Acetylon Pharmaceuticals Presents Data On The Use Of HDAC6 Inhibitors Ricolinostat (ACY-1215) And ACY-241 In Combination With Pomalidomide And Dexamethasone For The Treatment Of Multiple Myeloma

—Data Presented at 21^st Congress of the European Hematology Association—

BOSTON--(BUSINESS WIRE)--Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, today announced that it presented data from multiple clinical trials evaluating the safety and efficacy of two selective HDAC6 inhibitors in combination with pomalidomide (Pom) (Pomalyst®, Celgene) and dexamethasone (Dex) for the treatment of relapsed or relapsed-and-refractory multiple myeloma (RRMM) at the 21^st Congress of the European Hematology Association in Copenhagen, Denmark. Positive results from a Phase 2 clinical trial of ricolinostat were presented in an oral presentation by Noopur Raje, M.D. of Massachusetts General Hospital in Boston, Massachusetts. In addition, results of a Phase 1b clinical trial of an alternative liquid formulation of ricolinostat were presented in a poster presentation by Sumit Madan, M.D. of University of Texas Southwestern Medical Center. Early favorable results from a Phase 1a/1b clinical trial of ACY-241, a selective HDAC6 inhibitor administered in tablet form, were also presented as an e-poster.

“The data from these studies demonstrate that selective HDAC6 inhibition combines favorably with Pom and Dex, and support the continued clinical development of our selective HDAC6 inhibitors for the treatment of relapsed or relapsed-and-refractory multiple myeloma”

“The data from these studies demonstrate that selective HDAC6 inhibition combines favorably with Pom and Dex, and support the continued clinical development of our selective HDAC6 inhibitors for the treatment of relapsed or relapsed-and-refractory multiple myeloma,” said Catherine Wheeler, SVP Clinical Development & CMO of Acetylon. “The results of the Phase 2 ACE-MM-102 trial have established proof of concept for selective HDAC6 inhibition and demonstrated that the addition of ricolinostat to Pom/Dex treatment increases response rate and progression-free survival compared to Pom/Dex alone in relapsed-and-refractory MM. We believe that this approach has the potential to become a powerful treatment option for patients with multiple myeloma without the severe side effects commonly seen with pan-HDAC inhibition. We are further encouraged by early results with ACY-241 in a similar patient population that it will deliver the same efficacy and safety as ricolinostat, however in a tablet form.”

Phase 2 ACE-MM-102 Data

The ACE-MM-102 clinical trial is a multicenter, single arm, open-label Phase 2 study designed to evaluate the safety and efficacy of ricolinostat administered at an optimal dose and schedule in combination with Pom and Dex in patients with RRMM. Results of this study indicated that treatment with ricolinostat in combination with Pom and Dex was very well tolerated, and toxicities were predominantly low grade. Pharmacokinetic and pharmacodynamic analysis demonstrated selective inhibition of HDAC6 at therapeutic doses. Analysis of 67 efficacy-evaluable patients enrolled at least 6 months prior to the data cut confirmed an overall response rate (ORR) of 46%, a clinical benefit rate (CBR) of 58%, a disease control rate (DCR) of 82%, 9 months duration of response (DOR), and 7 months progression free survival (PFS). These data compare favorably to mature historical data for the MM-002 and MM-003 trials of Pom and Dex alone which demonstrated 31-33% ORR, 7-8 months DOR, and 4 months median PFS. More mature data on the entire 96 patient study population will be available by the end of the year.

Phase 1b ACE-MM-104 Data

The Phase 1b ACE-MM-104 clinical trial is a dose-escalation study of an alternative liquid formulation (ALF) of ricolinostat in combination with Pom and Dex in patients with RRMM. Daily dosing (QD) was better tolerated than twice-daily dosing. One dose-limiting toxicity (DLT), neutropenia, was observed at 180 mg QD, and cohort expansion to 6 patients showed no further DLTs. Pharmacokinetic and pharmacodynamic analysis demonstrated selective inhibition of HDAC6 at therapeutic doses, with no evidence of ricolinostat accumulation or drug-drug interaction with Pom. Early efficacy data indicates a confirmed ORR of 53% and a DCR of 87% after 6 months median follow-up. These results demonstrate that the alternative liquid formulation of ricolinostat is well tolerated in combination with Pom and Dex at doses up to 180 mg QD without major toxicities. This formulation of ricolinostat is also being used in ongoing investigator-sponsored studies in combination with paclitaxel and abraxane to treat solid tumors.

Preliminary Phase 1a/1b ACE-MM-200 Data

The Phase 1a/1b ACE-MM-200 clinical trial utilizes a sequential monotherapy/combination trial design to establish the safety, pharmacokinetics, and pharmacodynamics of ACY-241 as both a monotherapy and in combination with Pom and Dex in patients with relapsed or relapsed-and-refractory MM. ACY-241 is an orally available selective HDAC6 inhibitor that is structurally similar to ricolinostat and administered in tablet form. Results of the study demonstrated that ACY-241 is well tolerated as a monotherapy and in combination with Pom and Dex, and toxicities did not differ substantially in frequency or severity from those reported with Pom and Dex alone. Pharmacokinetic and pharmacodynamic analysis indicated dose-linear increases in exposure and dose-dependent, selective increases in acetylated tubulin and histones. ACY-241 achieved exposures several fold higher than ricolinostat without severe toxicity, both alone and in combination with Pom and Dex. Early efficacy data for combination treatment indicates a confirmed ORR of 50% and a DCR of 95% after 3.5 months median follow-up. These results indicate that ACY-241 is well tolerated in combination with Pom and Dex, and early response data for combination treatment even with short follow-up are similar to those of ricolinostat in combination with Pom and Dex. Cohort expansion at biologically relevant combination doses is ongoing.

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 to enable the development of optimized treatment regimens, including maximally effective combination drug therapies.

About Acetylon

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 and Phase 1b clinical development for the treatment of multiple myeloma, respectively. 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