Glucocorticoid Receptor (GR) program: ORIC-101
GR is a nuclear hormone receptor that mediates responses to glucocorticoid hormones involved in regulating a range of cellular functions, such as metabolism, cell growth and differentiation. The original hypothesis for our lead program targeting GR was borne out of work conducted in the laboratory of Dr. Sawyers at Memorial Sloan Kettering Cancer Center in search of explanatory factors underlying resistance to anti-androgen prostate cancer therapies, including Xtandi and Erleada. His work demonstrated that GR signaling is a bypass mechanism to anti-androgen therapy, and that increased expression of GR in prostate cancer is correlated with resistance to Xtandi. We and others have shown that, in addition to prostate cancer, GR is also overexpressed across over 20 advanced solid tumors including pancreatic, triple negative breast (TNBC) and ovarian cancers, and that GR overexpression is associated with worse survival outcomes.
Our lead product candidate, ORIC-101, is a potent and selective small molecule GR antagonist designed to inhibit GR transcriptional activity and block pro-survival signals downstream of its activation that confer resistance to anti-androgen therapies and chemotherapies. Since its initial discovery at ORIC, we have rapidly advanced ORIC-101 through preclinical studies that have informed the design of a robust clinical development plan. Following the successful completion of two Phase 1a trials in over 50 healthy volunteers, we initiated in 2019 two separate Phase 1b trials of ORIC-101 in combination with: (1) Xtandi (enzalutamide) in metastatic prostate cancer and (2) Abraxane (nab-paclitaxel) in advanced or metastatic solid tumors. These trials are intended to establish safety, pharmacokinetics , pharmacodynamics, preliminary anti-tumor activity and a recommended Phase 2 dose of ORIC-101 in combination with each of these therapeutics. To help inform which patients may be most suitable for treatment with ORIC-101, we have developed a proprietary immunohistochemistry (IHC) assay that measures GR protein expression levels as well as a proprietary GR gene activation signature that measures GR signaling activity, both of which are being utilized in our ongoing clinical trials and may be used for patient selection in future clinical trials.
More information about our clinical trials is available here.
CD73 inhibitor program: ORIC-533
Many cancers usurp the anti-inflammatory adenosine pathway to avoid detection by the immune system, thereby reducing the effectiveness of certain chemotherapy- and immunotherapy-based treatments. Accumulation of adenosine in the tumor microenvironment is implicated in local immune suppression that leads to tumor proliferation. CD73 is an enzyme that controls the rate at which extracellular adenosine is produced and its overexpression is associated with poor prognosis in several cancers, including TNBC, NSCLC, melanoma and prostate, among others. Several global pharmaceutical companies are developing anti-CD73 antibodies, but due to significant medicinal chemistry challenges, to our knowledge, there are no orally bioavailable inhibitors of CD73 in clinical development. Our second product candidate, ORIC-533, is an orally bioavailable small molecule inhibitor of CD73, which has demonstrated more potent adenosine inhibition in vitro compared to an antibody-based approach.
Other preclinical programs
We are also developing several potentially first-in-class therapies targeting other key mechanisms of resistance. Our other additional programs targeting resistance mechanisms are in various states of preclinical drug discovery and are directed towards a variety of solid tumors with a focus on breast, prostate and lung cancers.