On March 10, 2021 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of resistance in cancer, reported four preclinical poster presentations at the 2021 American Association for Cancer Research (AACR) (Free AACR Whitepaper) virtual annual meeting on April 10-15, 2021 (Press release, ORIC Pharmaceuticals, MAR 10, 2021, View Source [SID1234576398]).
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"We are pleased to present these compelling preclinical data on our four product candidates, which continue to validate our scientific platform focused on overcoming resistance in cancer," said Lori Friedman, chief scientific officer. "In particular, we are encouraged to see our lead program ORIC-101 reversing GR-mediated resistance in a variety of tumor models and contexts. Furthermore, ORIC-533, ORIC-944 and ORIC-114 each continue to show mounting evidence of potential best-in-class differentiation. We look forward to the continued advancements of these programs and our discovery research pipeline as we work to improve the lives of patients with cancer."
ORIC-101: Glucocorticoid Receptor (GR) Antagonist
Title: GR antagonist ORIC-101 overcomes GR-mediated resistance to the combination of AR and AKT inhibition in preclinical prostate cancer cell lines
Date: Poster release on April 10, 2021
Session: Reversal of Drug Resistance
Abstract: 1420
ORIC-101 is a potent and selective GR antagonist, with two distinct mechanisms of action being evaluated in two Phase 1b trials in combination with: (1) Abraxane (nab-paclitaxel) in advanced or metastatic solid tumors and (2) Xtandi (enzalutamide) in metastatic prostate cancer. It has previously been demonstrated that ORIC-101 reverses GR-mediated resistance to enzalutamide and to AR degraders in preclinical prostate cancer cell lines. This preclinical study evaluated whether activated GR confers resistance to the combination of AKT inhibitors with enzalutamide and whether co-treatment with ORIC-101 reverses GR-mediated resistance to the combination. It was observed that GR upregulation and activation, an established resistance mechanism for antiandrogens, may drive resistance when antiandrogens are combined with AKT inhibitors, and our data demonstrated that ORIC-101 was able to overcome this resistance and restore antitumor activity.
ORIC-533: CD73 Inhibitor
Title: Blocking adenosine production with ORIC-533, a CD73 inhibitor with best-in-class properties, reverses immunosuppression in high-AMP environments
Date: Poster release on April 10, 2021
Session: Modifiers of the Tumor Microenvironment
Abstract: LB-163
ORIC-533 is a highly potent, orally bioavailable CD73 inhibitor and has demonstrated greater potency in preclinical studies compared to an antibody approach and other small molecule CD73 inhibitors. In these studies, nanomolar concentrations of ORIC-533 efficiently rescued cytotoxic T-cell function in the presence of high AMP concentrations, reflective of levels observed in tumors. Additionally, inhibitors of adenosine receptors A2A or A2A/B were only able to rescue CD8+ T-cell function in the context of low micromolar AMP, thus may be ineffective in tumors with moderate or high AMP and adenosine levels. These preclinical results indicate that ORIC-533 has potential best-in-class properties in reversing immunosuppression in tumors.
ORIC-944: PRC2 Inhibitor
Title: ORIC-944, a potent and selective allosteric PRC2 inhibitor, demonstrates robust in vivo activity in prostate cancer models
Date: Poster release on April 10, 2021
Session: Epigenetic Targets
Abstract: 1131
ORIC-944 is a potent and selective allosteric inhibitor of polycomb repressive complex 2 (PRC2) and targets its regulatory embryonic ectoderm development (EED) subunit. The unique EED targeting strategy may more completely inhibit PRC2, and may address certain resistance mutations in EZH2 and the possible compensatory escape mechanism of EZH1. ORIC-944 has potential best-in-class drug properties compared to first generation PRC2 inhibitors, and superior in vivo efficacy was observed when compared to tazemetostat in a DLBCL model. In prostate cancer, ORIC-944 demonstrated strong tumor growth inhibition as a single agent with once daily dosing in both enzalutamide-responsive and enzalutamide-resistant models.
ORIC-114: EGFR/HER2 Inhibitor
Title: ORIC-114, a brain penetrant, orally bioavailable, irreversible inhibitor selectively targets EGFR and HER2 exon20 insertion mutants and regresses intracranial NSCLC xenograft tumors
Date: Poster release on April 10, 2021
Session: Tyrosine Kinase and Phosphatase Inhibitors
Abstract: 1466
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. Assessment of kinase panels showed ORIC-114 is highly selective to the EGFR family of receptors, with superior kinome selectivity compared to other exon 20 inhibitors. ORIC-114 also demonstrated low nanomolar potency across exon 20 insertion variants in biochemical and cell-based assays. Regressions were observed in multiple EGFR exon 20 patient-derived xenograft models using once daily oral administration. Importantly, ORIC-114 displayed superior brain exposure relative to other compounds targeting exon 20 and significantly regressed established EGFR-driven intracranial NSCLC tumors, commensurate with the superior brain exposure of ORIC-114.