Clinical validation of NS-0200, a fixed combination drug product for the treatment of hypertension

PROJECT SUMMARY Hypertension is a major cause of premature death globally, responsible for 10.4 million deaths annually. Around 1.28 billion adults aged between 30-79 worldwide have hypertension, of which only 1 in 5 adults (21%) have it under control. Hypertension is diagnosed when blood pressure (BP) is consistently ≥130 (systolic BP (SBP)) and/or ≥80 mmHg (diastolic BP (DBP)). It is associated with both an increased risk of cardiovascular disease (CVD) and reduced life expectancy. The prescribed first line of hypertension drugs belongs to the thiazide diuretics, calcium antagonists, angiotensin converting enzyme (ACE) and angiotensin receptor blockers (ARB) classes of drugs. Other diuretics and beta blockers are considered secondary either due to safety and tolerability issues or due to weaker clinical outcomes. According to the American Heart Association (AHA) and the American College of Cardiology (ACC) 2018 hypertension guidelines, the on-treatment target BP is <130/80 mmHg. In general, at least 2 antihypertensive drugs with different mechanisms of action are required to achieve proper BP control. However, in spite of the multiple classes of drugs, efficient BP control is only achieved in 30.4% of treated adults. NuSirt Sciences, Inc. (NuSirt) developed a fixed dose combination (FDC) of L-leucine, metformin and sildenafil (NS-0200) as a hypertensive drug with potential to improve other cardiometabolic risk factors (bodyweight (BW), hyperlipidemia and glycemic control). L-leucine with low doses of metformin and sildenafil activates the Sirt1/AMPK/eNOS energy metabolism pathway thereby modulating Sirt1-dependent metabolism and serving as a partial mimetic of calorie restriction on BP regulation. In the present SBIR Phase II project, NuSirt will manufacture NS-0200 under GMP conditions to conduct a 12-week randomized clinical trial on hypertensive adults to determine the efficacy of the drug in controlling BP compared to placebo. Primary endpoint analysis will be the evaluation of change in mean seated SBP from baseline to study termination. Secondary endpoint analysis will comprise the evaluation of change in DBP and body weight. Exploratory analysis will consist of assessing the effect of NS-0200 on blood glucose and lipid levels. Safety will be assessed throughout the study by examination of adverse events (AE), concomitant medications, clinical laboratory evaluations, vital signs, physical examinations and 12-lead ECGs. Completion of this SBIR Phase II will serve as a foundation to pursue a Phase III clinical program, aiming to compare the efficacy of NS-0200 with other hypertension drugs currently available in the market.