TLC-6740 / OrsoBio - LARVOL DELTA

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

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

New P1 trial