Courage Incorporated

NEW AWARD UNDER THE NEW PARTNERS INTIATIVE

DEVELOPMENT OF NOVEL MELANOCORTIN-4 RECEPTOR PEPTIDE AGONISTS FOR THE TREATMENT OFMC4R HAPLOINSUFFICIENCY - THE MELANOCORTIN PEPTIDE THERAPEUTIC SETMELANOTIDE, (IMCIVREETM), IS HIGHLY EFFECTIVE IN THE TREATMENT OF THE RARE OBESITY SYNDROMES, POMC AND LEPTIN RECEPTOR DEFICIENCY. HOWEVER, THE DRUG IS INEFFECTIVE FOR THE MOST COMMON SYNDROMIC OBESITY, MELANOCORTIN-4 RECEPTOR (MC4R) DEFICIENCY (MC4R HAPLOINSUFFICIENCY), FOUND AT A PREVALENCE GREATER THAN 1/1000 INDIVIDUALS. FURTHER, THE DRUG IS INEFFECTIVE IN THE TREATMENT OF DIETARY OBESITY. IN ADDITION TO THE FACT THAT IMCIVREE DOES NOT ADDRESS THE UNMET MEDICAL NEEDS IN PATIENTS WITH SYNDROMIC OBESITY DUE TO MC4R DEFICIENCY, IMCIVREE IS A PAN-AGONIST OF FOUR MELANOCORTIN RECEPTORS AND CAUSES HYPERPIGMENTATION BY ACTIVATING THE MELANOCORTIN-1 RECEPTOR (MC1R) ON DERMAL AND FOLLICULAR MELANOCYTES. LASTLY, THE FORMULATION OF IMCIVREE IS NOT IDEAL, REQUIRING DAILY SUBCUTANEOUS ADMINISTRATION. IN OUR PHASE I APPLICATION, WE PROPOSED TO DEVELOP MELANOCORTIN-3 RECEPTOR ANTAGONISTS AS PEPTIDE THERAPEUTICS FOR MC4R DEFICIENCY, SINCE THE MC3R IS A NEGATIVE REGULATOR OF MC4R NEURONS. HOWEVER, IN THE COURSE OF DEVELOPING THESE MOLECULES, CURRENTLY STILL IN PROGRESS, WE MADE A STRIKING DISCOVERY. BASED ON THE EXTENSIVE STRUCTURE-ACTIVITY RELATIONSHIP (SAR) WORK INITIATED IN PHASE 1, WE ALSO IDENTIFIED FOUR NOVEL FAMILIES OF MC4R AGONISTS. CHARACTERIZING SELECT PEPTIDES IN A VALIDATED OBESE MOUSE MODEL OF HUMAN MC4R DEFICIENCY (MC4R+/- MICE), WE DISCOVERED TWO FAMILIES OF THESE MC4R AGONIST PEPTIDES THAT, UNLIKE IMCIVREE, HAVE SIGNIFICANT WEIGHT LOSS EFFICACY IN MC4R HAPLOINSUFFICIENCY, AS WELL AS IN DIETARY OBESITY. MORE RECENT WORK PROVIDES MODIFIED VERSIONS OF THESE PEPTIDES THAT HAVE REDUCED MC1R EFFICACY AS WELL. FINALLY, WE HAVE SHOWN THAT MELANOCORTIN PEPTIDES CAN BE FORMULATED IN INJECTABLE PLGA MICROSPHERES BY A NEW REMOTE-LOADING TECHNIQUE, YIELDING STEADY RELEASE OF PEPTIDE FOR MORE THAN 30 DAYS OFFERING THE POTENTIAL FOR OPTIMIZING THE THERAPEUTIC WINDOW, IMPROVING PATIENT COMPLIANCE, AND REDUCING COST. IN THIS PHASE II APPLICATION, WE PROPOSE TO 1) COMPLETE THE CHEMICAL DEVELOPMENT OF MC4R AGONIST PEPTIDES FOR THE TREATMENT OF MC4R DEFICIENCY, 2) COMPLETE PRE-GLP SAFETY STUDIES FOR UP TO THREE PEPTIDE DEVELOPMENT CANDIDATES FOR MC4R DEFICIENCY, AND 3) FORMULATE AND CHARACTERIZE THE PHARMACOKINETICS, EFFICACY, AND SIDE EFFECT PROFILE OF THESE PEPTIDES IN OUR MOUSE MODEL OF HUMAN MC4R DEFICIENCY. THE PRODUCT OF THIS PHASE II STTR PROPOSAL WILL BE ONE OR MORE THERAPEUTIC CANDIDATES FOR THE TREATMENT OF MC4R HAPLOINSUFFICIENCY, AND A PATHWAY TO COMMERCIALIZATION OF THESE THERAPEUTICS.

