Project Grant R44DK139835

FROM FORMULATION TO IND: OPTIMIZATION OF A DUAL CROMOLYN-CETIRIZINE ENTERIC SOFTGEL FOR CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME - ABSTRACT CHRONIC PROSTATITIS/CHRONIC PELVIC PAIN SYNDROME (CP/CPPS) IS A DEBILITATING UROLOGIC CONDITION AFFECTING BETWEEN 7-12% OF ADULT MEN GLOBALLY. THERE ARE CURRENTLY NO FDA APPROVED THERAPEUTICS FOR CPPS. MOUNTING EVIDENCE IMPLICATES MAST CELL ACTIVATION AND NEUROIMMUNE DYSFUNCTION IN CP/CPPS PATHOGENESIS, YET NO APPROVED THERAPIES DIRECTLY TARGET THESE PATHWAYS. THE STANDARD OF CARE REMAINS A COMBINATION OF OFF-LABEL THERAPIES. DOLOR THERAPEUTICS HAS DEVELOPED A NOVEL ORAL FORMULATION COMBINING CROMOLYN SODIUM (A MAST CELL STABILIZER) AND CETIRIZINE (A HISTAMINE 1 RECEPTOR ANTAGONIST). PRELIMINARY DATA SUGGESTS THE ACTIVE PHARMACEUTICAL INGREDIENTS DELIVER PROMISING CLINICAL EFFICACY IN CP/CPPS. HOWEVER, LIMITATIONS IN ORAL ABSORPTION OF THE CROMOLYN SODIUM IN THIS COMBINATION RESTRICTED CLINICAL UTILITY. DOLOR WAS FORMED TO OVERCOME THESE CHALLENGES AND DEVELOP A FORMULATION FOR COMMERCIALIZATION TO TREAT CP/CPPS. IN A SUCCESSFUL PHASE I STTR, DOLOR AND ITS COLLABORATORS AT NU DEVELOPED A LEAD FORMULATION (DT101) THAT SHOWED PRONOUNCED IMPROVEMENT IN BIOAVAILABILITY OF CROMOLYN IN DOGS, YIELDING A ~17.7-FOLD INCREASE OVER ORAL GAVAGE. THESE RESULTS WERE OBTAINED WITH DIRECT DUODENAL DELIVERY OF A LIQUID FORMULATION. IN THIS PHASE II SBIR, DOLOR WILL OPTIMIZE THE FORMULATION AND COMPLETE LARGE- ANIMAL PHARMACOKINETIC (PK) AND TOXICOLOGY STUDIES THAT WILL BE PERFORMED IN PREPARATION FOR FDA APPROVAL THROUGH THE 505(B)(2) PATHWAY AS A FIRST-IN-CLASS, MECHANISM-BASED ORAL THERAPY FOR CP/CPPS. AIM 1: OPTIMIZE AND VALIDATE THE ENHANCED CROMOLYN-CETIRIZINE OPTIGEL DR SOFTGEL FORMULATION (DT101) AND CONFIRM REGULATORY ALIGNMENT THROUGH PRE-IND CONSULTATION. DOLOR WILL COLLABORATE WITH A LEADING CONTRACT DEVELOPMENT AND MANUFACTURING ORGANIZATIONS TO OPTIMIZE INTEGRATION OF DT101 INTO THE OPTIGEL DR SYSTEM, ALLOWING FOR PRODUCTION OF A GMP-COMPLIANT PILOT BATCH. RELEASE TESTING WILL INCLUDE ENTERIC RELEASE VALIDATION, DRUG LOADING, SHORT-TERM STABILITY, AND ANALYTICAL METHOD DEVELOPMENT FOR POTENCY AND DISSOLUTION. IN ADDITION, THE COMPANY WILL ATTEND A PRE-IND MEETING WITH THE FDA. AIM 2: COMPLETE DOG PK AND PHASE 1 ENABLING TOXICOLOGY STUDIES AND COMPLETE FDA SUBMISSION UNDER 505(B)(2) PATHWAY. DOLOR WILL PARTNER WITH A CONTRACT RESEARCH ORGANIZATION TO CONDUCT GLP-COMPLIANT PK AND TOXICOLOGY STUDIES IN BEAGLE DOGS. THE PK STUDY WILL FOCUS ON DETERMINING THE APPROPRIATE DOSING SCHEDULE FOR DT101. TOXICOLOGY STUDIES WILL EVALUATE CLINICAL SAFETY, PATHOLOGY, AND TOXICOKINETICS ACROSS THE IDEAL DOSE DETERMINED IN THE PK STUDY. STUDIES ARE EXPECTED TO DEMONSTRATE NO TREATMENT-LIMITING TOXICITIES. A FINAL PHASE II MILESTONE WILL BE A FULL PACKET SUBMISSION TO THE FDA. AT THE END OF PHASE II, DOLOR THERAPEUTICS WILL BE POSITIONED TO ESTABLISH A STRATEGIC PARTNERSHIP WITH A LEADING UROLOGY PHARMACEUTICAL COMPANY. PRELIMINARY DISCUSSIONS WITH SUCH COMPANIES SUGGEST INTEREST IN MILESTONE-BASED AGREEMENTS CONTINGENT ON FAVORABLE PK, TOXICOLOGY, AND ALIGNMENT WITH FDA REQUIREMENTS. COMBINED PHASE IIB/CRP FUNDING AND ANTICIPATED PARTNER INVESTMENT WILL SUPPORT PHASE 2 CLINICAL TRIALS, WHILE LONGER-TERM EFFORTS WILL EXPAND DT101 AND DOLOR INTO ADDITIONAL INDICATIONS DRIVEN BY MAST CELL ACTIVATION.