On April 13, 2022 Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, reported that it has deprioritized further development of ONCT-216 to reallocate resources to zilovertamab, the Company’s investigational anti-ROR1 monoclonal antibody, and its Phase 3 registrational trial that the Company expects to initiate in Q3 2022 (Press release, Oncternal Therapeutics, APR 13, 2022, View Source [SID1234612154]). As such, the Company has discontinued enrollment in the Phase 1/2 study evaluating ONCT-216 in patients with relapsed or refractory Ewing sarcoma.
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"This asset prioritization allows us to further sharpen our focus on hematological malignancies and prostate cancer, while deploying our capital towards meaningful catalysts as we navigate this historically challenging pandemic, geopolitical and capital markets macroenvironment," said James Breitmeyer, MD, PhD, Oncternal’s President and CEO. "We believe this focused approach, along with prudent cash management, will enable us to fund our operations well into the third quarter of 2023, as we continue to explore all potential sources of capital to enable us to reach our milestones."
The Company expects to initiate its global registrational Phase 3 Study ZILO-301 in the third quarter of 2022, taking into account the impact of geopolitical factors and COVID-19 related supply chain issues. The study will randomize patients with relapsed or refractory MCL who have experienced stable disease or a partial response after receiving four months of oral ibrutinib therapy to receive either blinded zilovertamab or placebo, and all patients will continue receiving oral ibrutinib. The novel ZILO-301 design is supported by encouraging data from the Company’s ongoing Phase 1/2 clinical trial of zilovertamab plus ibrutinib for patients with MCL or CLL, as well as by a successful End-of-Phase-2 meeting with the U.S. Food and Drug Administration (FDA).
The Company’s lead autologous ROR1-targeted CAR-T cell therapy program candidate, ONCT-808, is advancing according to plan towards an Investigational New Drug (IND) application submission expected in mid-2022, based on supportive manufacturing and preclinical data as well as a productive pre-IND meeting with the FDA earlier this year.
Finally, the Company continues to advance ONCT-534, its lead candidate in its DAARI program, and expects to initiate IND-enabling GLP toxicology studies and GMP manufacturing later this quarter. ONCT-534 has shown anti-tumor activity in preclinical studies relevant to multiple clinically important forms of resistance for patients with prostate cancer, including those involving overexpression of the androgen receptor, or expression of mutants of the androgen receptor, or splice variants such as AR-V7.
About Zilovertamab (formerly Cirmtuzumab)
Zilovertamab is an investigational, humanized, potentially first-in-class monoclonal antibody targeting Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1). Zilovertamab is currently being evaluated in a Phase 1/2 clinical trial in combination with ibrutinib for the treatment of patients with MCL or chronic lymphocytic leukemia (CLL), in a collaboration with the University of California San Diego (UC San Diego) School of Medicine and the California Institute for Regenerative Medicine (CIRM). In addition, Oncternal is supporting two investigator-sponsored studies being conducted at the UC San Diego School of Medicine, a Phase 1b clinical trial for patients with metastatic castration-resistant prostate cancer (mCRPC), and a Phase 2 clinical trial of zilovertamab in combination with venetoclax, a Bcl-2 inhibitor, for patients with relapsed/refractory CLL. Both are open for enrollment.
ROR1 is a potentially attractive target for cancer therapy because it is an onco-embryonic antigen, not usually expressed on adult cells, but its expression confers a survival and fitness advantage when reactivated and expressed by tumor cells. Researchers at the UC San Diego School of Medicine discovered that targeting a critical epitope on ROR1 was key to specifically inhibiting ROR1 expressing tumors. This led to the development of zilovertamab which binds this critical epitope of ROR1, highly expressed on many different cancers but not on normal tissues. Preclinical data showed that when zilovertamab bound to ROR1, it blocked Wnt5a signaling, inhibited tumor cell proliferation, migration and survival, and induced differentiation of the tumor cells. The FDA has granted Orphan Drug Designations to zilovertamab for the treatment of patients with MCL and CLL/small lymphocytic lymphoma. Zilovertamab is in clinical development and has not been approved by the FDA for any indication.