OTHER-TECH

COURAGE MEDICINE'S SAGE CLINIC: SEXUAL HEALTH CLINIC FOR ANTI OPPRESSION, GENDER AFFIRMATION, AND EMPOWERMENT

MENTORING PROGRAM GRANTS

MIDLANDS COMMUNITIES OF RECOVERY (MCOR): BROADENING PEER-BASED COMMUNITIES OF RECOVERY FOR ADOLESCENTS, EMERGING ADULTS, AND FAMILIES IN THE SOUTH CAROLINA MIDLANDS THROUGH EVIDENCE-BASED PRACTICES - THE MIDLANDS COMMUNITIES OF RECOVERY (MCOR) PROJECT ACTIVITIES WILL SERVE SUBSTANCE MISUSING ADOLESCENTS AND EMERGING ADULTS, AND THEIR FAMILY MEMBERS, IN LEXINGTON COUNTY, SOUTH CAROLINA (SC). THE COURAGE CENTER (TCC) WILL SERVE 380 PARTICIPANTS IN YEAR 1 AND 475 IN YEAR 2 AND 600 IN YEAR 3 FOR A TOTAL OF 1455.

THE COURAGE TO SPEAK FOUNDATION SUBSTANCE ABUSE PREVENTION FOR PARENTS AND CHILDREN CAPACITY BUILDING PROJECT

COURAGE TO SPEAK SUBSTANCE ABUSE PREVENTION AND EDUCATION CAPACITY BUILDING PROJECT

ENGINEERING CHEMICALLY MODIFIED RNPS FOR EFFECTIVE TREATMENT OF ANGELMAN SYNDROME - ANGELMAN SYNDROME (AS) IS A NEUROGENETIC DISORDER CAUSED BY THE DEFICIENCY OF THE MATERNAL UBE3A AND CHARACTERIZED BY SEVERE DEVELOPMENTAL DELAY. CURRENT TREATMENT ONLY HELPS MANAGE SYMPTOMS AND CANNOT MEET CLINICAL NEED TO EFFECTIVELY TREAT AS. THE EXPRESSION OF UBE3A IN NEURONS CAN BE ACTIVATED THROUGH INHIBITION OF NON-CODING ANTISENSE RNA OF UBE3A (UBE3A- ATS). GENOME EDITING STRATEGY TARGETING UBE3A-ATS IS A PROMISING THERAPEUTIC APPROACH FOR AS. AAV IS THE MOST WIDELY USED VECTOR FOR GENOME EDITING. HOWEVER, AAV PRESENTS POTENTIAL SAFETY CONCERNS OF IMMUNOGENICITY AND OFF-TARGET EFFECTS. THUS, THERE IS A CLEAR UNMET NEED FOR NOVEL NONVIRAL DELIVERY TECHNOLOGIES FOR SAFE AND EFFICIENT DELIVERY OF THE CRISPR MACHINERY TO NEURONS FOR AS TREATMENT. IN THIS APPLICATION, COURAGENE PROPOSES TO DEVELOP A NOVEL, CHEMICALLY MODIFIED RIBONUCLEOPROTEIN (CRNP) COMPLEXED WITH CAS9 PROTEIN AND GRNA FOR DELIVERY OF CRISPR MEDIATED GENE EDITING TO THE BRAIN FOR TREATMENT OF AS. CRNPS HAVE BEEN PREVIOUSLY SHOWN TO ENABLE BRAIN-WIDE GENOME EDITING AND ACHIEVE LONG-TERM PERSISTENT THERAPEUTIC BENEFITS IN AS MICE THROUGH SINGLE INTRATHECAL (IT) ADMINISTRATION. THE PROPOSED PROJECT WILL FOCUS ON FORMULATION OPTIMIZATION OF THE CRNP FOR DELIVERY OF GENOME EDITING TO NEURONAL CELLS IN VITRO IN AIM 1, SEEKING TO ACHIEVE OVER 70% EDITING EFFICIENCY IN PRIMARY AS NEURONAL CELLS. THE LEADING CRNP FORMULATION WILL THEN BE CHARACTERIZED IN AIM 2 TO DETERMINE CRNP-BASED GENOME EDITING DELIVERY EFFICIENCY AND SAFETY IN UBE3A-YFP AS REPORTER MICE. WE AIM TO ACHIEVE BRAIN-WIDE GENOME EDITING WITH OVER 50% NEURONAL EDITING EFFICIENCY WITHOUT SIGNIFICANT TOXICITY THROUGH SINGLE INTRATHECAL INJECTION IN AS MOUSE. THE SUCCESSFUL COMPLETION OF THE PROPOSED WORK WILL BUILD A SOLID FOUNDATION FOR PHASE II PROJECTS WHERE FURTHER BIODISTRIBUTION AND PHENOTYPIC RESCUE EVALUATION IN UBE3A MATERNAL DEFICIENCY MICE, OFF-TARGET STUDY AND IND-ENABLING STUDIES WITH POTENTIAL PARTNERS WILL TAKE PLACE. THE PROJECTS WILL EVENTUALLY RESULT IN A NONVIRAL GENOME EDITING THERAPY WITH COURAGENE’S INNOVATIVE CHEMICALLY MODIFIED RIBONUCLEOPROTEIN CRNP TECHNOLOGY, GREATLY ENHANCING THE CLINICAL TREATMENT FOR PATIENTS WITH AS.

