A Phase 2a Clinical Study of a Cardiac Hormone for the Outpatient Treatment of Worsening Heart Failure

Abstract/Summary Madeleine Pharmaceuticals, Inc. The Specific Aim of this SBIR Phase IIB proposal is to carry out the first phase 2a clinical trial of our Phase 2 program using rMP3167, a recombinant human form of the naturally occurring cardiac hormone proANP 31-67, for the treatment of worsening heart failure (WHF). This is part of our broad drug development objective, supported by leading cardiologists, to introduce the first new cardiorenal drug for the treatment of heart failure since nesiritide in 2001. Current standard of care (SOC) for these and acute HF patients is the diuretic furosemide, discovered in 1962. As many as 2.4 million HF individuals in the US have impaired renal function or cardiorenal syndrome (CRS). These WHF patients present with advancing symptoms of dyspnea, edema, high blood pressure, and compromised cardiac function. Moreover 25-40% of CRS individuals become refractory to loop diuretics over time, damaging renal function and exacerbating their condition. Current WHF treatment attempts acute symptom relief to avoid index or re-hospitalizations – the latter a substantial economic burden to the healthcare system. ProANP 31-67 acts locally in distal tubules/collecting ducts and glomeruli through prostaglandin E2 to inhibit NaK ATPase (resulting in natriuresis/diuresis) and improve renal vasodilation (increasing GFR, BUN and creatinine clearance) with little undesirable side effects seen in 80 unique clinical exposures (normal/CHF/AHF) to date. Readily formulated as a simple injectable and available to general practitioners and specialists, it can be prescribed as a “take home” self-administrative regimen - adaptive to current evolving WHF outpatient SOC. Initially, as a co-therapy to frontline cardiocentric care with limited renal improving options, rMP3167 will alleviate WHF through restored hemodynamics and renal function, and improve patient quality of life (QOL) (NYHA classification) and reduce annual hospitalizations. Our successful NIH SBIR Phase II focused on FDA recommended CMC and GLP toxicology studies in preparation for a lead-in clinical Phase 2a trial, which will be used to design and power a larger Phase 2b trial. In the proposed SBIR Phase IIB work, we will carry out these Tasks to achieve our Specific Aim: Task 1: Batch Production of ~50 grams of GMP grade recombinant proANP 31-67 (rMP3167) Task 2: File an IND for a U.S. Phase 2 clinical trial program to advance rMP3167 Task 3: Conduct the lead-in (pilot) clinical Phase 2a trial in WHF patients Criteria for Success: (1) no serious drug related adverse events that would prevent further use in humans, (2) no undesirable side effects that would be expected to prevent adoption, (3) predicable pharmacokinetic behavior for s.c. b.i.d delivery and (4) trending improvement in renal and cardiovascular biomarkers.