Orphagen Pharmaceuticals, Inc.

A Novel, Pleiotropic Oral Drug Class That Inhibits Gut Migration of Activated T Cells - Abstract Inflammatory Bowel Disease (IBD) Is a Lifelong Inflammatory Condition of the Gut in Which Modulation of the Immune System Is the Major Therapeutic Strategy. However, Despite Development of Novel Therapies, Including Antibodies to TNF and IL-12/IL-23P40, and Inhibitors of T Cell Gut Homing Such as Vedolizumab and Ozanimod, Only 30-50% of Patients Experience a Sustained Therapeutic Benefit. Orphagen Is Developing First-in-class Specific Small Molecule Antagonists to the Retinoic Acid Receptor-alpha (rar) That Regulate the Induction of Both the Gut Homing Integrin 47 and a Second Gut Homing Receptor, CCR9, During T Cell Activation. Our Preliminary Data Confirm That Inhibition of Retinoic Acid Signaling Through Rar Is a Promising Therapeutic Approach to Ibd. First, We Showed That a Probe Rar Antagonist Significantly Improved Gut Histology in a Mouse Naïve T Cell Transfer Colitis Model and Inhibited 47 Expression and Accumulation of Inflammatory T Cells in the Colonic Lamina Propria of Citrobacter Rodentium-infected Mice. Second, With a More Specific Rar Lead Antagonist, OR-812, an Orally Bioavailable New Chemical Entity Designed at Orphagen, We Showed in a Mouse Model of Oral Antigen Stimulation That the Induction of 47 and CCR9 in Activated T Cells Is Almost Completely Blocked at Very Low Doses, <0.4 MG/KG; Thus, Antagonism of Rar by OR-812 Potently Blocks the Induction of Two Key Gut Homing Factors Simultaneously. Third, OR-812 Was Well Tolerated in a 14-DAY Toxicity Study in Mice at 30 MG/KG Following Significant Systemic Exposure, Indicating a Strong Safety Margin for This New Drug Class. Our Major Objectives Are to Qualify OR-812 as a Candidate for Preclinical Development, Confirming Efficacy in a Murine Model of Colitis, Scaling Up Sufficient Compound for Safety Studies, and Executing an Exploratory Safety Study in a Non-rodent Species. in Aim 1, We Evaluate the Efficacy and Potency of OR-812 in a Mouse Naïve T Cell Transfer Colitis Model. in Aim 2, We Develop Improved Methods for Synthesis of OR-812 and Ultimately Prepare a 500G Batch for the Non-rodent Exploratory Safety Studies. in Aim 3, We Identify a Non-rodent Species for in Vivo Toxicology Studies Based on in Vitro Metabolism of OR-812 in Comparison to Human and Confirm Adequate Pharmacokinetics and Bioavailability in the Selected Non-rodent Species. in Aim 4, We Conduct a 7-DAY Maximum Tolerated Dose (MTD) Safety Study in the Non-rodent Species and, Based on This, Conduct a 14-DAY Dose-range Finding Safety Study in Non-rodents With Extensive Assessment of Target Organ Histopathology to Determine the No Observed Adverse Effect Level (noael). the Overall Goal of These Non-glp Safety Studies Is to Identify Potential Toxicities and Confirm a Preliminary Safety Margin for OR-812 Based on the Efficacious Dose in a Mouse Colitis Model. These Investigations, If Satisfactory, Would Prepare OR-812 for Its Next Stage: Regulated Animal Safety and Chemical Manufacturing Studies Appropriate for Submission of an Investigational New Drug (IND) Application to the Food and Drug Administration (FDA) for a Novel Drug Class for Treatment of Ibd.