HEALTH CARE INNOVATION CHALLENGE

DEVELOPMENT OF MELANOCORTIN-3 RECEPTOR PEPTIDE AGONISTS FOR THE TREATMENT OF ANOREXIA NERVOSA - ANOREXIA NERVOSA (AN) IS A DEVASTATING NEUROPSYCHIATRIC DISEASE WITH A HIGH PREVALENCE (UP TO 2.2% OF WOMEN) AND SIGNIFICANT MORBIDITY AND MORTALITY. THERE ARE CURRENTLY NO EFFECTIVE THERAPEUTIC AGENTS FOR THE DISORDER. THE GOAL OF COURAGE THERAPEUTICS IS THE DEVELOPMENT OF MELANOCORTIN-3 RECEPTOR (MC3R) -SPECIFIC AGONIST PEPTIDES FOR THE TREATMENT OF ANOREXIA NERVOSA. THE PRODUCT OF THIS PHASE I STTR WILL BE A PATENTABLE MC3R AGONIST LEAD DEVELOPMENT CANDIDATE THAT CAN GO INTO ADVANCED ANIMAL TESTING AND ADME/PK FOR DEVELOPMENT OF A THERAPEUTIC FOR ANOREXIA NERVOSA, DURING A PHASE II STTR. IN PRELIMINARY RESULTS PRESENTED HERE, WE SHOW THAT MC3R IS EXPRESSED IN NEARLY ALL AGRP NEURONS IN THE ARCUATE NUCLEUS. ACTIVATION OF THESE MC3R-EXPRESSING NEURONS IN THE ARCUATE CAN STIMULATE FOOD INTAKE WHILE REDUCING ANXIETY. FURTHER, WE DEMONSTRATE THAT ADMINISTRATION OF A MC3R-SPECIFIC PEPTIDE RESULTS IN POTENT STIMULATION OF FOOD INTAKE IN MICE THAT IS AGRP NEURON DEPENDENT. MELANOCORTIN PEPTIDE DRUGS APPEAR TO BE SAFE AND EFFECTIVE THERAPEUTICS FOR A NUMBER OF OTHER INDICATIONS, HOWEVER NO MC3R SPECIFIC THERAPEUTICS HAVE BEEN DEVELOPED. BASED ON THESE DATA, WE PROPOSE THAT MC3R-SPECIFIC AGONIST PEPTIDES MAY BE DEVELOPED INTO SAFE AND EFFECTIVE THERAPEUTICS FOR EATING DISORDERS SUCH AS ANOREXIA NERVOSA. WE HAVE IDENTIFIED FOUR PROMISING MC3R AGONIST STARTING POINTS, INCLUDING BOTH D-TRP8--MSH AND AC-ARG-ARG-D-PHE(4-I)-D-TIC-NH2 AS EXEMPLARY PARENT LEADS THAT POTENTLY STIMULATE FOOD INTAKE IN SATED ANIMALS. IN ONE AIM OF THIS APPLICATION, COURAGE THERAPEUTICS WILL DESIGN ANALOGUES BASED ON THESE TWO MC3R-SPECIFIC AGONISTS AS PROMISING LINEAR PEPTIDES TO IMPROVE THEIR OVERALL POTENCY, EFFICACY, AND RECEPTOR-SUBTYPE SPECIFICITY. COURAGE WILL ALSO CONDUCT SIMILAR STUDIES ON TWO CYCLIC MELANOCORTIN PEPTIDES LACKING RECEPTOR SPECIFICITY, RELATED TO SETMELANOTIDE (RHYTHM), WHICH HAS BEEN HIGHLY SUCCESSFUL IN CLINICAL TRIALS FOR THE TREATMENT OF SYNDROMIC OBESITY. IN THIS CASE, THE STARTING PEPTIDES ARE ALREADY KNOWN TO HAVE DRUG-LIKE PROPERTIES, AND THE CHEMICAL GOAL WILL BE ENGINEER MC3R-SPECIFICITY IN THIS CHEMICAL CLASS OF MELANOCORTIN PEPTIDES. IN AIM 2, PEPTIDES WITH APPROPRIATE PHARMACOLOGICAL PROPERTIES (EC50 BELOW 10NM, EMAX>50%, AND A 1000X MC3R/MC4R AGONIST SPECIFICITY) WILL BE MODIFIED TO IMPROVE STABILITY AND BIOAVAILABILITY. PEPTIDES WILL THEN BE TESTED FOR IN VIVO EFFICACY ON FEEDING, WEIGHT GAIN, AND ANXIETY IN BOTH NORMAL ANIMALS AND A MODEL OF STRESS-INDUCED ANOREXIA. PEPTIDES WILL ALSO BE TESTED FOR HALF LIFE AND DISTRIBUTION IN VIVO IN SERUM AND BRAIN. THE PRODUCT OF THIS PHASE I STTR WILL BE PATENTABLE MC3R AGONIST LEAD DEVELOPMENT CANDIDATES THAT CAN GO INTO ADVANCE PRECLINICAL TESTING AND FULL ADME/PK AND SAFETY FOR DEVELOPMENT OF A THERAPEUTIC FOR AN, TO BE COMPLETED UNDER PHASE II OF THIS APPLICATION. A CLINICAL TRIAL FOR THE SUCCESSFUL DEVELOPMENT CANDIDATE WOULD THEN TEST EFFECTIVENESS IN A PLACEBO CONTROLLED RANDOMIZED STUDY FOR FEMALE RESTRICTING ANOREXIA NERVOSA IN POST-ACUTE HOSPITALIZATION RECOVERY. PRIMARY TRIAL END-POINTS WOULD INCLUDE TIME TO ACHIEVE WEIGHT RESTORATION, MEAL COMPLETION, IMPROVEMENT OF SELF REPORTED EDE-Q (EATING DISORDER EXAMINATION QUESTIONNAIRE) AND RELATED SELF-REPORTED EATING ATTITUDE SCORES.

