BOSTON, Mass. – June 20, 2013 – Acetylon Pharmaceuticals Inc., the leader in targeted epigenetic drug discovery and development for enhanced therapeutic outcomes, today announced that collaborators from Columbia University Medical Center presented an oral presentation on preclinical data of selective histone deacetylase (HDAC) 6 inhibitor, ACY-1215, in combination with bortezomib (Velcade®, Takeda Millennium Pharmaceuticals) for the treatment of lymphoma at the 12th International Conference on Malignant Lymphoma (ICML), on June 19, 2013, in Lugano, Switzerland. First author Jennifer E. Amengual, M.D., of Columbia University Medical Center presented the study, “Dual targeting of protein degradation pathways with the selective HDAC6 inhibitor, ACY-1215 (ACY), and bortezomib (Bor), demonstrates synergistic antitumor activity in preclinical models of lymphoma.”
“Although advances have been made in the treatment of lymphoma, there still remains a need for new treatments that can serve those patients who progress or relapse with current standard of care,” said Owen O’Connor, M.D., Ph.D., Professor of Medicine and Experimental Therapeutics, Director of the Center for Lymphoid Malignancies, and Co-Program Director of the Lymphoid Development and Malignancy Program in the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and Principal Investigator of the study. “These data presented at ICML support a novel and synergistic approach for the treatment of lymphoma through the combination of selective targeting of HDAC6 with ACY-1215 and proteasome inhibition with bortezomib.”
“Acetylon Pharmaceuticals is building a franchise for ACY-1215 in cancers beyond multiple myeloma, bolstered by data such as these invited to be presented at the ICML conference and demonstrating the potential synergistic antitumor effect of ACY-1215 in combination with standard of care therapy," commented Simon S. Jones, Ph.D., Vice President of Biology and Preclinical Development at Acetylon. “We have two ongoing studies of ACY-1215 for the treatment of multiple myeloma which are generating promising clinical results, and we plan to initiate a Phase 1b/2 clinical trial for the treatment of lymphoma by early 2014, based in part on the favorable preclinical data presented at ICML.”
The study, authored by Drs. Amengual, O’Connor and P.M. Johannet of Columbia University Medical Center and Dr. Jones of Acetylon Pharmaceuticals, investigated the therapeutic impact and mechanism of ACY-1215 alone and in combination with bortezomib in preclinical models of lymphoma. Single agent concentration-effect curves were generated for 17 lymphoma cell lines, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and T-cell lymphoma (TCL). In combination with bortezomib, synergistic effects with ACY-1215, as measured by relative risk ratio (RRR), were seen in DLBCL (RRR=0.39), MCL (RRR=0.78), and TCL (RRR=0.28), where values of less than one represent the synergistic effect of the two drugs (whereas values equal to one would indicate the mean additive effect). Treatment with ACY-1215 led to inhibition of the aggresome pathway, evidenced by acetylation of α-tubulin and increased poly-ubiquitinated proteins, and cell death occurred via apoptosis, evidenced by caspase cleavage and other molecular markers. All pharmacodynamic effects of ACY-1215 were enhanced with the addition of bortezomib. These are the first published results to indicate that dual targeting of different protein degradation pathways may represent a novel and synergistic approach for the treatment of select lymphoma subtypes.
Blood cancers such as multiple myeloma and lymphoma are characterized by successive genetic mutations resulting in uncontrolled cell proliferation and dysfunctional production of intracellular proteins. ACY-1215 selectively inhibits the intracellular enzyme HDAC6, which leads to an accumulation of excess protein and in addition may disrupt critical proliferative signals in malignant cells. Disruption of these molecular processes in cancer cells triggers programmed cell death, called "apoptosis," with little or no effect on normal cells. Currently available HDAC drugs affect the expression of numerous genes in normal cells as well as cancer cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDAC6 is expected to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and may enable the development of optimized treatment regimens, including maximally effective combination drug therapies.
About Acetylon Pharmaceuticals
Acetylon Pharmaceuticals, Inc. is a leader in the development of novel small molecule drugs targeting epigenetic mechanisms for the enhanced therapeutic outcome of cancer and other critical unmet medical needs. The Company’s epigenetic drug discovery platform has initially yielded a proprietary library of optimized, orally-administered Class I and Class II histone deacetylase (HDAC) selective compounds. Alteration of HDAC regulation through selective HDAC inhibition is thought to be applicable to a broad range of diseases, including cancer, sickle cell disease, beta-thalassemia, and autoimmune and neurodegenerative diseases. Acetylon’s lead drug candidate, ACY-1215, is a selective HDAC6 inhibitor in clinical development for the treatment of multiple myeloma.
Walter C. Ogier
President and Chief Executive Officer
MacDougall Biomedical Communications