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Chaitanya Dutt,1 Joao Eduardo Nunes Salles,2 Shashank Joshi,3 Tiny Nair,4 Subhankar Chowdhury,5 Ambrish Mithal,6 Viswanathan Mohan,7 Ravi Kasliwal,8 Satyawan Sharma,9 Jan Tijssen,10 Nikhil Tandon11 1Research and Development, Torrent Pharmaceuticals Ltd, Ahmedabad, Gujarat, India; 2Discipline of Endocrinology, Medical Sciences of Santa Casa de São Paulo, São Paulo, Brazil; 3Department of Endocrinology, Lilavati Hospital, Mumbai, Maharashtra, India; 4Department of Cardiology, PRS Hospital, Thiruvananthapuram, Kerala, India; 5Department of Endocrinology, Institute of Post-Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, West Bengal, India; 6Department of Endocrinology & Diabetes, Max Healthcare, New Delhi, India; 7Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India; 8Medanta- The Medicity, Gurgaon, Haryana, India; 9Department of Cardiology, Bombay Hospital and Medical Research Center, Mumbai, Maharashtra, India; 10Academic Medical Center - University of Amsterdam, Amsterdam, the Netherlands; 11Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, IndiaCorrespondence: Chaitanya Dutt, Research & Development, Torrent Pharmaceuticals Ltd., Ahmedabad, Gujarat, India, Tel +91 9825606901, Email Cdutt@torrentpharma.comAbstract: The epidemic of obesity or adiposity-based chronic diseases presents a significant challenge with the rising prevalence of morbidities and mortality due to atherosclerotic cardiovascular diseases (ASCVD), especially in low- and middle-income countries (LMIC). The underlying pathophysiology of metabolic inflexibility is a common thread linking insulin resistance to cardiometabolic-based chronic disease (CMBCD), including dysglycemia, hypertension, and dyslipidemia progressing to downstream ASCVD events. The complex CMBCD paradigm in the LMIC population within the socio-economic and cultural context highlights considerable heterogeneity of disease predisposition, clinical patterns, and socio-medical needs. This review intends to summarize the current knowledge of CMBCD. We describe recently established or emerging trends for managing risk factors, assessment tools for evaluating ASCVD risk, and various pharmacological and non-pharmacological measures particularly relevant for LMICs. A CMBCD model positions insulin resistance and β-cell dysfunction at the summit of the disease spectrum may improve outcomes at a lower cost in LMICs. Despite identifying multiple pathophysiologic disturbances constituting CMBCD, a large percentage of the patient at risk for ASCVD remains undefined. Targeting dysglycemia, dyslipidemia, and hypertension using antihypertensive, statins, anti-glycemic, and antiplatelet agents has reduced the incidence of ASCVD. Thus, primordial prevention targeting pathophysiological changes that cause abnormalities in adiposity and primary prevention by detecting and managing risk factors remains the foundation for CMBCD management. Therefore, targeting pathways that address mitochondrial dysfunction would exert a beneficial effect on metabolic inflexibility that may potentially correct insulin resistance, β cell dysfunction and, consequently, would be therapeutically effective across the entire continuum of CMBCD.Keywords: mitochondrial modulator, insulin resistance, diabetes mellitus, dyslipidemia hypertension, non-high-density lipoprotein-cholesterol, triglycerides, apolipoprotein B

Deepa Joshi,1 Prashant GJ,1 Shohini Ghosh,1 Anookh Mohanan,1 Shashank Joshi,2 Viswanathan Mohan,3 Subhankar Chowdhury,4 Chaitanya Dutt,1 Nikhil Tandon5 1Torrent Pharmaceuticals Ltd., Ahmedabad, Gujarat, India; 2Lilavati Hospital, Mumbai, India; 3Dr. Mohan’s Diabetes Specialities Centre (Madras Diabetes Research Foundation), Tamil Nadu, India; 4Department of Endocrinology, Institute of Post-Graduate Medical Education and Research and Seth Sukhlal Karnani Memorial Hospital, Kolkata, India; 5Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, IndiaCorrespondence: Deepa Joshi, Research & Development, Torrent Pharmaceuticals Ltd., Ahmedabad, Gujarat, India, Tel + 91 7971315571, Email deepajoshi@torrentpharma.comBackground: 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/m2, 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.Keywords: cardiometabolic-based chronic disease, mitochondrial modulator, type 2 diabetes, non-HDL cholesterol, hypertension, dyslipidemia

TRC150094, a novel mitochondrial modulator, can restore metabolic flexibility by improving insulin resistance in preclinical studies. This study primarily aims to evaluate the safety, tolerability, and pharmacokinetics (PK) of oral TRC150094 after conducting two double-blind, randomized, Phase-I studies, single ascending dose (SAD) and multiple ascending dose (MAD), with n = 46, in overweight/obese adult and elderly subjects. In addition, the effect of TRC150094 on pharmacodynamic (PD) efficacy markers was evaluated. PK assessments, including maximum concentration (Cmax), area under the plasma concentration (AUC), time to Cmax (Tmax), and elimination half-life (t½), were assessed at pre-specified time points. PD assessments included apolipoprotein B (ApoB), triglycerides, hepatic fat by magnetic resonance spectroscopy (MRS) and cardiopulmonary exercise testing (CPET) parameters. TRC150094 was rapidly absorbed, and the AUC of TRC150094 increased in a dose-dependent manner across all doses in non-elderly and elderly cohorts. Cmax was more than the dose-proportional for all doses in all cohorts. Tmax ranged from 0.25 to 4 h, and t½ ranged from 15 to 18 h, making TRC150094 suitable for once-daily dosing. Food did not interfere with the overall absorption of the drug. The metabolites of TRC150094 were glucuronide and sulfate conjugates, and 20% of the drug was excreted unchanged in the urine. TRC150094 at 50 mg showed an improving trend in triglycerides. A significant reduction in Apo B was observed after 50 mg dose (−2.34 vs. 13.24%, p = 0.008), which was, however, not the case after 150 mg (8.78 vs. 13.24%, p = 0.1221). Other parameters such as hepatic fat and insulin sensitivity indices (HOMA-IR, MATSUDA Index derived from OGTT) showed an improving trend for the dose of 50 mg. In terms of safety, all the AEs reported were mild to moderate in severity. None of the adverse events was considered definitely or probably related to treatment, and there were no abnormal laboratory findings. In conclusion, the PK of TRC150094 was linear with no clinically significant food effect. TRC150094 and its metabolites suggest a lesser likelihood of drug-drug interactions. Overall, TRC150094 ensured safety and exhibited suitability for all subjects. Clinical Trial Registration: EUDRA CT: 2009-014941-10 (SAD) and CTR-India registration: CTRI/2009/091/000601 (MAD) [ABSTRACT FROM AUTHOR]