DEVELOPMENT OF MELANOCORTIN-3 RECEPTOR PEPTIDE ANTAGONISTS FOR THE TREATMENT OF OBESITY AND MAINTENANCE OF WEIGHT LOSS

RURAL COOPERATIVE DEVELOPMENT INITIATIVE GRANTS

TO PROVIDE ENGLISH CONVERSATION CLASSES FOR THE STUDENTS IN MIYAKOJIMA AREA TO IMPROVE THEIR ENGLISH SKILLS.

HOMELESS ASSISTANCE

PURPOSE: TO SUPPORT STAFF SALARIES AND ADMINISTRATIVE COSTS FOR HARMONY UNIVERSITY A PROFESSIONAL ARTISTIC DEVELOPMENT PROJECT FOR MUSIC EDUCATORS AND DIRECTORS COORDINATED BY THE BARBERSHOP HARMONY SOCIETY.

PURPOSE: TO SUPPORT STAFF SALARIES AND ADMINISTRATIVE COSTS FOR HARMONY UNIVERSITY A PROFESSIONAL ARTISTIC DEVELOPMENT PROJECT FOR MUSIC EDUCATORS AND DIRECTORS.

PURPOSE: TO SUPPORT STAFF SALARIES AND ADMINISTRATIVE COSTS FOR HARMONY UNIVERSITY A PROFESSIONAL ARTISTIC DEVELOPMENT PROJECT FOR MUSIC EDUCATORS AND DIRECTORS.

TO SUPPORT HARMONY UNIVERSITY AN ONLINE PROFESSIONAL ARTISTIC DEVELOPMENT PROJECT FOR MUSIC EDUCATORS AND DIRECTORS.

TO SUPPORT HARMONY UNIVERSITY A PROFESSIONAL ARTISTIC DEVELOPMENT PROJECT FOR MUSIC EDUCATORS AND DIRECTORS.

