On March 8, 2022 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported three poster presentations and one oral presentation at the 2022 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting taking place April 8-13, 2022, in New Orleans, LA (Press release, ORIC Pharmaceuticals, MAR 8, 2022, View Source [SID1234609665]). The presentations will highlight preclinical data regarding two Phase 1 programs, including ORIC-533, a highly potent, orally bioavailable CD73 inhibitor, and ORIC-114, a brain penetrant, orally bioavailable, irreversible inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations. The presentations will also introduce a new program targeting a synthetic lethality pathway in breast cancer.
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Details of the presentations are as follows:
Title: ORIC-533, a small molecule CD73 inhibitor with best-in-class properties, reverses immunosuppression and has potential as an immunomodulatory therapy in patients with multiple myeloma
Session Title: Immunomodulatory Agents and Interventions 1
Date and Time: April 11, 2022, 1:30 p.m. – 5:00 p.m.
Abstract Number: 2074
Abstract Highlights
Using an autologous ex vivo assay, bone marrow aspirates from patients with multiple myeloma were evaluated to assess the impact of CD73 inhibition. The results showed that CD73 inhibition stimulated the activation of plasmacytoid dendritic cells and T cell activation. Moreover, the ORIC CD73 inhibitor as a single agent overcame immune suppression and triggered significant lysis and cell death of multiple myeloma cells by autologous T-cells in the bone marrow microenvironment. Taken together, these results demonstrate that the ORIC small molecule CD73 inhibitor potently inhibits the adenosine pathway, which restores anti-tumor immunity and therefore holds potential for patients with multiple myeloma.
Oral Presentation Title: Optimizations leading to ORIC-533: A potent orally bioavailable CD73 inhibitor that restores anti-tumor immunity in high AMP environments
Session Title: Chemistry to the Clinic, Part 2 of 3: Progress in Small Molecule Cancer Immunology Therapy
Date and Time: April 9, 2022, 11:00 a.m. – 11:30 a.m.
Title: ORIC-114, an orally bioavailable, irreversible kinase inhibitor, has superior brain
penetration and antitumor activity in subcutaneous and intracranial NSCLC models
Session Title: Tyrosine Kinase and Phosphatase Inhibitors
Date and Time: April 12, 2022, 1:30 p.m. – 5:00 p.m.
Abstract Number: 3335
Abstract Highlights
Oral administration of ORIC-114 resulted in tumor regressions in an EGFR exon 20 NSCLC model, with superior efficacy relative to CLN-081 and BDTX-189. Additional studies confirmed the brain-penetrance and free unbound exposure in the CNS, which translated to greater anti-tumor activity compared to TAK-788 in an intracranial NSCLC model. Taken together, these data confirm ORIC-114 as a potent, selective, irreversible, brain penetrant EGFR exon 20 inhibitor, and a promising therapeutic candidate, including for patients with CNS metastases.
Title: Discovery of novel, highly selective inhibitors of PLK4 that demonstrate in vivo regressions in TRIM37 high xenografts
Session Title: Novel Targets and Pathways
Date and Time: April 12, 2022, 9:00 a.m. – 12:30 p.m.
Abstract Number: 2633
Abstract Highlights
ORIC discovered novel, potent, orally bioavailable small molecule inhibitors of PLK4 that are highly selective, including against the closely related aurora kinases and PLK1-3. Cell viability assessment across a cancer cell line panel revealed that the highly selective ORIC PLK4 inhibitors showed greater potency in TRIM37 high cancer cell lines as compared to TRIM37 low cell lines. In contrast, less selective compounds, including from the clinical literature, did not display differential potency in TRIM37 high versus low cancer cell lines. Importantly, cell potency in TRIM37 high cancer cells was rescued with knockdown of TRIM37, illustrating that selective PLK4 inhibitors are synthetic lethal with TRIM37 amplification. Oral administration of ORIC PLK4 inhibitors resulted in strong anti-tumor activity of TRIM37 high xenograft tumors, with corresponding pharmacodynamic effects and no body weight loss.
Abstracts are available for viewing in the AACR (Free AACR Whitepaper) Online Itinerary Planner located here, View Source!/10517.