for safety, tolerability, and weight loss compared with tirzepatide monotherapy...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)...TLC-6740 was safe and well tolerated in combination with tirzepatide....OrsoBio plans to present these findings at a scientific conference and pursue peer-reviewed publication in 2026."

P1/2 data • Obesity

Weight Loss with the Protonophore TLC-6740 Combined with or Post Incretin Withdrawal in DIO Mice (OBESITY WEEK 2025) - "In DIO mice, TLC-6740 combination with low-dose SEMA was more efficacious than high-dose SEMA, and maintained weight loss and glucose tolerance when used as monotherapy following SEMA discontinuation. These data support evaluation of TLC-6740 in combination with incretins in obesity and associated metabolic disorders."

Preclinical • Genetic Disorders • Metabolic Disorders • Obesity

OATP1B1/1B3 Genetic Variants Do Not Alter PK or Safety of the Liver-Targeted Protonophore TLC-6740 (OBESITY WEEK 2025) - P1 | "Genetic variants associated with reduced function of OATP1B1 and/or OATP1B3 hepatic uptake transporters do not affect the PK or safety of the mitochondrial protonophore TLC-6740, suggesting redundancy in transporters that contribute to its preferential hepatic uptake."

Clinical • Genetic Disorders • Obesity

Impact of Gastric Acid Suppression and Food on the Pharmacokinetics of the Protonophore TLC-6740 (OBESITY WEEK 2025) - "Neither alteration in gastric pH nor delayed gastric emptying (via omeprazole coadministration and/or food) meaningfully alters the PK profile of TLC-6740. These findings suggest that TLC-6740 can be administered without regard to food and with gastric acid suppressants. Importantly, coadministration with GLP-1 receptor agonists, which delay gastric emptying and impact gastric pH, is not expected to result in clinically relevant changes in TLC-6740 exposure."

PK/PD data • Genetic Disorders • Obesity

Poster-255: Weight Loss with the Protonophore TLC-6740 Combined with or Post Incretin Withdrawal in DIO Mice (Businesswire) - "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."

Preclinical • Obesity

Poster-618: OATP1B1/1B3 Genetic Variants Do Not Alter PK or Safety of the Liver-Targeted Protonophore TLC-6740 (Businesswire) - "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."

P1 data • PK/PD data • Obesity

Poster-617: Impact of Gastric Acid Suppression and Food on the Pharmacokinetics of the Protonophore TLC-6740 (Businesswire) - "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."

P1 data • Obesity

Sequential Combination of the Mitochondrial Protonophore (MP) TLC-6740 with Semaglutide Normalizes Body Weight and Preserves Lean Mass in DIO Mice (ADA 2025) - "In DIO mice, '6740 combo with SEMAlow was more efficacious than SEMAhigh, maintained weight loss post SEMA D/C, and was LM neutral. These data support evaluation of '6740 in combo with incretins in obesity and associated metabolic disorders."

Preclinical • Metabolic Disorders • Obesity

Sequential Combination of the Mitochondrial Protonophore TLC-6740 With Semaglutide Normalizes Body Weight and Preserves Lean Mass in DIO Mice (Businesswire) - "OrsoBio...announced new preclinical data being presented at the 85th Scientific Sessions of the American Diabetes Association (ADA)....This preclinical study assessed TLC-6740 alone, in combination with low-dose semaglutide (sequential combination), and as maintenance therapy following semaglutide discontinuation in DIO mice. The sequential combination of TLC-6740 with low-dose semaglutide produced superior body weight and fat mass loss, and improved glycemic parameters compared with TLC-6740 alone and high-dose semaglutide. Initiating TLC-6740 after semaglutide discontinuation maintained body weight and fat mass loss, and glycemic benefits."

Preclinical • Obesity

Phase 1/1b Study of TLC-6740 in Healthy Subjects and Subjects With Obesity, With or Without Diabetes (clinicaltrials.gov) - P1 | N=514 | Recruiting | Sponsor: OrsoBio, Inc | Trial completion date: Aug 2025 ➔ Dec 2025 | Trial primary completion date: Jun 2025 ➔ Oct 2025

Trial completion date • Trial primary completion date • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Phase 1/1b Study of TLC-6740 in Healthy Subjects and Subjects with Obesity, with or Without Diabetes (clinicaltrials.gov) - P1 | N=506 | Recruiting | Sponsor: OrsoBio, Inc | N=341 ➔ 506 | Trial completion date: Mar 2025 ➔ Aug 2025 | Trial primary completion date: Jan 2025 ➔ Jun 2025

Enrollment change • Trial completion date • Trial primary completion date • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

TLC-6740, a liver-targeted mitochondrial protonophore, increases energy expenditure and lipid utilisation in obese mice (EASD 2024) - "The protonophore TLC-6740 increases EE, inducing negative energy balance and weight loss. These data support evaluation of TLC-6740 for obesity and highlight the complementarity of this mechanism to agents that reduce oral intake (e.g., incretins)."

