Orphagen Pharmaceuticals, Inc.

Preclinical Development of OR-449, a Novel Targeted Therapy for Adrenocortical Cancer - Abstract Adrenocortical Carcinoma (ACC) Is a Rare, Aggressive Cancer. the Majority of Cases Are Metastatic or Locally Advanced at Diagnosis With a Dismal Five-year Survival of <15%. the Only Fda-approved Chemotherapeutic Agent, Mitotane, Is Highly Toxic, Difficult to Dose, and Only Modestly Effective. Alternative Chemotherapy Regimens and 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 to Steroidogenic FACTOR-1 (SF-1 or NR5A1), an Orphan Nuclear Receptor and Transcription Factor That Is Essential for the Growth and Development of the Adrenal Gland. Multiple Findings Indicate That SF-1 Has a Crucial Role in the Pathogenesis of Acc: (i) Higher Levels of Intra-tumoral SF-1 Expression Correlate With Poor Prognosis in Adult Acc, (II) SF-1 Is a Diagnostic Marker of Metastatic Acc; (III) SF-1 Is Chromosomally Amplified and SF-1 Protein Is Elevated, Relative to Normal Adrenal Tissue, in Pediatric Acc. Further, the Fda, in Consultation With Nci, Has Included 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 Completely Inhibited the Growth of SJ-ACC3, a Pediatric Acc Tumor Xenograft Originally Isolated at ST. Jude Children’s Research Hospital. OR-449 Also Blocked Dna Synthesis in Cultures of Dissociated SJ-ACC3 Tumor Cells. the Dose-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 Dog and Was Well-tolerated at 100 MG/KG in an Oral, Two-week Daily Dosing Murine Safety Study. the Proposed Sbir Direct to Phase Ii Project Builds on the Highly Effective Inhibition of Acc Tumor Growth and Promising Preliminary Safety Profile of OR-449. Our Project Goal Is to Complete All Preclinical Safety Studies Required 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 at Doses 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 Analytical Methods, and Complete a 1-KILOGRAM Scale-up Synthesis of OR-449 to Supply Further Nonclinical Safety Studies and Prepare for GMP Manufacturing; 3) Conduct High-dose PK Studies in Dogs Followed by Non-glp 7-DAY Toleration 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 Project Will Provide the Necessary Data to Select a Starting Dose for a Phase 1 Clinical Trial of OR-449 in Acc. Ultimately, Commercialization of OR-449 Could Provide a Safe and Effective Targeted Therapy to Significantly Improve Survival for Acc Patients.