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LABORATORY DEVELOPED TEST (LDT) TO SUPPORT CLINICAL EVALUATION OF A DRUG FOR PAINFUL DIABETIC NEUROPATHY - ABSTRACT CHRONIC PAIN, ESPECIALLY NEUROPATHIC PAIN THAT AFFECTS THE NORMAL FUNCTIONING OF NERVES, REPRESENTS AN UNMET MEDICAL NEED, BECAUSE A LARGE PERCENTAGE OF PATIENTS WITH NEUROPATHIC PAIN CONDITIONS DO NOT RECEIVE ADEQUATE PAIN RELIEF RESULTING IN SUFFERING AND REDUCED QUALITY OF LIFE. INFLAMMATION PLAYS AN IMPORTANT ROLE IN VARIOUS NEUROPATHIC PAIN CONDITIONS, INCLUDING PAINFUL DIABETIC NEUROPATHY (PDN). CHEMOKINES AND THEIR RECEPTORS ARE THOUGHT TO PLAY A CRITICAL ROLE IN INFLAMMATION-RELATED PAINFUL CONDITIONS; AND PAST EFFORTS IN THE PHARMACEUTICAL INDUSTRY HAVE LED TO THE DEVELOPMENT OF COMPOUNDS THAT MODULATE INDIVIDUAL COMPONENTS OF THE CHEMOKINE- RECEPTOR NETWORK. ONE OF THE DRUG TARGETS IS A SPECIFIC CHEMOKINE RECEPTOR, BECAUSE OF ITS ROLE IN MODULATING NEUROPATHIC PAIN CONDITIONS. PREVIOUSLY, A SELECTIVE ANTAGONIST FOR THIS RECEPTOR WAS STUDIED IN A NUMBER OF CLINICAL TRIALS, INCLUDING SEVERAL PHASE II CLINICAL TRIALS, ONE OF WHICH AIMED AT NEUROPATHIC PAIN CONDITIONS IN PDN. THESE CLINICAL TRIALS DEMONSTRATED THE FAVORABLE SAFETY AND TOLERABILITY PROFILES OF THIS DRUG IN HUMANS. HOWEVER, PATIENTS' GENETIC PROFILES WERE NOT TAKEN INTO ACCOUNT, LEADING TO LESS FAVORABLE RESULTS FROM THE CLINICAL STUDIES. WE OBTAINED ACCESS TO THE CLINICAL DATASET PACKAGE, BLOOD SAMPLES COLLECTED DURING CLINICAL STUDIES, AND THE POTENTIAL TO CONTINUE DEVELOPING THE COMPOUND. THROUGH OUR PRELIMINARY STUDIES, WE IDENTIFIED THIS RECEPTOR’S GENE EXPRESSION LEVELS AS AN IMPORTANT BIOMARKER FOR PREDICTING THE CLINICAL EFFICACY OF THE DRUG IN TREATING PAINFUL DIABETIC NEUROPATHY (PDN). THIS SUGGESTS THAT THE GENE EXPRESSION LEVELS MAY BE USED AS AN ENROLLMENT INCLUSION CRITERION, TO ENRICH THE PDN PATIENT POPULATION MOST LIKELY TO RESPOND TO THE DRUG TREATMENT IN CLINICAL STUDIES. FOR THIS SBIR GRANT APPLICATION, WE PROPOSE TO DEVELOP A LABORATORY DEVELOPED TEST (LDT), TO BE USED AS AN ENROLLMENT INCLUSION CRITERION, IN THE CLINICAL DEVELOPMENT OF THIS DRUG AS A THERAPEUTIC FOR PDN. OUR OVERALL RATIONALE FOR THE LDT DEVELOPMENT IS TO FOLLOW A TEST AND CONFIRM STRATEGY. THE PROPOSED STUDIES IN THIS SBIR GRANT ARE DESIGNED TO IMPLEMENT THIS RELATIVELY STRAIGHTFORWARD STRATEGY: WE WILL DESIGN A QPCR ASSAY AS THE LDT TO MEASURE THE SPECIFIC GENE MRNA LEVELS, AND THEN USE IT TO MEASURE THE RECEPTOR AS THE BIOMARKER WITH A SET OF CLINICAL TRIAL SAMPLES.

