SAN DIEGO, April 8, 2022 — Orphagen Pharmaceuticals Inc., a biotech company pioneering the screening, discovery, and development of small molecule ligands that modulate orphan or unexplored members of the nuclear receptor family, today announced a late-breaking presentation of new preclinical data for OR-449 at the American Association for Cancer Research (AACR) Annual Meeting 2022 being held April 8-13 both virtually and in-person in New Orleans. The data presented demonstrate efficacy in a preclinical model of a Leydig cell tumor (LCT) of OR-449, the company’s first-in-class small molecule antagonist to the nuclear receptor steroidogenic factor-1 (SF-1 or NR5A1) and support the continued development of OR-449 as a novel targeted therapy for the treatment of LCTs as well as adrenocortical cancer (ACC), the primary indication for which it is being developed.

“OR-449 was strategically designed at Orphagen and is the first antagonist to SF-1 to be taken into development – potent and orally bioavailable small molecules of this class have not previously been identified,” said Scott Thacher, Ph.D., CEO and Founder of Orphagen. “The data presented at AACR 2022 demonstrate that OR-449, a potent SF-1 antagonist, has clear potential for clinical efficacy in malignant LCTs as well as ACC. There is an urgent need for new therapies for LCT and ACC, and we are focused on completing IND-enabling studies of OR-449 with the goal of filing an investigational new drug application by the end of the year.”

The incidence of ACC in the U.S. is 300 patients per year, and existing therapies are very limited. LCTs represent about 3% of all testicular cancers. Testicular cancer is in turn one of the most frequently diagnosed cancers in American males between the ages of 15 and 35. Malignant LCTs, though rare, are an estimated 10% of all LCTs. They are resistant to chemotherapy and radiation, responding primarily to surgery. Median survival from diagnosis is two years for these patients.

Summary of Results

  • OR-449 exhibits striking anti-proliferative activity in the rat Leydig tumor cell (LCT) line R2C, inhibiting DNA synthesis by >90% at 1 mM with an estimated IC50 of 68 nM.
  • In cell lines lacking SF-1 expression, such as HEK293, OR-449 has no anti-proliferative activity up to 20 mM, indicating that the anti-proliferative effect on R2C is SF-1-mediated and is not due to cytotoxicity.
  • OR-449 inhibits R2C xenograft tumor growth in immunocompromised mice at oral doses of 3, 10, and 30 mg/kg/day, with complete inhibition at a daily dose of 30 mg/kg.
  • Based on an mRNA response signature first identified in R2C culture, OR-449 appears to directly engage with SF-1 in the R2C tumors.
  • The in vivo potency and efficacy of OR-449 in the R2C model corresponds to what we previously reported for SJ-ACC3 (Crowe et al, ENDO 2021), a pediatric ACC patient-derived tumor xenograft (PDX) model.

These results highlight that OR-449 antagonism of SF-1 is a novel targeted therapeutic approach with potential utility in the treatment of ACC and malignant LCTs. Orphagen has initiated IND-enabling studies of OR-449 with an anticipated IND-filing date at the end of 2022.

The poster (abstract #LB144) titled, “Antagonism of SF-1 as a potential targeted therapy for malignant Leydig cell tumors,” will be available on the AACR Annual Meeting 2022 website for registered attendees to view from Friday, April 8 through Wednesday, July 13. The poster is available here. The poster will be presented in person on Tuesday, April 12 from 9 am to 12:30 pm CT at the New Orleans Convention Center, Exhibit Halls D-H, Poster Section 27, Poster Board Number 17.

The authors acknowledge the support of the following NIH grants: R43 DK 102221, R43 CA 150540, R43 HD 068078, R43 CA 099875, R44 CA 265639.

Reference: Crowe, et al. A Novel Steroidogenic Factor-1 Antagonist, OR-449, as a Targeted Therapy for Adrenocortical Cancer. ENDO 2021: J Endocr Soc, Vol5, Supplement_1, A1010

About OR-449

OR-449 is the lead candidate identified from Orphagen’s proprietary screening technology, which has led to successful discovery of the first drug-like small molecules to several orphan nuclear receptors. OR-449 is a first-in-class, orally bioavailable small molecule antagonist to SF-1, an orphan nuclear receptor that is essential for the embryonic growth and development of adrenal and gonadal tissues. Clinical targets for SF-1 antagonism by OR-449, such as ACC and malignant LCT, are derived from these tissues and express very high levels of this novel drug target.

About Orphagen Pharmaceuticals

Orphagen unlocks the power of orphan nuclear receptors. Our scientists excel in discovery and development of small molecule ligands to these largely unexplored drug targets. Starting with a therapeutic area agnostic approach, we are exploring proprietary lead molecules with potential in autoimmune disease and oncology. Orphagen successfully partnered its first program for ROR-gamma antagonists with a mid-size pharmaceutical company ahead of all competitors in the field. Funding from its partnerships and other non-dilutive sources, including federal grants, has allowed Orphagen to advance its proprietary first-in-class drug discovery programs, including OR-449 for LCTs and adrenocortical cancer. For more info, visit


Company Contact: Scott Thacher, Ph.D., CEO, Orphagen,

Media Contact: Jessica Yingling, Ph.D., Little Dog Communications Inc.,,   +1.858.344.8091