TLC-3595 / Shionogi, OrsoBio - LARVOL DELTA

Genetic deletion or pharmacological inhibition of acetyl-CoA carboxylase 2 enhances fatty acid oxidation and improves cardiac function and survival in the murine ATGL knockout model of severe heart failure. (PubMed, J Mol Cell Cardiol Plus) - "Metabolite profiling of cardiac tissue of Atgl/Acc2 double KO mice and Atgl KO mice treated with TLC-3595 revealed ACC2-specific changes, including reduced malonyl-CoA and increased short-, medium-, and long-chain acylcarnitines, consistent with improved FAO. These findings support the therapeutic targeting of ACC2 for the treatment of heart failure associated with impaired FAO."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • ACACB

Novel Combination of a Mitochondrial Protonophore (MP) and an Acetyl-CoA Carboxylase 2 (ACC2) Inhibitor Causes Weight Loss and Preserves Lean Mass in Obese Mice (ADA 2025) - "Introduction and Objective: TLC-1180 , a novel MP, and TLC-3595, an ACC2-selective inhibitor, enhance fatty acid oxidation via complementary mechanisms and are in development for obesity-associated disorders. In DIO mice, a novel combo of a MP and an ACC2 inhibitor caused comparable weight loss to an incretin but preserved lean mass. In sum, these data support the evaluation of combinations of these agents in people living with obesity and associated metabolic disorders."

Preclinical • Metabolic Disorders • Obesity • ACACB

Novel Combination of a Mitochondrial Protonophore and an Acetyl-CoA Carboxylase 2 (ACC2) Inhibitor Causes Weight Loss and Preserves Lean Mass in Obese Mice (Businesswire) - "OrsoBio...announced new preclinical data being presented at the 85th Scientific Sessions of the American Diabetes Association (ADA)....This preclinical study evaluated the effects of the mitochondrial protonophore, TLC-1180, and the ACC2 inhibitor, TLC-3595—as monotherapy and in combination—and semaglutide in DIO mice. TLC-3595 dose dependently reduced body weight, fat mass, and liver biochemistry while preserving lean mass in DIO mice. A combination of TLC-3595 with TLC-1180 had similar weight loss efficacy to semaglutide, but preserved lean mass."

Preclinical • Obesity

Inhibition of Acetyl -CoA Carboxylase 2 (ACC2) enhances fatty acid oxidation and improves cardiac function and survival in a severe model of heart failure (AHA 2024) - "In summary, ACC2 deletion or pharmacologic inhibition restored cardiac energy metabolism towards increased FAO in Atgl KO mice, resulting in improved cardiac function and survival. These findings support the therapeutic targeting of ACC2, including with the selective small molecule ACC2 inhibitor TLC-3595, for the treatment of patients with HF associated with FAO deficiency."

Cardiovascular • Congestive Heart Failure • Diabetes • Fibrosis • Heart Failure • Immunology • Metabolic Disorders • Type 2 Diabetes Mellitus • ACACB

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

A Study Evaluating Daily Oral Doses of TLC-3595 in Participants With Insulin Resistance (clinicaltrials.gov) - P2 | N=76 | Active, not recruiting | Sponsor: OrsoBio, Inc | Recruiting ➔ Active, not recruiting | Trial completion date: May 2024 ➔ Dec 2024 | Trial primary completion date: Mar 2024 ➔ Sep 2024

Enrollment closed • Trial completion date • Trial primary completion date

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

A Study Evaluating Daily Oral Doses of TLC-3595 in Participants With Insulin Resistance (clinicaltrials.gov) - P2 | N=75 | Recruiting | Sponsor: OrsoBio, Inc | Phase classification: P2a ➔ P2 | N=50 ➔ 75 | Trial completion date: Jan 2024 ➔ May 2024 | Trial primary completion date: Nov 2023 ➔ Mar 2024

Enrollment change • Phase classification • Trial completion date • Trial primary completion date

Antidiabetic Effects of TLC-3595, a Selective ACC2 Inhibitor, in ZDF Rats (ADA 2023) - "T2D progression and IS by hyperinsulinemic-euglycemic clamp were assessed in 30% diet-restricted ZDF rats treated with TLC-3595 (1.67, 5, or 15mg/kg) or pioglitazone (Pio, 0.75mg/kg) daily for 5-12 weeks. TLC-3595 or an analog caused rapid and sustained IMCL reduction (~50%) in lean and dysmetabolic rodents. TLC-3595 reduced IMCL, improved IS, and delayed T2D progression comparable to Pio in ZDF rats. These data provide strong rationale for evaluation of TLC-3595 to treat insulin resistance and T2D."

Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • ACACB

TLC-3595, a selective acetyl-CoA carboxylase 2 (ACC2) inhibitor, improves steatosis and fibrosis in murine models of NASH via pleiotropic mechanisms (EASL-ILC 2023) - "High-fat diet (HFD)-fed, diet-induced obese (DIO) mice, Fatty Liver Shionogi-Lepob/Lepob (FLS-ob/ob) mice, or choline-deficient, L-amino acid-defined HFD (CDAHFD)-fed mice were treated with TLC-3595 (5-60 mg/kg BID) or the nonselective, liver-targeted ACC inhibitor firsocostat (FIR, 0.5-1.5 mg/kg BID) for 4–8 weeks. TLC-3595 has beneficial effects on steatosis and fibrosis in NASH via multiple mechanisms, including direct effects in hepatocytes, hepatic stellate cells, adipocytes, and skeletal muscle, without causing hypertriglyceridemia as seen with nonselective ACC inhibitors. These data support the development of TLC-3595 in patients with NASH. Figure: Veh icl e TLC-35 95 FIR 0 1 2 3 A di po ne ct in (μ g/ m L) **** ####A."

Preclinical • Diabetes • Dyslipidemia • Fibrosis • Hepatology • Hypertriglyceridemia • Immunology • Liver Cirrhosis • Non-alcoholic Steatohepatitis • Obesity • Type 2 Diabetes Mellitus • ACACA • ACACB • CASP3 • CASP7 • FGF21

A Study Evaluating Daily Oral Doses of TLC-3595 in Participants With Insulin Resistance (clinicaltrials.gov) - P2a | N=50 | Recruiting | Sponsor: OrsoBio, Inc | Trial completion date: Jul 2023 ➔ Jan 2024 | Trial primary completion date: Jun 2023 ➔ Nov 2023

Trial completion date • Trial primary completion date

A Study Evaluating Daily Oral Doses of TLC-3595 in Participants With Insulin Resistance (clinicaltrials.gov) - P2a | N=50 | Recruiting | Sponsor: OrsoBio, Inc | Not yet recruiting ➔ Recruiting

Enrollment open

A Study Evaluating Daily Oral Doses of TLC-3595 in Participants With Insulin Resistance (clinicaltrials.gov) - P2a | N=50 | Not yet recruiting | Sponsor: OrsoBio, Inc

New P2a trial