–Studies demonstrate potential mechanistic synergies with the Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib, as well as with immunomodulation–
BOSTON – April 20, 2016 – Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, today announced the presentation of data demonstrating that selective HDAC6 inhibition results in dose-dependent increases in cell killing as a single treatment and in combination with Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (Imbruvica®), in patient-derived cell lines and preclinical models of chronic lymphocytic leukemia (CLL). The studies were completed in collaboration with the laboratory of Javier Pinilla-Ibarz, M.D., Ph.D. at the Moffitt Cancer Center and the data were presented by Moffitt investigator, Eva Sahakian, Ph.D., in a poster presentation at the American Association for Cancer Research (AACR) Annual Meeting 2016 in New Orleans.
In CLL, malignant B cells evade immune detection and lead to immune suppression. Recently, histone deacetylases (HDACs) have been shown to play an active role in the regulation of pathogenesis and immune-related pathways in CLL, although their role in B-cell receptor signaling remains unknown. Previously, aberrant overexpression of HDAC6 has been demonstrated in CLL cell lines and patient samples, and the authors sought to understand the mechanistic role of HDAC6 in CLL.
In collaboration with Acetylon scientists, the authors demonstrated that selective HDAC6 inhibition in CLL cell lines resulted in dose-dependent reductions in IL-10, a cytokine that regulates cell proliferation in CLL, as well as dose-dependent increases in cell death and a synergistic reduction in cell viability in combination with the BTK inhibitor, ibrutinib. Genetic knockdown of HDAC6 in CLL cells reduced expression of PD-L1 and other immune checkpoint markers, while increasing markers related to antigen presentation, including MHC II. Using an animal model of CLL, the authors then demonstrated with systemic administration of a selective HDAC6 inhibitor, a reduction in disease burden and increased survival in parallel with diminished expression of immune checkpoint markers on T-cells and B-cells, as well as a reduction in the number of immunosuppressive T-cells (Tregs).
“The preclinical findings presented at AACR today demonstrate that selective HDAC6 inhibition may provide a successful combination immunotherapeutic strategy for the treatment of CLL,” said Steven Quayle, Ph.D., Senior Scientist at Acetylon.
“Overall these data further support the broad versatility and immunomodulatory capability of our selective HDAC6 inhibitors in multiple drug combinations across a breadth of oncology applications, including hematologic as well as solid tumor indications,” said Simon S. Jones, Ph.D., Senior Vice President, Head of Research and Preclinical Development at Acetylon.
Details of the presentation are as follows:
Date: Wednesday, April 20, 2016
Time: 7:30 AM -11:00 AM CDT
Location: Section 4
Session: Epigenetic Biomarkers and Therapies
Poster Board Number: 29
Abstract Number: 4485
Title: Regulation of chronic lymphocytic leukemia (CLL) immunobiology by histone deacetylase 6 (HDAC6)
About HDAC6 Inhibition
Ricolinostat (ACY-1215) and ACY-241 selectively inhibit 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 also affect the expression of numerous other 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.
Acetylon Pharmaceuticals, Inc., based in Boston, Massachusetts, is a leader in the development of novel small molecule drugs targeting epigenetic mechanisms for the enhancement of therapeutic outcomes in cancer and other critical human diseases. The Company’s epigenetic drug discovery platform has yielded a proprietary portfolio of optimized Class I and Class II histone deacetylase (HDAC) selective compounds for oral administration. Alteration of HDAC regulation through selective HDAC inhibition is thought to be applicable to a broad range of diseases including cancer, sickle cell disease and beta-thalassemia, and autoimmune and neurodegenerative diseases. Acetylon’s lead drug candidates, ricolinostat (ACY-1215) and ACY-241, are selective HDAC6 inhibitors currently in Phase 2 clinical development for the treatment of multiple myeloma. In 2013, the Company announced a strategic collaboration agreement with Celgene Corporation, which includes an exclusive option for the future acquisition of Acetylon by Celgene. Acetylon’s scientific founders are affiliated with Harvard University, the Dana-Farber Cancer Institute, the Massachusetts General Hospital, and Harvard Medical School. www.acetylon.com
Walter C. Ogier
President and Chief Executive Officer
MacDougall Biomedical Communications