Clinical-stage biotechnology company Oncternal Therapeutics announced the closing of an $18.4 million Series B financing. The company which develops first-in-class and novel therapies for both rare and common cancers by focusing on targets that are uniquely expressed within cancer cells, intends to use the proceeds to further clinical development programs for cirmtuzumab and TK216, and to advance preclinical development of a new ROR1-targeted antibody-drug conjugate or ADC program.

The Receptor Tyrosine Kinase-Like Orphan Receptor 1 or ROR1 is an oncofetal protein which has gained much attention in cancer therapy since its initial discovery as a relatively specific surface antigen on B cell chronic lymphocytic leukemia (CLL). [1] Researchers have confirmed that ROR1 mediates several oncogenic pathways in a cancer type- and context-dependent manner. They have also found that ROR1 is mainly expressed in cells during embryogenesis and is re-expressed in a growing number of cancer types including, among others, malignant melanoma, breast cancer, and prostate cancer. [2][3]

According to the latest 2016 data from the National Cancer Institute an estimated 8,960 people were diagnosed with Chronic lymphocytic leukemia or CLL in the United States and 4,660 died of the disease, which is characterized by reposition of malignant B cells in the blood, bone marrow, spleen and lymph nodes. Over the last few years major breakthroughs have been made to prolong the survival and improve the health of patients. However, despite these advances, CLL is still recognized as a disease without definitive cure.

Cirmtuzumab, also known as UC-961, is a humanized IgG1 monoclonal antibody designed and developed to bind with high affinity to a biologically important epitope on the extracellular domain of ROR1. As a first-in-class anti-ROR1 monoclonal antibody being developed to treat patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). ROR1 expression identifies cancer stem cells in a number of hematologic malignancies and solid tumors, and that certain antibodies against ROR1 inhibit malignant behavior. Initial findings from the ongoing Phase Ia clinical trial in patients with relapsed or refractory CLL, including signs of pharmacological activity and prolonged progression-free survival, were presented at the American Society of Hematology (ASH) Meeting in December 2016. [4]

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The investigational drug cirmtuzumab was developed at the University of California San Diego based on the pioneering scientific research of Thomas Kipps, M.D. Ph.D, and his colleagues at the Moores Cancer Center. Oncternal holds an exclusive worldwide license to develop and commercialize antibodies and antibody-related binding agents recognizing ROR1.

Ets-family transcription factor oncoproteins
Oncternal is also developing another drug. Called TK216, this investigational agent is a first-in-class small molecule that inhibits the biological activity of ets-family transcription factor oncoproteins in a variety of tumor types, inhibiting cancer cell growth and tumor formation in nonclinical models. In Ewing sarcoma, TK216 is designed to target a fusion protein that causes the disease. A Phase I clinical trial in patients with relapsed or refractory Ewing sarcoma is currently underway. Oncternal has received Orphan Drug Designation and Fast Track status from the U.S. Food and Drug Administration (FDA) for TK216 in Ewing sarcoma and will be eligible to receive a Rare Pediatric Disease Priority Review Voucher if approved for this indication. [5]

Antibody-drug conjugate
Oncternal is also investigating the potential of an ROR1-targeted antibody-drug conjugates. Preclinical models show that upon binding, ROR1 antibodies such as cirmtuzumab are rapidly internalized and traffic inside the cell in a manner that is ideal for delivering a cytotoxic payload. Based on this understanding, Oncternal is generating and evaluating a series of ROR1-targeted antibody-drug conjugates utilizing several different toxic payloads, linkers and conjugation chemistry. Preclinical evaluation of these candidates will continue during 2017.

“We are extremely pleased with the rapid progress we have made in our clinical development programs since Oncternal was formed just nine months ago, and we appreciate the strong support of our shareholders and new investors,” said James Breitmeyer, M.D., Ph.D., Oncternal’s President and CEO. “We have reached the top dose group in our Phase 1a clinical trial of cirmtuzumab without safety issues and with evidence of pharmacological activity. We are preparing to launch a Phase Ib/II clinical trial of cirmtuzumab combined with ibrutinib as treatment for patients with CLL and MCL. With TK216, we have progressed through four dose levels in our Phase Ia study for patients with Ewing sarcoma without dose limiting toxicity, and have new nonclinical data to support development of TK216 for patients with hematologic malignancies. Additionally, we have initiated an anti-ROR1 ADC program and are testing product candidates from the program to add to our development pipeline.”

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