Preclinical • Metabolic Disorders • Obesity

Combinations of the mitochondrial protonophore TLC-6740 and/or the ACC2 inhibitor TLC-3595 provide additive glycaemic benefits to glucagon-like-peptide-1 receptor agonist in db/db mice (EASD 2024) - "In db/db mice, TLC-6740 monotherapy improved glucose tolerance, fasting glycemia, and HbA1c similarly to an approved GLP-1RA. Addition of TLC-6740 and/or TLC-3595 to the GLP-1RA improved glycemic parameters, supporting evaluation of the combinations of these agents with approved incretin therapies for diabetes."

Preclinical • Diabetes • Metabolic Disorders • Obesity • ACACB

Phase 1/1b Study of TLC-6740 in Healthy Subjects and Subjects With Obesity, With or Without Diabetes (clinicaltrials.gov) - P1 | N=311 | Recruiting | Sponsor: OrsoBio, Inc | N=236 ➔ 311

Enrollment change • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

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 (ADA 2024) - "In db/db mice, 6740 improved glucose tolerance, FG, and HbA1c similarly to SEMA. Addition of 6740 and/or 3595 to SEMA improved glycemic parameters, supporting evaluation of combinations with GLP-1R agonists for diabetes."

Preclinical • Diabetes • Metabolic Disorders • Obesity • ACACB

TLC-6740, a Liver-Targeted Mitochondrial Protonophore, Increases Energy Expenditure and Lipid Utilization in Obese Mice (ADA 2024) - "The protonophore TLC-6740 increases EE, inducing negative energy balance and weight loss. These data support evaluation of TLC-6740 for obesity and highlights the complementarity of this mechanism to agents that reduce oral intake (e.g., incretins)."

Preclinical • Metabolic Disorders • Obesity

Safety, PK, and Preliminary Efficacy of the Liver-Targeted Mitochondrial Protonophore TLC-6740—A Phase 1 Study (ADA 2024) - P1 | "In this Ph 1 study, the liver-targeted protonophore TLC-6740 was well tolerated and led to dose-dependent improvements in lipids, supporting its potential for treatment of obesity."

Clinical • Late-breaking abstract • P1 data • Metabolic Disorders • Obesity

Phase 1/1b Study of TLC-6740 in Healthy Subjects and Subjects With Obesity (clinicaltrials.gov) - P1 | N=236 | Recruiting | Sponsor: OrsoBio, Inc | N=156 ➔ 236 | Trial completion date: Mar 2024 ➔ Mar 2025 | Trial primary completion date: Jan 2024 ➔ Jan 2025

Enrollment change • Trial completion date • Trial primary completion date • Genetic Disorders • Obesity

OrsoBio to Present Phase 1 Data for the Liver-Targeted Mitochondrial Protonophore TLC-6740 in Development for the Treatment of Obesity at ObesityWeek 2023 (Businesswire) - P1 | N=148 | NCT05822544 | Sponsor: OrsoBio, Inc | "OrsoBio, Inc...today announced preliminary safety and pharmacokinetic (PK) data from the single ascending dose (SAD) portion of an ongoing Phase 1 trial of TLC-6740....In cohorts treated with single doses of TLC-6740... only mild and non-serious adverse events (AEs) were reported....In cohorts treated with single doses of TLC-6740 (3, 6, 15, 30, 60, and 120 mg), only mild and non-serious adverse events (AEs) were reported.....The PK profile of TLC-6740 includes a prolonged half-life (17 to 46 hours), supporting once-daily, oral dosing. Due to liver targeting, plasma concentrations are projected to remain >80-fold below exposures associated with hyperthermia in preclinical studies, providing large safety margins for human use. The results also suggest that low doses of TLC-6740 will reach therapeutic exposures, supporting its potential efficacy for obesity and associated disorders."

P1 data • Diabetes • Metabolic Disorders • Non-alcoholic Steatohepatitis • Obesity

A Study to Evaluate Single and Multiple Doses of TLC-6740 in Healthy Subjects (clinicaltrials.gov) - P1 | N=148 | Recruiting | Sponsor: OrsoBio, Inc | Not yet recruiting ➔ Recruiting

Enrollment open