Preliminary evidence of clinical antimyeloma activity, including reduction in paraprotein, demonstrated in multiple patients
Clean safety profile with only Grade 1 and 2 treatment related adverse events and no dose limiting toxicities or dose reductions
Clinical activity, safety profile, and dose-dependent increases in immune cell activation support potential for combination studies with other multiple myeloma agents, including BCMA- and CD38-directed therapies
Company to pursue strategic partnership for combination studies, resulting in extension of cash runway into 2026
SOUTH SAN FRANCISCO, CA and SAN DIEGO, CA, USA I December 11, 2023 I ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, today announced initial data from the ongoing ORIC-533 Phase 1 dose escalation trial in patients with relapsed/refractory multiple myeloma at the 65th American Society of Hematology (ASH) Annual Meeting (poster here).
“ORIC-533 demonstrated an exceptionally well-tolerated safety profile and preliminary evidence of clinical antimyeloma activity in heavily pretreated relapsed/refractory multiple myeloma patients, which to our knowledge is the first reported single agent activity for a CD73 inhibitor in any oncology indication,” said Pratik Multani, MD, chief medical officer. “We believe the Phase 1 data presented today position ORIC-533 as an ideal candidate for combinations with other immune-based antimyeloma therapies, including bispecific anti-BCMA-CD3 antibodies, CAR-T therapies, and anti-CD38 antibodies.”
“We’re excited that multiple ORIC programs have achieved preliminary proof of concept that justify advancement into later stage studies. Given our desire to advance both ORIC-114, our EGFR/HER2 exon 20 inhibitor for lung cancer, and ORIC-944, our PRC2 inhibitor for prostate cancer, into Phase 2 and beyond, those two programs will require a level of focus from our team that necessitates the prioritization of our clinical pipeline,” said Jacob M. Chacko, MD, chief executive officer. “As such, we intend to complete the single agent dose escalation for ORIC-533 in the coming months, and then combination studies will only be pursued with the operational and financial backing of a future partner for that program. This prioritization extends our projected cash runway into 2026, even with the increased expenses associated with moving ORIC-114 and -944 towards registrational studies.”
ORIC-533 Phase 1 Study Design
ORIC-533 is being evaluated in a Phase 1 dose escalation trial in patients with relapsed/refractory multiple myeloma. The primary objectives of the trial are safety and determination of the recommended Phase 2 dose (RP2D). Additional objectives include characterization of the pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.
ORIC-533 Phase 1 Dose Escalation Data
As of November 28, 2023, a total of 23 patients with multiple myeloma received doses ranging from 400 mg to 2400 mg once daily. The study included a heavily pretreated patient population where 100% of patients were triple-class refractory, 91% were penta-refractory, and 57% also received prior anti-BCMA bispecific antibody and/or CAR-T therapy.
ORIC-533 demonstrated a favorable pharmacokinetic profile with an estimated plasma half-life of ~24 hours, which supports QD dosing. ORIC-533 clinical exposures achieved concentrations associated with efficacy in ex vivo models. ORIC-533 also demonstrated strong inhibition of soluble CD73 enzymatic activity across all dose levels, highlighting good target engagement, including in the bone marrow.
ORIC-533 was well tolerated with only Grade 1 and 2 treatment-related adverse events (TRAEs), without any specific recurrent toxicity. There were no dose limiting toxicities, dose reductions or treatment-related serious adverse events.
ORIC-533 exhibited clear evidence of immune activation in the majority of patients dosed at ≥ 1200 mg, as evidenced by an increased abundance and fraction of activated CD8+ T cells and NK cells. At the 1600 mg dose, there were notable reductions in soluble BCMA levels in serum, indicating that ORIC-533 was having a measurable antimyeloma effect. Soluble BCMA levels have been reported to correlate with clinical response on treatment and predict progression free survival of various therapies. Finally, there were multiple examples of clinical activity, including a confirmed minor response in a patient with penta-refractory myeloma who had progressed on an anti-BCMA bispecific antibody 3 months before study entry.
Next Steps
The company intends to complete dose escalation for ORIC-533 in the first quarter of 2024. Given the overall profile of ORIC-533, it is an ideal candidate for development in combination with other immune-based antimyeloma therapies, and the company intends to evaluate strategic partnerships to enable such development.
Conference Call and Webcast Details
To join the conference call via phone and participate in the live Q&A session, please pre-register online here to receive a telephone number and unique passcode required to enter the call. 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.
About ORIC Pharmaceuticals, Inc.
ORIC Pharmaceuticals is a clinical stage biopharmaceutical company dedicated to improving patients’ lives by Overcoming Resistance In Cancer. ORIC’s clinical stage product candidates include (1) ORIC-114, a brain penetrant inhibitor designed to selectively target EGFR and HER2 with high potency against exon 20 insertion mutations, being developed across multiple genetically defined cancers, (2) ORIC-944, an allosteric inhibitor of the polycomb repressive complex 2 (PRC2) via the EED subunit, being developed for prostate cancer, and (3) ORIC-533, an 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, being developed for multiple myeloma. Beyond these three product candidates, ORIC is also developing multiple precision medicines targeting other hallmark cancer resistance mechanisms. ORIC has offices in South San Francisco and San Diego, California. For more information, please go to www.oricpharma.com, and follow us on X or LinkedIn.
SOURCE: ORIC Pharmaceuticals