On April 12, 2022 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported that three preclinical poster presentations and one preclinical oral presentation at the 2022 American Cancer Research Association (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, ORIC Pharmaceuticals, APR 12, 2022, View Source [SID1234612066]).
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
"Our four presentations at AACR (Free AACR Whitepaper) reflect the broad and diverse pipeline of differentiated programs at ORIC," said Jacob M. Chacko, MD, chief executive officer. "Preclinical data further demonstrate the potential of CD73 inhibitor ORIC-533 as a treatment for multiple myeloma, as well as the compelling brain penetrant properties of ORIC-114 with its high potency against exon 20 insertion mutations. We also introduced our highly selective inhibitors of PLK4 as a potential treatment for breast cancer by leveraging a synthetic lethal liability. We look forward to the continued advancement of these programs as well as ORIC-944, with initial data for our three clinical programs expected in the first half of 2023."
Presentation details:
ORIC-533: CD73 Inhibitor
ORIC-533 is a highly potent, orally bioavailable small molecule inhibitor of CD73 that has demonstrated more potent adenosine inhibition in preclinical studies compared to an antibody approach and other small molecule inhibitors of the adenosine pathway and is currently being studied in a Phase1b trial in multiple myeloma.
Poster Presentation:
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
Oral Presentation:
Optimizations leading to ORIC-533: A potent orally bioavailable CD73 inhibitor that restores anti-tumor immunity in high AMP environments
Key findings of the presentations:
Target candidate profile for best-in-class CD73 inhibitor was met by ORIC-533 in preclinical analyses.
In an autologous ex vivo assay using bone marrow aspirates from patients with relapsed or refractory multiple myeloma, CD73 inhibition stimulated plasmacytoid dendritic cells and activated T cells.
ORIC-533, across multiple dose levels, overcame immune suppression and triggered significant lysis and cell death of multiple myeloma cells in an assay comprised of autologous bone marrow microenvironment.
These results demonstrate that single agent ORIC-533 potently inhibits the adenosine pathway, which restores anti-tumor immunity and therefore holds potential as a treatment for patients with multiple myeloma.
ORIC-114: EGFR/HER2 Inhibitor
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, and is currently being studied in a Phase 1b trial in patients with advanced solid tumors with EGFR or HER2 exon 20 alterations or HER2 amplifications.
Poster Presentation:
ORIC-114, an orally bioavailable, irreversible kinase inhibitor, has superior brain penetration and antitumor activity in subcutaneous and intracranial NSCLC models
Key findings of the presentation:
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 preclinical studies confirmed the brain-penetrance and free unbound exposure in the CNS, which translated to greater anti-tumor activity compared to mobocertinib (TAK-788) in an intracranial NSCLC model.
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.
PLK4 Inhibitor Program:
The PLK4 Inhibitor program is a small molecule therapeutic program intended to address a mechanism of innate resistance found in a subset of breast cancers, specifically a synthetic lethal interaction of polo-like kinase 4 (PLK4) inhibition in tumors bearing a TRIM37 DNA amplification.
Poster Presentation:
Discovery of novel, highly selective inhibitors of PLK4 that demonstrate in vivo regressions in TRIM37 high xenografts
Key findings of the presentation:
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.
Importantly, cell potency in TRIM37 high cancer cells was rescued with knockdown of TRIM37, illustrating that selective PLK4 inhibitors exhibit synthetic lethality 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.