LA JOLLA, Calif.—Kura Oncology Inc., a clinical-stage biopharmaceutical company, in early December presented preclinical data highlighting the identification and characterization of KO-947, its development candidate targeting ERK1/2 kinases. The company also presented preclinical data relating to the identification and optimization of potent and selective inhibitors of the menin-MLL interaction. Both presentations took place at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics (EORTC) in Munich, Germany.
“We are excited to present preclinical data from these two innovative programs at EORTC, both of which showed compelling activity in preclinical models of cancer,” Dr. Yi Liu, Kura’s chief scientific officer, said during the meeting. “Looking forward, we anticipate nominating a development candidate for our menin-MLL program by the end of 2016, and initiating a Phase 1 clinical trial for KO-947 in the first half of 2017.”
As for KO-947, Kura notes that the RAS/RAF/MEK pathway is estimated to be activated in more than 30 percent of human cancers, including cancers arising from mutations in KRAS, NRAS and BRAF. Although inhibitors of both BRAF and MEK have been approved for treatment of melanoma, acquired resistance to these inhibitors has been documented both in preclinical and clinical samples due to reactivation of ERK1/2 kinases.
In the preclinical studies presented at EORTC, KO-947 showed what Kura says is “potent inhibition” of ERK signaling pathways and proliferation of tumor cells exhibiting dysregulation of MAPK pathway, including mutations in BRAF, NRAS or KRAS. KO-947 also inhibits MAPK signaling and cell proliferation in preclinical models that are resistant to BRAF and MEK inhibitors.
Results obtained from screening a large panel of patient-derived xenograft models demonstrate that KO-947 induces tumor regressions in BRAF or RAS mutated tumor models as well as in tumor models lacking BRAF/RAS mutations but characterized by other dysregulation of the MAPK pathway.
KO-947 appears to be differentiated from other published ERK inhibitors by an extended residence time and prolonged pathway inhibition in vitro and in vivo, the company says. The data further suggest that the drug properties of KO-947 may allow Kura to maximize the therapeutic window with flexible administration routes and schedules, including intermittent dosing.
With regard to the menin-MLL interaction data, Kura notes that chromosomal translocations that affect the mixed lineage leukemia (MLL) gene result in aggressive acute myeloid and lymphoid leukemias that are often resistant to standard chemotherapy. Between 5 and 10 percent of acute leukemias in adults, and 70 percent of acute leukemias in infants, are characterized by tumors with abnormal MLL fusions. MLL fusion proteins require menin for leukemogenic activity, and selective disruption of the menin-MLL interaction represents a potential therapeutic approach for the treatment of acute leukemias with MLL rearrangements.
In preclinical studies presented at EORTC, inhibitors of the menin-MLL interaction showed potent inhibition of the proliferation of MLL leukemic cells. Inhibitors of the menin-MLL interaction displayed a greater than 50-fold reduction in potency in non-MLL-fusion leukemia cell lines and induced regression in a MV4:11 mouse xenograft model. The data show that the antitumor activity of menin-MLL inhibitors correlates with target engagement in tumors as well as inhibition of expression of downstream genes under the regulation of the fusion protein. Moreover, the inhibitors demonstrated potent efficacy in subcutaneous and disseminated models of MLL-fusion leukemias.
Kura’s pipeline consists of small molecules that target cancer signaling pathways where there is a strong scientific and clinical rationale to improve outcomes by identifying those patients most likely to benefit from treatment—that is, the company has a focus on precision medicine, also known as personalized medicine. Kura Oncology’s lead drug candidate is tipifarnib, a farnesyl transferase inhibitor, which is currently being studied in multiple Phase 2 clinical trials.