SBIR-STTR Award

Diuretics are the most widely prescribed class of drugs. As renal function deteriorates in patients with chronic kidney disease (CKD) whose glomerular filtration rate falls below 60 ml/min (stages 3 to 5) they become more salt-sensitive and require a low BP goal to slow the progression of their disease and to prevent the associated cardiovascular disease (CV) complications. This mandates a predictably effective diuretic. However, at CKD > 3-5, thiazides lose their efficacy. Patients are often switched to furosemide although this suffers from a number of limitations. Furosemide has a highly variable bioavailability (10 to 80%) that leads to unpredictable efficacy and its accumulation in advanced CKD leads to ototoxicity. It has a very short duration of action of about 4 hours that permit post- diuretic renal Na+ and fluid retention that limits the loss of body salt and water (efficacy) and t an abrupt action ("Niagara effect") that reduces the quality of life and causes neurohumoral activation, including aldosterone secretion, that are associated with bad clinical outcomes. Torsemide is a fully effective loop diuretic that is eliminated largely by hepatic metabolism and so does not accumulate in CKD. It has a high and constant bioavailability (80- 100%) in CKD, and blocks the secretion and action of aldosterone, thereby generally maintaining serum potassium concentrations. However, it too suffers from a limited duration of action (4 -8 hours). To address this unmet need and to provide a better diuretic for hypertensive CKD, we have formulated an extended release (ER) form of torsemide that releases the drugs over 8-10 hours in solution. This grant is a proposal for a phase 1 within - subject, cross over, single dose trialto contrast torsemide ER with torsemide immediate release (IR) in 8 normal individuals on fixed Na+ and K+ intakes. Aims 1 will compare pharmakokinetics; aim 2 pharmakodynamics (Na+ and K+ balances) and aim 3 neurohurmonal activation. If successful, this will lead to a similar phase 2 trial in patients with CKD 3-5. This would be followed by an efficacy and safety trial in patients with CKD 3-5 that includes the effects of torsemide ER compared with the standard-of-care drug, furosemide, comparing antihypertensive efficacy and safety in this population.

Public Health Relevance Statement:


Public Health Relevance:
Loop diuretics such as torsemide are required to reduce body salt and water and to control hypertension in patients with chronic kidney disease. However, the duration of action of torsemide is short, which allows time for the kidney to regain the salt and water lost by the action of the drug. We are proposing a clinical trial of an extended release formulation of torsemide to confirm that this extended release formulation leads to a prolonged delivery of torsemide to the blood and thereby to a better salt and water loss. This is the first step in developing a new long-acting diuretic for the two million Americans that suffer from high blood pressure and chronic kidney disease.

NIH Spending Category:
Cardiovascular; Clinical Research; Clinical Trials; Hypertension; Kidney Disease; Prevention

Project Terms:
Address; Aldosterone; American; Angiotensin II; Angiotensins; Antihypertensive Agents; Argipressin; Biological Availability; Blood; Bumetanide; Businesses; Cardiovascular Diseases; Caring; Cause of Death; Chronic Kidney Failure; Clinical; Clinical Trials; control trial; Defect; Development; Diabetic Nephropathy; Disease; Distal; Diuresis; Diuretics; Dose; Drug effect disorder; Drug Formulations; Drug Kinetics; Drug Prescriptions; drug testing; Duct (organ) structure; eplerenone; Equilibrium; experience; Extracellular Fluid; falls; FDA approved; Furosemide; Genetic Crossing Over; Glomerular Filtration Rate; Goals; Grant; Hepatic; Hour; Hyperaldosteronism; hyperkalemia; Hypertension; hypertension control; Individual; Insulin Resistance; Intake; Kidney; Lead; Legal patent; Letters; Life; Liquid substance; Marketing; Metabolism; Modeling; Natriuresis; novel; ototoxicity; Outcome; Oxidative Stress; Patients; Pharmaceutical Preparations; pharmacodynamic model; Pharmacodynamics; Phase; Phase II Clinical Trials; Plasma; podocyte; Population; Potassium; Prevalence; prevent; Principal Investigator; Probability; programs; Proteinuria; public health relevance; Quality of life; Randomized; Recommendation; Renal function; Renin; Research Personnel; Resistance; Risk; Risk Factors; Safety; salt sensitive; Serum; Sexual Dysfunction; Sodium; Sodium Chloride; Solutions; Spironolactone; Staging; success; Sympathetic Nervous System; Testing; thiazide; Time; Toxic effect; vascular endothelial dysfunction; volunteer; Water

