Advancing candidates designed to address resistance mechanisms in multiple cancers
Our portfolio of novel agents targets multiple resistance mechanisms by leveraging our specialized expertise in the following areas:
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 growth. 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, prostate cancer and multiple myeloma among others. Preclinical data using ex vivo autologous models from relapsed/refractory multiple myeloma patients revealed that single agent inhibition of CD73 could restore anti-cancer immunity, triggering significant lysis of multiple myeloma cells. Our product candidate, ORIC-533, is an orally bioavailable small molecule inhibitor of CD73 that has demonstrated more potent adenosine inhibition in vitro compared to an antibody-based approach, and single agent activity in myeloma model systems.
- Immunosuppressive adenosine generation from adenosine monophosphate (AMP) requires the activity of the cell surface ecto-5’-nucleotidase, CD73
- Patient data demonstrate relapsed/refractory (r/r) multiple myeloma is adenosine rich
– High CD73 and adenosine are associated with poor prognosis and therapeutic resistance in multiple myeloma
- Patient-derived ex vivo models from r/r multiple myeloma patients revealed single agent activity with ORIC CD73 inhibitor
– Preclinical activity favorable to standard of care therapies in cross literature comparisons
BRAIN PENETRANT EGFR/HER2 EXON 20 INHIBITOR PROGRAM: ORIC-114
The ErbB receptor tyrosine kinase family is involved in key cellular functions, including cell growth and survival. Epidermal growth factor receptor (EGFR, or ErbB1) and human epidermal growth factor receptor 2 (HER2, or ErbB2) exon 20 insertion mutations are observed across multiple solid tumors, including NSCLC, breast, gastrointestinal, bladder and other cancers. EGFR exon 20 insertion mutations are observed in approximately 2% of all patients with NSCLC and have a worse prognosis than patients with NSCLC driven by other EGFR mutations. HER2 exon 20 insertion mutations are observed in approximately 1.5% of all patients with NSCLC. Approximately one-third of patients with exon 20 insertion mutations may develop brain metastases, which contributes to poor prognosis. Amplification of human epidermal growth factor receptor 2 (HER2) is an oncogenic driver found in up to 25% of breast cancer. Up to 50% of breast cancer patients with HER2 amplification may develop central nervous system (CNS) metastases over the course of their disease.
ORIC-114 is a brain penetrant, orally bioavailable, irreversible inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations. ORIC-114 has demonstrated greater brain exposure in preclinical studies compared to other compounds being developed against exon 20 mutations and HER2 targeted agents. Additionally, ORIC-114 demonstrates strong intracranial anti-tumor activity in EGFR-driven NSCLC and HER2-driven breast cancer models. ORIC-114 is a promising therapeutic candidate for development in patients with EGFR/HER2 exon20 and HER2+ tumors including those with brain metastases.
of EGFR/HER2 driven cancers, including in patients with active brain metastases
PRC2 INHIBITOR PROGRAM: ORIC-944
The dysregulation of Polycomb Repressive Complex 2 (PRC2) methyltransferase activity can lead to tumorigenesis in a wide range of cancers including prostate cancer, breast cancer, and hematological malignancies. EED is a core component of PRC2 and allosteric inhibition of EED impacts the assembly, stabilization, and activation of PRC2. Several companies are developing EZH2 inhibitors; however, the pharmacologic properties of these compounds result in high doses that achieve only partial target inhibition in the clinic. Additionally, preclinical studies suggest drug resistance to EZH2 inhibitors may develop via EZH1 bypass compensation or acquired mutations in EZH2. ORIC-944 is a potent and selective allosteric inhibitor of PRC2/EED and is efficacious in enzalutamide-resistance prostate cancer models in preclinical studies.
- Two druggable subunits:
– EED: responsible for histone binding; target of ORIC-944
– EZH2: responsible for histone methylation; target of first-generation inhibitors
- Dysregulation of PRC2 linked to several cancers – Decreased expression of target genes associated with poor prognosis in prostate cancer
- First-generation inhibitors, designed to inhibit EZH2, have demonstrated promising clinical activity and chemoresistance via – Approved for epithelioid sarcoma and follicular lymphoma – Limited progress made for treatment of prostate cancer
therapeutic potential in prostate cancer, among other indications
DISCOVERY RESEARCH PROGRAMS
In addition to our product candidates, we are leveraging our resistance platform in pursuit of multiple discovery research programs that focus on our expertise within hormone-dependent cancers, precision oncology and key tumor dependencies. These programs highlight our medicinal chemistry and structure-based design expertise, thus for the most part utilize a small molecule therapeutic approach to target oncogenic drivers in solid tumors like prostate, breast and lung cancer that relapse with innate, acquired or bypass resistance. Our most advanced discovery research programs are currently in lead optimization.
PLK4 Inhibitor Program
Polo family of serine/threonine protein kinase 4, PLK4, is a cell cycle protein that regulates centriole duplication. Recent research identified a synthetic lethal relationship between PLK4 inhibition and TRIM37 amplification/overexpression commonly found in breast cancer and neuroblastoma.
ORIC discovered novel, potent, orally bioavailable small molecule inhibitors of PLK4 that are highly selective, in contrast to the candidate in clinical development. Preclinical data demonstrates that the highly selective ORIC PLK4 inhibitors showed greater potency in TRIM37 high cancer cell lines as compared to TRIM37 low cell lines and demonstrates strong antitumor activity in TRIM37 high xenograft models.
Tumor Cells with TRIM37 Amplifications
Discovery and Development Rationale
- Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase that controls centrosome duplication during cell division
- Cells with TRIM37 amplifications require PLK4 function for growth and survival
– provides an opportunity for synthetic lethal targeting
- TRIM37 amplifications occur in breast cancer (~20%) and neuroblastoma (~55%), and have been associated with early relapse and poor prognosis