CONTINUUM OF CARE PROGRAM

COMMUNITY FACILITY GRANTS

CONTINUUM OF CARE PROGRAM

CONTINUUM OF CARE PROGRAM

CONTINUUM OF CARE PROGRAM

HOMELESS ASSISTANCE

HOMELESS ASSISTANCE

SUPPORTIVE HOUSING PROGRAM

HOMELESS ASSISTANCE

PURPOSE:THE PROPOSED PROJECT AIMS TO ENHANCE SOCIAL SECURITY ACCESS AND WORKER PROTECTIONS FOR INTERNAL MIGRANT WORKERS AND THEIR FAMILIES IN BANGLADESH. OVER A FOUR-YEAR PERIOD, THIS PROJECT WILL TARGET APPROXIMATELY 500,000 INTERNAL MIGRANTS AND THEIR FAMILY MEMBERS IN 15 DISTRICTS, INCLUDING DHAKA, NARAYANGANJ, CHATTOGRAM, COXS BAZAR AND KHULNA. THE PROJECT FOCUSES ON ADDRESSING THE ECONOMIC VULNERABILITIES AND EXPLOITATION RISKS OF THESE MIGRANTS, THROUGH DIRECT GRASSROOTS INTERVENTIONS, SYSTEMIC CHANGE INITIATIVES AND THE ESTABLISHMENT OF SUSTAINABLE FRAMEWORKS FOR SOCIAL PROTECTION.GEOGRAPHIC AREA TO BE SERVED: 15 DISTRICTS IN BANGLADESHPOPULATION TO BE SERVED: 500,000 INTERNAL MIGRANTS AND THEIR FAMILY MEMBERSFUNDING REQUESTED: USD 3 MILLIONPROJECT GOALS, OUTCOMES, AND ACTIVITIES TO BE PERFORMEDPROJECT GOALS: REDUCE RISKS OF CHILD LABOR, FORCED LABOR AND VIOLATIONS OF LABOR RIGHTS AMONG INTERNAL MIGRANT WORKERS AND THEIR FAMILY MEMBERS IN BANGLADESHPROJECT OBJECTIVE: INCREASE ACCESS TO SOCIAL SECURITY AND WORKER PROTECTION FOR INTERNAL MIGRANT WORKERS IN BANGLADESH PROJECT OUTCOMESOUTCOME 1: ENHANCED CAPACITY OF KEY STAKEHOLDERS TO USE EVIDENCE TO INFORM SOCIAL PROTECTION POLICIES AND PROGRAMSOUTCOME 2: INCREASED CAPACITY OF LOCAL ORGANIZATIONS TO FACILITATE ACCESS TO SOCIAL PROTECTION.OUTCOME 3: INCREASED ENGAGEMENT AND PARTNERSHIPS WITH GOVERNMENTS TO ENHANCE SOCIAL PROTECTION SYSTEMS.OUTCOME 4: INCREASED ENGAGEMENT AND PARTNERSHIPS WITH INDUSTRY TO ENHANCE SOCIAL PROTECTION SYSTEM THE PROJECT WILL HAVE THE FOLLOWING KEY INTERVENTIONS, WITH