EXTENDED RELEASE TORSEMIDE: PHASE 2

DESCRIPTION provided by applicant 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 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 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 andquot best in classandquot potassium neutral loop diuretic torsemide that releases the drug over hours A completed randomized double cross over phase I study funded by a phase SBIR grant compared the responses of healthy subjects consuming a fixed high Na intake mmol day to one mg dose of either immediate release IR torsemide or ER torsemide separated by a 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 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