SBIR-STTR Award

Direct to Phase II

Adrenocortical carcinoma (ACC) is a rare, aggressive cancer. The majority of cases are metastatic or locallyadvanced at diagnosis with a dismal five-year survival of <15%. The only FDA-approved chemotherapeuticagent, mitotane, is highly toxic, difficult to dose, and only modestly effective. Alternative chemotherapy regimensand immune checkpoint inhibitors provide limited benefit. There is an urgent need for new therapies.We propose to develop a targeted therapy for ACC based on first-in-class small molecule antagonists tosteroidogenic factor-1 (SF-1 or NR5A1), an orphan nuclear receptor and transcription factor that is essential forthe growth and development of the adrenal gland. Multiple findings indicate that SF-1 has a crucial role in thepathogenesis of ACC: (i) Higher levels of intra-tumoral SF-1 expression correlate with poor prognosis in adultACC, (ii) SF-1 is a diagnostic marker of metastatic ACC; (iii) SF-1 is chromosomally amplified and SF-1 proteinis elevated, relative to normal adrenal tissue, in pediatric ACC. Further, the FDA, in consultation with NCI, hasincluded SF-1 on its Pediatric Molecular Target List for oncology.Orphagen has identified a highly selective SF-1 antagonist, OR-449, that at 30 mg/kg daily oral dosing completelyinhibited the growth of SJ-ACC3, a pediatric ACC tumor xenograft originally isolated at St. Jude Children'sResearch Hospital. OR-449 also blocked DNA synthesis in cultures of dissociated SJ-ACC3 tumor cells. Thedose-responsive mRNA signature in the SJ-ACC3 xenografts supports direct engagement of SF1 by OR-449.Further, OR-449 showed excellent oral absorption and pharmacokinetic (PK) properties in mouse, rat, and dogand was well-tolerated at 100 mg/kg in an oral, two-week daily dosing murine safety study.The proposed SBIR Direct to Phase II builds on the highly effective inhibition of ACC tumor growth andpromising preliminary safety profile of OR-449. Our goal is to complete all preclinical safety studiesrequired to file an Investigational New Drug application for the first clinical trial of an SF-1 antagonist in ACC.The Aims are: 1) Conduct an exploratory (non-GLP), dose range-finding toxicity study of OR-449 in mice atdoses up to 400 mg/kg to identify any serious safety signals and to provide key dosing data for designing a 1-month regulatory (GLP) toxicology study; 2) Optimize synthetic chemistry processes, develop analyticalmethods, and complete a 1-kilogram scale-up synthesis of OR-449 to supply further nonclinical safety studiesand prepare for GMP manufacturing; 3) Conduct high-dose PK studies in dogs followed by non-GLP 7-daytoleration and 14-day dose range-finding safety studies with histology and cardiovascular monitoring; 4)Complete 1-month repeat dose GLP general toxicology studies in mouse and dog consistent with FDA guidance.Successful completion of the will provide the necessary data to select a starting dose for a Phase 1clinical trial of OR-449 in ACC. Ultimately, commercialization of OR-449 could provide a safe and effectivetargeted therapy to significantly improve survival for ACC patients.

Public Health Relevance Statement:
PROJECT NARRATIVE Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland with very limited treatment options and a poor prognosis. Surgery is not an option for most ACC patients because of the advanced stage of disease at diagnosis; and chemotherapy, which is only marginally effective in adult ACC, is neither safe nor effective in pediatric ACC. We propose to develop OR-449, a potent antagonist to a tissue-selective transcription factor that regulates growth and development in the adrenal gland, offering hope for the first targeted therapy that could markedly increase survival for ACC patients, both adult and pediatric.