CHEMOKINE-RECEPTOR PROFILING FOR PAINFUL DIABETIC NEUROPATHY IN BIOLOGICAL SAMPLES FROM HUMAN CLINICAL TRIALS - PROJECT SUMMARY/ABSTRACT CHRONIC PAIN IS A MAJOR HEALTHCARE BURDEN, REPRESENTING ECONOMIC COSTS OF UP TO $635B PER YEAR, MORE THAN CANCER, DIABETES, AND HEART DISEASE, ACCORDING TO A JOHNS HOPKINS STUDY PUBLISHED IN THE JOURNAL OF PAIN. PAIN IS A HIGHLY HETEROGENEOUS CONDITION COMPRISING NEUROPATHIC, NOCICEPTIVE AND INFLAMMATORY COMPONENTS, AND PATIENT RESPONSES TO CURRENTLY AVAILABLE DRUGS VARY GREATLY. A VERY PROMISING APPROACH TO TARGET VARIOUS FORMS OF PAIN IS THROUGH ANTAGONISM OF KEY PLAYERS IN NEURO- INFLAMMATION. SPECIFICALLY, THE CHEMOKINE RECEPTOR SYSTEM, A COMPLEX NETWORK OF OVER 20 DIFFERENT RECEPTORS AND OVER 80 LIGANDS, IS INTEGRAL TO NEUROINFLAMMATORY PROCESSES AND THE PHARMACEUTICAL INDUSTRY HAD BEEN VERY ACTIVE IN DEVELOPING COMPOUNDS TARGETING INDIVIDUAL RECEPTORS IN THE NETWORK. HOWEVER, THE BIOLOGICAL COMPLEXITY, LIGAND PROMISCUITY, AND RECEPTOR REDUNDANCY OF THE CHEMOKINE RECEPTOR SYSTEM HAS PRECLUDED SUCCESSFUL CLINICAL DEVELOPMENT OF THE COMPOUNDS AND MANY PHARMA HAVE EXITED THE PAIN THERAPEUTIC AREA. A MAJOR LIMITATION OF SUCCESSFUL TARGETING OF THIS NETWORK IS SUFFICIENT UNDERSTANDING OF THE MOLECULAR AND CELLULAR DYNAMICS OF THE CHEMOKINE NETWORK, AND HOW SPECIFIC RECEPTORS VARY IN CHRONIC PAIN CONDITIONS. IN THIS STUDY, WE AIM TO DETERMINE THE GENETIC EXPRESSION OF A CHEMOKINE RECEPTOR UTILIZING HUMAN CLINICAL SAMPLES COLLECTED IN A CLINICAL TRIAL EVALUATING A RECEPTOR ANTAGONIST. FURTHER, WE WILL UTILIZE THIS UNDERSTANDING IN CONJUNCTION WITH PATIENT EFFICACY DATA FROM THE CLINICAL TRIALS TO CONTINUE THE DEVELOPMENT OF OUR LEAD COMPOUND, A DRUG THAT SHOWED A STATISTICALLY SIGNIFICANT CLINICAL SIGNAL IN PAIN. RESULTS FROM THIS STUDY WILL ENABLE PATIENT STRATIFICATION AND EFFECTIVE CLINICAL TRIAL DESIGN BY INCLUDING PATIENTS WITH THE APPROPRIATE GENETIC AND PHENOTYPIC BACKGROUND AND THUS SIGNIFICANTLY INCREASE THE LIKELIHOOD ACHIEVING PRIMARY ENDPOINTS OF PAIN REDUCTION IN THE CLINIC.

CHEMOKINE-RECEPTOR EXPRESSION PROFILING IN BIOLOGICAL SAMPLES FROM HUMAN CLINICAL TRIALS

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