TRC150094, a Novel Mitochondrial Modulator, Reduces Cardio-Metabolic Risk as an Add-On Treatment: a Phase-2, 24-Week, Multi-Center, Randomized, Double-Blind, Clinical Trial

Abstract

Background TRC150094, a novel mitochondrial modulator, reduces insulin resistance and is expected to improve the trinity of dysglycemia, dyslipidemia, and hypertension. In this multi-dose phase-2 study, we evaluated the safety and efficacy of TRC150094 in diabetic subjects with dyslipidemia receiving standard of care. Methods A randomized, multicenter, double-blind, placebo-controlled, parallel-group, Phase 2 study was conducted in 225 subjects from July 2013 to August 2015. The key inclusion criteria were body mass index of 23–35 kg/m 2 , age between 30 and 65 years, fasting glucose of ≥126 or glycated hemoglobin (HbA1c) of ≥6.4% stabilized on treatment with ≤2 oral hypoglycemic agents, apolipoprotein-B (apo-B) ≥100 mg/dL, serum triglyceride (TG) ≥150 mg/dL, systolic blood pressure (SBP) ≥130 mmHg, and diastolic blood pressure (DBP) ≥85 mmHg with/without antihypertensive treatment. The subjects were randomly assigned to one of three TRC150094 doses (25, 50, or 75 mg) or placebo for 24 weeks. The outcomes assessed included fasting plasma glucose (FPG), insulin, mean arterial blood pressure (MAP), and apoB. In addition, safety and tolerability were assessed. Results A reduction for dose up to 50 mg was noted for FPG in the range of 13.9 to 21.7 mg/dL (p < 0.05 for TRC150094 25 and 50 mg), fasting insulin reduction in the range 2.7 to 6.0 mU/L (all doses, p > 0.05), and improved HOMA-IR (−2.0 to −2.5) (all doses, p > 0.05) compared to placebo after 24 weeks of treatment. Furthermore, a significant reduction in MAP in the range 3.1 to 4.2 mmHg (p < 0.05 for TRC150094 25 and 75 mg) was noted. In addition, TRC150094 treatment was weight neutral, had a favorable effect on lowering atherogenic lipid fractions, including non-HDL cholesterol (−6.8 mg/dL at 50 mg dose). Adverse events were mild to moderate in nature and not dose-related. One adverse event not related to treatment led to the discontinuation of the study. Overall, TRC150094 was safe and well tolerated for up to 24 weeks. Conclusion In this study, TRC150094 treatment in the dose range of 25 to 50 mg showed improvement in various components of CMBCD, ie, dysglycemia, dyslipidemia, and hypertension. Trial Registration This study was registered in the Clinical Trial Registry of India. Trial registration number: CTRI/2013/03/003444. Date of registration: 4th March 2013.

Optimal dose of tirzepatide for type 2 diabetes mellitus: A meta-analysis and trial sequential analysis

“…However, there are concerns about GLP-1RA-induced GI AEs such as nausea, vomiting, and diarrhea ( 49 , 50 ), and its efficacy remains limited in some patients with T2DM ( 49 ). As studies progress, novel hypoglycemic agents such as the novel mitochondrial modulator TRC150094 ( 51 ), the glucokinase activator dorzagliatin ( 52 ), and the GLP-1R and GIPR dual agonist TZP continue to be launched and show excellent hypoglycemic potential.…”

Potential Applications of Thyroid Hormone Derivatives in Obesity and Type 2 Diabetes: Focus on 3,5-Diiodothyronine (3,5-T2) in Psammomys obesus (Fat Sand Rat) Model

“…Although the action mode of 3,5-T2 is classified as non-genomic (non-nuclear), it should be noted that some questions remain unanswered related to 3,5-T2 pathway acts via nuclear HT receptor (like T3) or whether it induces to rapid additional signals (plasma membrane, cytosolic compartment) to mediate changes on gene expression, or mitochondrial function to regulate energy metabolism. Actually, beneficial prospects for the use of 3,5-T2 as a therapeutic arsenal are derived from the recent novel development of a synthetic 3,5-T2 analog TRC150094, which might be used in obesity, diabetes and cardio-metabolic therapy application [ 36 ].…”