Project Grant R42HL167327

NOVEL THERAPEUTICS FOR HEART FAILURE: MODIFIED, WATER-SOLUBLE CAVEOLIN-1 SCAFFOLDING DOMAIN PEPTIDES WITH IMPROVED CHARACTERISTICS FOR DRUG DEVELOPMENT: PHASE II - ABSTRACT OUR LONG-TERM GOAL IS TO FILL THE UNMET NEED FOR TREATMENTS FOR HEART FAILURE (HF). CAVEOLIN-1 IS A PROMISING THERAPEUTIC TARGET IN FIBROTIC DISEASES. THE PROFIBROTIC EFFECTS OF CAVEOLIN-1 DEFICIENCY IN CELLS AND MOUSE MODELS IS SUPPRESSED BY A PEPTIDE EQUIVALENT TO ITS ACTIVE SITE (CAVEOLIN-1 SCAFFOLDING DOMAIN, CSD). WE HAVE SHOWN THE BENEFICIAL EFFECTS OF CSD USING MODEL SYSTEMS FOR HEART, LUNG, SKIN, AND KIDNEY FIBROSIS. CSD ALMOST COMPLETELY BLOCKS THE ORGAN FUNCTION DEFICITS AND THE DRAMATIC INCREASES IN FIBROSIS, MICROVASCULAR LEAKAGE, AND INFLAMMATORY CELL INFILTRATION IN THESE MODELS. HOWEVER, CSD LACKS KEY PHARMACOLOGIC PROPERTIES FOR DRUG DEVELOPMENT. IN SUCCESSFUL PHASE I STUDIES, WE UNDERTOOK RATIONAL STEPS (DEVISING CSD FRAGMENTS, MAKING THE FRAGMENTS WATER SOLUBLE, COMPARING THEIR EFFICACY) TO SELECT A LEAD COMPOUND (W94-101). BOTH SUBCUTANEOUS (SC) INJECTIONS AND ORAL DELIVERY OF W94-101 WERE EFFECTIVE IN TWO DISTINCT MOUSE HF MODELS (ANGIOTENSIN II [ANGII]-INDUCED HF IN YOUNG MICE AND AGING-ASSOCIATED HF IN OTHERWISE UNTREATED AGED MICE). IN BOTH CASES DISEASE-ASSOCIATED PATHOLOGICAL EFFECTS ON HEART FUNCTION WERE REVERSED BY W94-101. THE EFFECT IN AGED MICE IS PARTICULARLY REMARKABLE BECAUSE IT CLEARLY DEMONSTRATES THAT W94-101 CAN REVERSE PRE-EXISTING DISEASE. OUR SELECTION OF A LEAD COMPOUND CAPABLE OF REVERSING DEFICITS IN ORGAN FUNCTION AND OUR DEMONSTRATION OF ITS ORAL EFFICACY PUTS US IN A STRONG POSITION TO SUCCESSFULLY PERFORM THE NEXT LOGICAL STEPS IN DEVELOPING W94-101 TO TREAT HF IN HUMAN PATIENTS. SPECIFICALLY, WE WILL: 1) OPTIMIZE W94-101 TREATMENT. WE WILL DETERMINE THE MINIMUM BENEFICIAL DOSE OF W94-101 AND THE OPTIMAL FREQUENCY OF ADMINISTRATION IN MOUSE MODEL SYSTEMS. HEART FUNCTION DETERMINED BY ECHOCARDIOGRAPHY WILL BE THE PRIMARY READOUT. (2) DETERMINE W94-101'S MECHANISM OF ACTION IN REGULATING MICROVASCULAR LEAKAGE. WE WILL DETERMINE WHETHER W94-101 REGULATES MICROVASCULAR LEAKAGE VIA THE PARACELLULAR OR TRANSCELLULAR ROUTE AND WHICH PROTEINS INVOLVED IN THESE PROCESSES ARE ALTERED IN EXPRESSION IN FIBROSIS, THEN RESCUED BY W94-101. 3) PERFORM IND-ENABLING STUDIES. TO BEGIN CLINICAL TRIALS, IND-ENABLING STUDIES MUST BE COMPLETED: TOXICOLOGY AND SAFETY, PHARMACOKINETICS AND STABILITY, AND ADME (ABSORPTION, DISTRIBUTION, METABOLISM, EXCRETION). LABCORP, A LEADING CRO, WILL PERFORM THESE STUDIES. RESULTS MEETING INDUSTRY STANDARDS WILL ESTABLISH W94-101'S SAFETY PROFILE AND TOLERABILITY AND PROVIDE A SAFETY MARGIN FOR USE IN HUMANS WHILE DEMONSTRATING SUFFICIENT PHARMACOLOGICAL ACTIVITY TO JUSTIFY PROGRESSION TO CLINICAL TRIALS. IN THE FUTURE, TO PREPARE FOR CLINICAL TRIALS WE WILL RECRUIT INVESTORS AND STRATEGIC INDUSTRY PARTNERS, COMPLETE IND-ENABLING STUDIES, CHOOSE A VENDOR FOR CGMP SYNTHESIS OF W94-101 FOR USE IN CLINICAL TRIALS, AND DEVELOP A REGULATORY STRATEGY TO PREPARE FOR MEETING WITH THE FDA.