BOSTON--(BUSINESS WIRE)--Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, today announced results from three Phase 1b clinical trials of the selective HDAC6 inhibitor, ricolinostat (ACY-1215), in different single-agent and combination regimens for the treatment of lymphoma and multiple myeloma. The data were presented in poster sessions on Saturday December 5 and Sunday December 6 at the American Society of Hematology (ASH) Annual Meeting in Orlando, Florida.
The safety and tolerability of ricolinostat (ACY-1215) was investigated in an open-label, single agent, multi-institutional Phase 1b clinical trial in patients with relapsed or refractory lymphoid malignancies. The study was conducted by investigators from the Columbia University Medical Center, New York, NY. The target population for enrollment included patients with histologically confirmed relapsed or refractory non-Hodgkin’s lymphoma or Hodgkin’s lymphoma, with an expansion cohort of patients with mantle cell lymphoma. Ricolinostat was well tolerated in these patients, dosed daily (QD) or twice daily (BID), with no dose-limiting toxicities. The most common adverse events were diarrhea, nausea, and pain, which were all low grade. Ricolinostat also demonstrated promising clinical activity in monotherapy with 37% of patients achieving stable disease on a 160 mg BID dose schedule. The promising clinical activity and favorable tolerability seen in this study support further exploration in Phase 2 studies.
“This is the first data to be reported on a selective HDAC inhibitor in the treatment of patients with lymphoid malignancies, and the favorable clinical activity and tolerability profile of ricolinostat (ACY-1215) as a monotherapy is promising,” said Catherine A. Wheeler, MD, Senior Vice President, Clinical Development and Chief Medical Officer of Acetylon. “The achievement of stable disease in 37% of patients with relapsed or refractory disease, which was in some cases durable, supports our plan to further explore the use of ricolinostat (ACY-1215) in combination with approved therapies for a variety of lymphoid malignancies in Phase 2 studies.”
The Phase 1b ACY-100 clinical trial was designed to determine the optimal dose of ricolinostat (ACY-1215) in combination with bortezomib (Velcade®, Millennium) and dexamethasone in patients with relapsed or relapsed-and-refractory multiple myeloma. Dosing data from this study indicate that a dose of 160 mg QD, in combination with intravenous or subcutaneous administration of bortezomib, is well tolerated. In the 18 patients receiving ricolinostat at 160 or 240 mg QD, an overall response rate (defined as partial response or better) of 33% was achieved, with many having durable responses of 6 months or more. In the 32 patients who were refractory to bortezomib, 69% had stable disease or better and 13% responded, including one very good partial response.
The Phase 1b ACE-MM-101 clinical trial was an open-label, multicenter study designed to determine the optimal dose of ricolinostat in combination with lenalidomide (Revlimid®, Celgene) and dexamethasone in patients with relapsed or relapsed-and-refractory multiple myeloma. In the study, ricolinostat was well tolerated in combination with lenalidomide and dexamethasone over a range of doses and schedules. The most common treatment emergent adverse events (AEs) were fatigue, diarrhea and hematologic toxicity, and most were low grade; no maximum tolerated dose was identified. A dose of 160 mg QD on days 1-21 of a 28-day cycle was chosen as the optimal Phase 2 dose based on the occurrence of dose-limiting toxicities in the two BID cohorts and similar observations of more favorable tolerability with once daily dosing in other ricolinostat combination studies. There were 38 patients that were evaluable for response and an overall response rate (defined as partial response or better) of 55% was achieved. An overall response rate of 25% was achieved in the 12 patients that were refractory to lenalidomide. Patients who responded to treatment were on study for a median duration of 12 months, with some patients continuing up to 33 months. Nine patients remain on study.
“These studies, together with others reported at this year’s American Society of Hematology Annual Meeting, demonstrate the particular promise of selective HDAC6 inhibition in combination with IMiD® drugs and with proteasome inhibitors, and we look forward to advancing these combinations further in clinical development for the treatment of different populations of multiple myeloma patients,” said Walter C. Ogier, President and Chief Executive Officer of Acetylon. “In addition, the consistent tolerability and promising clinical response rates that were achieved in these Phase 1b studies provide an excellent foundation for the expanded exploration of our HDAC6 inhibitors in a variety of Phase 2 combination studies involving other drug partners and other types of cancer where we have the opportunity to enhance effectiveness with little incremental toxicity.”
Details of the presentations are as follows:
Date: Saturday, December 5, 2015
Time: 5:30 PM-7:30 PM
Location:
Hall A, Level 2 (Orange County Convention Center)
Session:
605. Molecular Pharmacology, Drug Resistance – Lymphoid and Other
Diseases: Poster I
Abstract Number: 1280
Title:
Translational Focus on Targeting HDAC6 with Ricolinostat Confirms Potent
Activity in Preclinical Models of Lymphoma and a Favorable Toxicity
Profile in Patients with Relapsed or Refractory Lymphoma
Date: Saturday, December 5, 2015
Time: 5:30 PM-7:30 PM
Location:
Hall A, Level 2 (Orange County Convention Center)
Session:
653. Myeloma: Therapy, excluding Transplantation: Poster I
Abstract
Number: 1827
Title: Ricolinostat (ACY-1215), the First
Selective HDAC6 Inhibitor, in Combination with Bortezomib and
Dexamethasone in Patients with Relapsed or Relapsed-and-Refractory
Multiple Myeloma: Phase 1b Results (ACY-100 Study)
Date: Sunday, December 6, 2015
Time: 6:00 PM-8:00 PM
Location:
Hall A, Level 2 (Orange County Convention Center)
Session:
653. Myeloma: Therapy, excluding Transplantation: Poster II
Abstract
Number: 3055
Title: Ricolinostat (ACY-1215), the First
Selective HDAC6 Inhibitor, in Combination with Lenalidomide and
Dexamethasone in Patients with Relapsed and Relapsed-and-Refractory
Multiple Myeloma: Phase 1b Results (ACE-MM-101 Study)
About HDAC6 Inhibition
Ricolinostat (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 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.
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, 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 and beta-thalassemia, and autoimmune and neurodegenerative diseases. Acetylon’s lead drug candidate, ricolinostat (ACY-1215), is a selective HDAC6 inhibitor 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
Velcade® is a registered trademark of Millennium Pharmaceuticals, Inc. Revlimid® is a registered trademark of Celgene Corporation.
