Orphagen Pharmaceuticals presents data on downstream targets of SF-1 antagonist OR-449 at ENDO 2022


SAN DIEGO–(BUSINESS WIRE)–Orphagen Pharmaceuticals, an early-stage biopharmaceutical company focused on developing and commercializing novel therapies for cancer and other serious diseases with significant unmet need, today announced that additional data from of its preclinical program to develop OR-449 for the treatment of adrenocortical cancer (ACC) was presented at the 104th Annual Meeting of the Endocrine Society (ENDO 2022) held in Atlanta from June 11-14. ACC is a rare endocrine malignancy frequently diagnosed at an advanced stage with very limited treatment options. OR-449 is in preclinical development for the treatment of ACC with a first-in-human clinical trial scheduled for early 2023.

OR-449 is a potent, selective and orally bioavailable small molecule antagonist of steroidogenic factor-1 (SF-1 or NR5A1), a nuclear receptor and transcription factor essential for growth and development of the adrenal gland. SF-1 has recently been described as a candidate “master transcription factor” in adult ACC.1 ACC tumors often secrete a “malignant” but variable pattern of steroids not normally found in circulation. The reported preclinical results show, first, that a malignant steroid profile is also secreted from two distinct patient-derived ACC xenografts maintained in immunocompromised mice. Second, secreted steroids of SW1939, derived from pediatric ACC, were markedly up-regulated by treatment with OR-449. Similar steroid regulation in response to OR-449 treatment could occur in the clinic, facilitating the selection of a treatment dose for a phase 2 clinical trial.

Paul Crowe, Ph.D., Presenting Author and Vice President of Drug Discovery at Orphagen, said, “We are once again delighted to share preclinical data on the efficacy of OR-449 in the ‘ACC, this time in a new preclinical model, the pediatric ACC xenograft, SW1939, developed by Peter Houghton and colleagues at the UT Health Sciences Center in San Antonio. Not only does OR-449 inhibit the growth of this patient-derived xenograft, it also regulates levels of circulating adrenocortical tumor-derived steroids and steroid precursors. Circulating steroid secretion may provide a clinically relevant pharmacodynamic biomarker for OR-449 target engagement in ACC patients.

Orphagen CEO Scott Thacher, Ph.D. said, “This is a satisfying achievement for Orphagen’s corporate strategy to find first-in-class small molecules for receptor targets unexplored nuclear cells with efficacy in translationally relevant animal models of disease. Biomarker findings are a secondary, but potentially very valuable, outcome of these preclinical studies. We are grateful for the strong support we have received from leading clinical researchers in the field of ACC during this preclinical work, and we look forward to working with them on clinical trials for OR-449. Our hope is to bring a new and valuable treatment option to ACC patients.

Information on the presentation of the poster

Title: Downstream targets of steroidogenic factor-1 (SF-1) antagonist OR-449 in PDX models of ACC

Presenter: Paul D Crowe, PhD

Co-authors: Ray Fox, PhD, Haiyan Tao, PhD, Neil Raheja, PhD, Richard J. Auchus, MD, PhD, Peter Houghton, PhD, Scott Thacher, PhD

Poster session: PSUN355

1 Corces et al., Science. 2018; 362(6413); Reddy et al., Sci Adv. 2021; 7(48).

About Orphagen Pharmaceuticals

Orphagen unleashes the power of orphan nuclear receptors. Our scientists excel in the discovery and development of small molecule ligands for these largely unexplored drug targets. Starting with a therapeutic area independent approach, we explore proprietary lead molecules with potential in autoimmune diseases and oncology. Orphagen has successfully partnered its first ROR-gamma antagonist program with a mid-sized pharmaceutical company ahead of all its competitors in the field. Funding from its partnerships and other non-dilutive sources, including federal grants, has enabled Orphagen to advance its proprietary, first-in-class drug discovery programs, including OR-449 for adrenocortical cancer. For more information, visit www.orphagen.com.


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