Project Terms:
absorption ; Adrenal Glands ; Adrenals ; suprarenal gland ; Adult ; 21+ years old ; Adult Human ; adulthood ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Cardiovascular system ; Cardiovascular ; Cardiovascular Body System ; Cardiovascular Organ System ; Heart Vascular ; circulatory system ; Cardiovascular Physiology ; cardiovascular function ; Chemistry ; Clinical Trials ; Consultations ; Diagnosis ; Disease ; Disorder ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Europe ; Exhibits ; Future ; Goals ; Growth ; Generalized Growth ; Tissue Growth ; ontogeny ; Growth and Development function ; Growth and Development ; Histology ; Human ; Modern Man ; Insecticides ; Mus ; Mice ; Mice Mammals ; Murine ; Patients ; Drug Kinetics ; Pharmacokinetics ; Plasma Proteins ; Proteins ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Respiratory physiology ; respiratory function ; Messenger RNA ; mRNA ; Role ; social role ; Safety ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Survival Rate ; Testing ; Tissues ; Body Tissues ; Toxicology ; transcription factor ; Basal Transcription Factor ; Basal transcription factor genes ; General Transcription Factor Gene ; General Transcription Factors ; Transcription Factor Proto-Oncogene ; Transcription factor genes ; Genetic Transcription ; Gene Transcription ; RNA Expression ; Transcription ; Cultured Tumor Cells ; Cultured Neoplastic Cells ; Immunocompromised Host ; Immunocompromised ; Immunocompromised Patient ; Immunosuppressed Host ; immunosuppressed patient ; Investigational New Drug Application ; SF1 ; AD4BP protein ; Ad4-binding protein ; FTZF1 protein ; Fushi tarazu factor homolog 1 ; NR5A1 protein ; SF 1 ; SF-1 transcription factor ; adrenal 4 binding protein ; nuclear receptor 5A1 protein ; steroid hormone receptor Ad4BP ; steroidogenic factor 1 ; transcription factor sf1 ; analytical method ; base ; dosage ; improved ; Procedures ; Clinical ; Residual state ; Residual ; Phase ; Nuclear Receptors ; Adrenocortical carcinoma ; Adrenal Cortex Carcinoma ; Adrenal Cortical Carcinoma ; Ensure ; Childhood ; pediatric ; Recovery ; Binding Proteins ; Ligand Binding Protein ; Ligand Binding Protein Gene ; Protein Binding ; bound protein ; Orphan ; Development Plans ; Adrenergic Antagonists ; Adrenergic Blockaders ; Adrenergic Blockers ; Adrenergic Receptor Antagonists ; Adrenergic Receptor Blockaders ; Adrenergic-Blocking Agents ; Adrenolytic Agents ; Adrenolytic Drugs ; Adrenolytics ; Anti-Adrenergics ; Anti-adrenergic Agents ; Antiadrenergic Agents ; Antiadrenergics ; Oncology ; Oncology Cancer ; Toxicokinetics ; Therapeutic ; Adrenal Cortex Cancer ; Adrenocortical Cancers ; Malignant Adrenocortical Neoplasm ; Malignant Adrenocortical Tumor ; Malignant Tumor of the Adrenal Cortex ; Malignant neoplasm of adrenal cortex ; Chemotherapy Protocol ; Chemotherapy Regimen ; Chemotherapy, Cancer, General ; Combination Chemotherapy Regimen ; Quimioterapia ; cancer chemotherapy ; Chemotherapy-Oncologic Procedure ; Kilogram ; Oral ; Heterograft ; Heterologous Transplantation ; Xenograft ; Xenotransplantation ; xeno-transplant ; xeno-transplantation ; Xenograft procedure ; Operative Procedures ; Surgical ; Surgical Interventions ; Surgical Procedure ; surgery ; Operative Surgical Procedures ; meetings ; Tumor Cell ; neoplastic cell ; DNA Replication ; DNA Synthesis ; DNA biosynthesis ; tumor growth ; Toxicities ; Toxic effect ; Pathogenesis ; chemotherapeutic agent ; Adrenal Cancers ; Malignant Adrenal Gland Neoplasm ; Malignant Adrenal Neoplasm ; Malignant Adrenal Tumor ; Malignant Tumor of the Adrenal Gland ; Adrenal Gland Cancer ; Maximal Tolerated Dose ; Maximally Tolerated Dose ; Maximum Tolerated Dose ; Local Cancer ; Localized Cancer ; Localized Malignancy ; Localized Malignant Neoplasm ; Property ; Early-Stage Clinical Trials ; Phase 1 Clinical Trials ; phase I protocol ; Phase I Clinical Trials ; small molecule ; Nuclear Orphan Receptor ; Address ; Dose ; Data ; Molecular Target ; Synthesis Chemistry ; Synthetic Chemistry ; Chromosomal Duplication ; Chromosomal Amplification ; Saint Jude Children's Research Hospital ; Saint Jude ; Saint Jude Children's Cancer Center ; St. Jude ; St. Jude Children's Cancer Center ; St. Jude Children's Research Hospital ; St. Jude Children's Research Hospital Comprehensive Cancer Center ; St.Jude Children's Cancer Center ; St.Jude Children's Research Hospital ; St.Jude Children's Research Hospital Comprehensive Cancer Center ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Monitor ; Process ; Development ; developmental ; Behavioral ; safety study ; virtual ; design ; designing ; tumor xenograft ; Outcome ; scale up ; 4 year old ; 4 years of age ; age 4 years ; four year old ; four years of age ; chemotherapy ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; commercialization ; tumor ; new therapeutic target ; new drug target ; new druggable target ; new pharmacotherapy target ; new therapy target ; novel drug target ; novel druggable target ; novel pharmacotherapy target ; novel therapeutic target ; novel therapy target ; FDA approved ; preclinical safety ; pre-clinical safety ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; crystallinity ; diagnostic biomarker ; diagnostic marker ; Formulation ; Polymorph ; clinical candidate ; clinical development ; preclinical development ; pre-clinical development ; Immune checkpoint inhibitor ; Checkpoint inhibitor ; immune check point inhibitor ; rare cancer ; cancers that are rare ; rare malignancy ; rare tumor ; side effect ; Phase I/II Clinical Trial ; Phase 1/2 Clinical Trial ; patient derived xenograft model ; PDX model ; Patient derived xenograft ; Prognosis ;