Diuretics are one of the most widely prescribed drugs, yet there has been little innovation for decades. Patients with congestive heart failure (CHF) often have chronic kidney disease (CKD) and retain Na+ and fluid, which causes pulmonary congestion and troublesome lower limb edema. Most of these 7 million patients are treated with the loop diuretic furosemide despite its many limitations. These include low and highly variable bioavailability, frequent hypokalemia, reduction in glomerular filtration rate (GFR and very short duration of action (approximately 3 hours) which permits the kidney to regain much of the salt and water lost in between doses. Therefore, it is not surprising that many patients become furosemide resistant (i.e. retain fluid despite furosemide therapy). This is a frequent cause for hospital readmission and a cause of dangerous complications such as bronchopneumonia. To address these manifest deficiencies of furosemide therapy, we have developed an extended release (ER) formulation of the "best in class" potassium-neutral loop diuretic torsemide that releases the drug over 8-10 hours. A completed randomized, double cross-over phase I study, funded by a phase 1 SBIR grant, compared the responses of 10 healthy subjects consuming a fixed, high Na+ intake (300 mmol*day-1) to one 20 mg dose of either immediate release (IR) torsemide or ER torsemide (separated by a 3 week washout period). Torsemide ER caused twice as much loss of fluid and Na+ and reduction in body weight and BP and half as much fall in GFR. The present phase II SBIR grant test the hypothesis that torsemide ER will cause a more rapid and complete correction of edema (from measurements of lower limb edema) as compared to furosemide IR in patients with CHF +/- CKD. Patients with CHF (+/- CKD) and residual edema despite ongoing furosemide therapy will enter a phase IIb/III double blinded, double-placebo randomized clinical trial comparing torsemide ER to furosemide IR. The primary endpoint will be reduction in edema, measured by water displacement by the lower limbs over one week. Secondary and additional endpoints will include changes in body weight, plasma volume (from ¿ hematocrit), cardiac stretch (from brain natriuretic hormone), neurohormonal activation and quality of life. Based on our study in healthy subjects, we anticipate that torsemide ER will cause a more complete correction of edema and reduction in volume overload. The data generated should be sufficient to register torsemide ER with the FDA to market it with a superiority label over furosemide. Torsemide ER would improve diuretic therapy and thereby address an unmet need to keep patients with edema free of recurrent congestion and repeated hospital readmissions.

Public Health Relevance Statement:


Public Health Relevance:
Loop diuretics such as torsemide are required to reduce body salt and water and to control hypertension in patients with congestive heart failure (CHF) with or without chronic kidney disease (CKD). However, the duration of action of torsemide is short, which allows time for the kidney to regain the salt and water lost by the action of the drug. In a phase I clinical trial in healthy subjects, we have confirmed that a novel extended release formulation of torsemide leads to twice as much fluid and sodium loss over one day. We now wish to test if it also is more effective in reducing edema in patients with congestive heart failue with/without CKD. After the completion of healthy volunteer study as proposed in the phase I SBIR application, this is the next step in developing a new and improved long-acting diuretic for millions of Americans that suffer from CHF and/or CKD.

Project Terms:
Achievement; Address; Adherence (attribute); Adverse effects; American; Azotemia; base; Biological Availability; Blood; Blood Plasma Volume; Blood Pressure; Body Weight; Body Weight decreased; Brain; Brain natriuretic peptide; Bronchopneumonia; Cardiac; Chronic Kidney Failure; Congestive; Congestive Heart Failure; control trial; Creatinine clearance measurement; Data; Diuretics; Dose; Double-Blind Method; Drug effect disorder; Drug Formulations; Drug Prescriptions; Dysuria; Edema; Excretory function; falls; Fatigue; Frequencies (time pattern); Funding; Furosemide; Genetic Crossing Over; Glomerular Filtration Rate; Goals; Grant; healthy volunteer; Heart; Hematocrit procedure; Hospital Readmission; Hour; hypertension control; Hypokalemia; improved; Incontinence; indexing; innovation; Intake; Kidney; Label; Left; Legal patent; Liquid substance; Lower Extremity; Lung; Marketing; Measurement; Measures; Methods; micturition urgency; Modeling; Natriuresis; Natriuretic Factors; novel; Paroxysmal Dyspnea; patient safety; Patients; Pharmaceutical Preparations; Phase; phase 1 study; Phase I Clinical Trials; Placebos; Plasma; Potassium; public health relevance; Quality of life; Questionnaires; Randomized; Randomized Clinical Trials; Recurrence; Residual state; Resistance; response; salt intake; Sampling; Shortness of Breath; Small Business Innovation Research Grant; Sodium; Sodium Chloride; Stretching; Testing; Therapeutic Effect; Thiazide Diuretics; Time; Translating; Treatment Efficacy; trial comparing; Urine; Water