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Clinical and Preclinical Results for Acetylon Pharmaceuticals' ACY-1215 for the Treatment of Multiple Myeloma Presented at the 54th Annual Meeting of the American Society of Hematology


Acetylon Pharmaceuticals Inc., a leader in targeted epigenetic drug discovery and development for enhanced therapeutic outcomes, today presented clinical and preclinical results for its selective histone deacetylase (HDAC) 6 inhibitor, ACY-1215, for the treatment of multiple myeloma (MM) at the 54th Annual Meeting of the American Society of Hematology (ASH) taking place in Atlanta, Georgia. Preliminary results from the Phase 1/2 study of ACY-1215 suggest that selective inhibition of HDAC6 with ACY-1215 in combination with bortezomib (Velcade®, Takeda Millennium Pharmaceuticals) and dexamethasone may provide a well-tolerated treatment option for relapsed or relapsed/refractory MM. In addition, preclinical results for ACY-1215 indicate a potential beneficial role of HDAC6 inhibition in MM-related bone disease. Together, these results show that selective HDAC6 inhibition through ACY-1215 may act favorably on both tumors and bone forming cells to benefit patients with MM.

“Clinical and preclinical studies with ACY-1215 are continuing to validate the potential of selective inhibition of HDAC6 in multiple myeloma. ACY-1215, in combination with bortezomib, has previously demonstrated potent anti-tumor activity in preclinical studies and may have a favorable effect on multiple myeloma bone disease,” said Catherine A. Wheeler, MD, Vice President, Clinical Development of Acetylon. “We believe ACY-1215 holds promise as a potentially safe and effective treatment option for patients with relapsed or relapsed/refractory disease. The preliminary results from the first-in-human studies in multiple myeloma show that ACY-1215 is well-tolerated, and we are gathering further information regarding safety and disease response in combination with proteasome inhibition.”

Preliminary Phase 1/2 Study Results

Patients with relapsed or relapsed/refractory multiple myeloma (MM), previously exposed to both proteasome inhibitor and immunomodulatory agents, were enrolled in an ongoing, 3-part, Phase 1/2, single-arm, open-label study. A group sequential dose-escalation design was used to identify optimal dosing of ACY-1215 alone followed by evaluation of the objective response rate and safety of the combination of ACY-1215 with bortezomib plus dexamethasone.

Of the first 22 patients, 15 were treated with monotherapy and 7 with the combination of ACY-1215 and bortezomib plus dexamethasone. The patients were heavily pretreated, and 18 had refractory myeloma. Monotherapy was well tolerated, with no dose-limiting toxicities (DLTs) and predominantly low grade adverse events (AEs). Two patients treated on monotherapy had hematologic grade 3 AEs that were possibly related to ACY-1215 treatment. Six monotherapy patients had stable disease up to 10 months as best response. The first combination cohort at 40 mg ACY-1215 and 1.0 mg of bortezomib was expanded due to a single dose-limiting toxicity (DLT, elevated amylase) without occurrence of further DLTs, and one patient had a partial response to combination therapy. ACY-1215 was rapidly absorbed with no accumulation of the drug and displayed approximately dose-linear pharmacokinetics up to 160 mg dose level. At higher dose levels of 240 mg and 360 mg, an exposure plateau was observed, with maximum pharmacodynamic acetylation of tubulin, a biomarker of HDAC6 inhibition, in peripheral blood cells observed at the 240 mg dose.

Preliminary results from the first clinical evaluation of ACY-1215 suggest that selective inhibition of HDAC6 with ACY-1215 is well tolerated as monotherapy at exposures that demonstrate increased acetylation of tubulin, a biomarker of HDAC6 inhibition, versus acetylation of histones, a Class I HDAC inhibitory effect. Continued dose escalation in combination with bortezomib is ongoing. The results were presented today by Noopur Raje, MD, of Massachusetts General Hospital and Harvard Medical School during an ASH poster session in a poster titled, “Rocilinostat (ACY-1215), a Selective HDAC6 Inhibitor, Alone and in Combination with Bortezomib in Multiple Myeloma: Preliminary Results from the First-in-Humans Phase I/II Study.”

Preclinical Study Results

Bone lesions are a common occurrence in multiple myeloma (MM) and are a result of two compounding factors: an increase in myeloma cells inhibits bone-forming cells (osteoblasts) and increases bone destroying cells (osteoclasts), leading to the metabolic breakdown of bone (resorption). Osteoclasts normally act to clear old or decaying bone, but without osteoblasts to rebuild the lost bone, patients are left with bone lesions that can cause severe pain and increased risk of fracture. ACY-1215 was evaluated for its effects on MM bone disease. In both in vitro and in vivo results, ACY-1215 alone, or in combination with bortezomib, decreased markers of bone resorption and increased markers of bone formation (e.g. osteocalcin). A separate study tested HDAC6 effects on MM cell growth supported by bone marrow stromal cells (BMSC) from either normal or HDAC6 gene knockout mice. BMSC isolated from HDAC6 knockout mice showed a significant increase in osteocalcin and a reduction in MM cell proliferation, versus BMSC with the HDAC6 gene. Together, these data indicate a potential beneficial role of HDAC6 inhibition in MM bone disease.

The preclinical results were presented today at ASH by Loredana Santo, MD, of Massachusetts General Hospital and Harvard Medical School in an oral presentation titled, “Role of selective HDAC6 inhibition on multiple myeloma bone disease.”

About ACY-1215

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 complications. 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 Inc.

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.

Acetylon Pharmaceuticals Inc.
Walter C. Ogier, 617-245-1300
President and Chief Executive Officer
MacDougall Biomedical Communications
Kari Watson, 781-235-3060
Michelle Avery, 781-235-3060

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