KEY CONTRIBUTIONS FROM SUBRECIPIENT ORGANIZATIONS (IMPLEMENTING PARTNERS) ACROSS BANGLADESH:1.SOCIAL SECURITY FACILITATION2.WORKER PROTECTION INITIATIVES3.STRENGTHENING GOVERNMENT INFRASTRUCTURE AND ACTIVATING INDUSTRY 4. EXPECTED OUTCOMES1.OUTCOME 1: ENHANCE THE CAPACITY OF KEY STAKEHOLDERS TO USE EVIDENCE TO INFORM SOCIAL PROTECTION POLICIES AND PROGRAMS.2.OUTCOME 2: INCREASED CAPACITY OF LOCAL ORGANIZATIONS TO FACILITATE ACCESS TO SOCIAL PROTECTION.3.OUTCOME 3: INCREASED ENGAGEMENT AND PARTNERSHIPS WITH GOVERNMENTS TO ENHANCE SOCIAL PROTECTION SYSTEMS.4.OUTCOME 4: INCREASED ENGAGEMENT AND PARTNERSHIPS WITH INDUSTRY TO ENHANCE SOCIAL PROTECTION SYSTEM INTENDED BENEFICIARIESTHE PRIMARY BENEFICIARIES OF THE PROJECT ARE APPROXIMATELY 500,000 INTERNAL MIGRANT WORKERS AND THEIR FAMILIES. THE PROJECT WILL FOCUS ON MIGRANTS WORKING IN SECTORS SUCH AS GARMENT MANUFACTURING, CONSTRUCTION AND DOMESTIC WORK. THESE WORKERS OFTEN FACE INFORMAL EMPLOYMENT CONDITIONS, LEAVING THEM VULNERABLE TO EXPLOITATION AND WITHOUT ACCESS TO FORMAL SOCIAL PROTECTION SYSTEMS.SUBRECIPIENT ACTIVITIESTHIS PROJECT WILL BE IMPLEMENTED THROUGH PARTNERSHIPS WITH FOUR LOCAL IMPLEMENTING PARTNERS ORGANIZATIONS:ASSOCIATION FOR COMMUNITY DEVELOPMENT (ACD): THEY WILL WORK IN TANGAIL, SIRAJGANJ AND RAJSHAHI DISTRICTS.BANGLADESH NARI SRAMIK KENDRA (BNSK): THEY WILL WORK IN DHAKA, MANIKGANJ AND SYLHET DISTRICTS KARMOJIBI NARI (KN): THEY WILL WORK IN BHOLA, MYMENSINGH AND GAZIPUR DISTRICTS OVIBASHI KARMI UNNAYAN PROGRAM (OKUP): THEY WILL WORK IN SHATKHIRA, KHULNA AND KURIGRAM DISTRICTS NEW SUB RECIPIENTS: BASED ON THE SPREAD OF THE DISTRICTS, IT MAY BE NECESSARY TO INCLUDE AT LEAST 1 MORE SUB RECIPIENT IN THE PROJECT. THIS PROSPECTIVE IMPLEMENTING PARTNER WILL WORK IN CUMILLA, CHITTAGONG AND COXS BAZAR DISTRICTS.