EntreMed, Inc. announced the publication of preclinical data for its phase 2 oncology drug candidate, ENMD-2076 an Aurora A/angiogenic kinase inhibitor, which demonstrated significant activity against multiple myeloma (MM) cell lines and in MM models in vivo. Results of the study, conducted by EntreMed's collaborator, Sherif Farag, M.D., Ph.D., and colleagues at the Indiana University School of Medicine, were published in the on-line version of the British Journal of Haematology on June 15, 2010 and are scheduled to be published in print in the August 1, 2010 issue. Dr. Farag is the Principal Investigator for the ongoing Phase 1 study with ENMD-2076 in multiple myeloma patients.
The company recently initiated a phase 2 study for ENMD-2076 in ovarian cancer patients. Ovarian cancer was selected as the initial Phase 2 indication based on results from the phase 1 study in patients with solid tumours where the clinical benefit of ENMD-2076 was observed in this patient population. Six sites are participating in the phase 2 study and all are actively recruiting patients.
In the recently published preclinical data, ENMD-2076 was shown to have significant cytotoxicity against MM cell lines as well as against primary MM cells taken from human patients, with minimal toxicity seen towards haematopoietic progenitor cells, which are essential for the production of normal blood cells. ENMD-2076 was observed to exert its activity through multiple mechanisms important to MM growth and survival, including inhibition of the phosphoinositide 3-kinase/AKT pathway, and downregulation of X-linked inhibitor of apoptosis seen as early as six hours after treatment. G2/M cell cycle arrest and inhibition of the Aurora A and B kinases were seen after 24 to 48 hours of exposure. In murine models implanted with H929, a human plasmacytoma cell line, oral treatment resulted in dose-dependent inhibition of tumor growth with concomitant reduction in mechanism-specific markers of ENMD-2076 activity including phospho-histone H3, Ki-67, angiogenesis, and phospho-FGFR3. These data on ENMD-2076's mechanism of action provide additional support for ENMD-2076's potential therapeutic applicability in a broad range of oncology indications. ENMD-2076 has been the subject of multiple Phase 1 studies and is currently in a multi-centre phase 2 study in ovarian cancer patients.
In addition to the publication of these preclinical data, Dr. Sherif Farag's laboratory at the Division of Hematology and Oncology, Department of Medicine, Indiana University School of Medicine and the Indiana University Melvin and Bren Simon Cancer Center, has been awarded a research grant for $319,550 sponsored by the National Cancer Institute to continue his efforts to assess the mechanisms of action of ENMD-2076 and its potential use as a therapeutic to treat MM, an incurable cancer with current treatment.
Dr. Mark R Bray, vice president research at EntreMed commented, "Dr. Farag's work has generated important additional insights into the mechanism of action of our multi-kinase inhibitor. ENMD-2076 is shown to target multiple myeloma cells through several mechanisms that are vital to their growth and survival. Data from Dr. Farag's laboratory expands and validates our knowledge regarding how ENMD-2076 acts to kill cancer cells, and thereby increases our understanding of how best to continue to utilize the compound in the clinic to treat patients. We are very encouraged by the data generated and the correlation of these findings with our clinical work and will continue to advance our Phase 2 development of ENMD-2076."
"We are pleased to have these preclinical results published as they further support ENMD-2076's potential to treat patients with haematological and solid tumours," commented Dr. Carolyn F. Sidor, EntreMed's vice president and chief medical officer. "Additional preclinical evaluations, as well as data complied from our ongoing clinical studies, provide further insight into the scope of ENMD-2076's activity and aide in the process of selecting additional phase 2 indications."
ENMD-2076 is an orally-active, Aurora A/angiogenic kinase inhibitor with a unique kinase selectivity profile and multiple mechanisms of action. Preclinical studies with ENMD-2076 demonstrated significant anti-tumour activity, including tumour regression, in multiple solid and haematological malignancies. ENMD-2076 has been shown to inhibit a distinct profile of angiogenic tyrosine kinase targets in addition to the Aurora A kinase. Aurora kinases are key regulators of mitosis (cell division), and are often over-expressed in human cancers. ENMD-2076 also targets the VEGFR, Flt-3 and FGFR3 kinases which have been shown to play important roles in the pathology of several cancers. While ENMD-2076 is currently in a Phase 2 trial in ovarian cancer, preclinical and clinical activities are ongoing in assessing the compound's applicability in other forms of cancer.
EntreMed, Inc. is a clinical-stage pharmaceutical company committed to developing ENMD-2076, a selective angiogenic kinase inhibitor, for the treatment of cancer.