On December 13, 2021 ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance reported that preclinical data with ORIC’s small molecule inhibitor of CD73 in multiple myeloma at the American Society of Hematology (ASH) (Free ASH Whitepaper), in collaboration with Dr. Kenneth Anderson’s research laboratory at Dana-Farber Cancer Institute (Press release, ORIC Pharmaceuticals, DEC 13, 2021, View Source [SID1234597018]). The abstract and presentation are available for online viewing via the ASH (Free ASH Whitepaper) Annual Meeting website.

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"ORIC-533 has a differentiated profile, demonstrating stronger potency in a high AMP environment compared to benchmark CD73 inhibitors and adenosine receptor antagonists in preclinical studies," said Lori Friedman, chief scientific officer. "Based on a strong mechanistic rationale and compelling single agent activity in patient-derived autologous ex vivo assays, we are excited to pursue clinical development in multiple myeloma."

Multiple myeloma patient samples have demonstrated that the tumor environment is adenosine rich, and studies have shown that high CD73 and adenosine levels are associated with poor prognosis and therapeutic resistance.

The ASH (Free ASH Whitepaper) presentation focused on the role of adenosine signaling in immunosuppression in patients with relapsed or refractory multiple myeloma and the ability of ORIC’s small molecule inhibitor of CD73 to restore antitumor immune activity.

Key highlights from a series of experiments utilizing bone marrow aspirates from patients with multiple myeloma include:

CD73 inhibition addressed adenosine mediated immunosuppression, which stimulated T-cell proliferation, T-cell activation, and activation of plasmacytoid dendritic cells in ex vivo assays derived from patients with multiple myeloma.
ORIC’s small molecule inhibitor of CD73 overcame immunosuppression and triggered significant lysis and cell death of multiple myeloma cells by autologous T-cells from the bone marrow microenvironment.
ORIC’s CD73 inhibitor demonstrated single agent activity, comparing favorably to standard of care therapies, in bone marrow-derived mononuclear cell assays from relapsed or refractory myeloma patients.
The company plans to pursue a single agent clinical development plan for ORIC-533 in multiple myeloma and initiate a Phase 1 trial in the fourth quarter of 2021.

Additional Pipeline Updates:

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. The company recently disclosed that ORIC-114 induced tumor regressions in a subcutaneous HER2 positive breast cancer xenograft model. In a new study, ORIC-114 demonstrated significant tumor growth inhibition in an intracranial HER2 positive breast cancer model, with superior antitumor activity versus tucatinib. The CTA has been filed in South Korea, and initiation of a Phase 1 trial is expected in early 2022.

ORIC-944 PRC2 Inhibitor

ORIC-944 is a potent and selective allosteric inhibitor of polycomb repressive complex 2 (PRC2) that targets its regulatory embryonic ectoderm development (EED) subunit and has demonstrated single agent efficacy in multiple enzalutamide-resistant prostate cancer models in preclinical studies. The IND was cleared by the FDA in December, and initiation of a Phase 1 trial is expected in early 2022.

Webcast and Conference Call Details

ORIC will host a conference call and webcast, today at 5:30 p.m. ET. To participate in the conference call, please dial (833) 651-0991 (domestic) or (918) 922-6080 (international) and refer to conference ID 7989199. A live webcast and audio archive of the conference call will be available through the investor section of the company’s website at www.oricpharma.com. The webcast will be available for replay for 90 days following the presentation.

About ORIC-533

ORIC-533 is a highly potent, orally bioavailable small molecule inhibitor of CD73, a key node in the adenosine pathway believed to play a central role in resistance to chemotherapy and immunotherapy-based treatment regimens. ORIC-533 has demonstrated greater potency in preclinical studies compared to an antibody approach, as well as other small molecule inhibitors of CD73 and adenosine receptor antagonists. Preclinical data demonstrated that ORIC-533 binds CD73 with high affinity and effectively blocks adenosine-driven immunosuppression in a high AMP environment, reflective of AMP levels observed in tumors. In preclinical studies, nanomolar concentrations of ORIC-533 efficiently rescued cytotoxic T-cell function in the presence of high AMP concentrations, as well as in ex vivo bone marrow aspirates from relapsed or refractory multiple myeloma patients.