- Additional Preclinical Data Presented on Ricolinostat in Potential New Drug Combinations and HDAC6 Biomarkers in Multiple Myeloma -

Boston, MA (Press Release) - Acetylon Pharma­ceu­ticals, Inc., the leader in the devel­op­ment of selective histone deacetylase (HDAC) inhibitors for en­hanced thera­peutic out­comes, today announced that positive interim clin­i­cal data from the two proof-of-concept clin­i­cal trials with selective HDAC6 inhibitor, ricolinostat (ACY-1215), were presented at the 55th Annual Meeting of the American Society of Hematology (ASH) in New Orleans, LA. The two trials are the Phase 1b dose escalation portion of a Phase 1/2 study of ricolinostat in com­bi­na­tion with bor­tez­o­mib (Velcade®) and dexa­meth­a­sone and a Phase 1b dose escalation study of ricolinostat in com­bi­na­tion with lena­lido­mide (Revlimid®) and dexa­meth­a­sone, both for the treat­ment of patients with re­lapsed or refractory multiple myeloma (MM).

Data from the com­bi­na­tion study in­­clud­ing ricolinostat and lena­lido­mide was presented in a poster session on Sunday, December 8 and appeared particularly promising with no dose-limiting toxicities to date. All 16 (100%) of the evaluable patients ex­peri­enced clin­i­cal benefit (disease stabilization or better) and 11 patients (69%) responded to ther­apy (partial response or better). The most common treat­ment emergent adverse events (AEs) were fatigue, upper res­pira­tory in­fec­tion, neu­tro­penia, headache, diarrhea, and muscle spasms, all of which were mild or mod­er­ate in severity and without rela­tion­ship to the dose of ricolinostat, and most were not con­sidered related to ricolinostat.

Combination ther­apy in­­clud­ing ricolinostat and bor­tez­o­mib was also well tolerated, with primarily low grade and unrelated AEs of hematology changes, creatinine elevation, fatigue, de­creased appetite, diarrhea and changes in laboratory in­ves­ti­ga­tions, with 12 out of 20 evaluable patients experiencing clin­i­cal benefit (60%) and 5 patients (25%) responding to treat­ment with a trend to­wards en­hanced response at the highest dose. Data from this Phase 1/2 study were presented in an oral presentation on Monday, December 9. Clinical benefit has been durable in both studies, with patients remaining on treat­ment for up to 16 cycles of treat­ment (1 year) to date.

“Ricolinostat thus far has dem­onstrated an excellent safety profile, allowing physicians to keep patients on ther­apy for much longer than the traditional pan-HDAC inhibitors and explore the full poten­tial that selective inhibition of HDAC6 can provide for patients with MM,” said Noopur Raje, MD, Associate Professor, Department of Medicine, Harvard Medical School, Director, Multiple Myeloma Program, Medical Oncology, Massachusetts General School, and investigator in both clin­i­cal studies of ricolinostat. “I am highly encouraged by the initial clin­i­cal response signals that we are seeing, both with lena­lido­mide and bor­tez­o­mib, and believe that ricolinostat has the poten­tial to become an important addi­tion to com­bi­na­tion regi­mens for the treat­ment of MM.”

Five addi­tional poster presentations at ASH in­cluded data from pre­clin­i­cal studies with ricolinostat demonstrating highly synergistic activity in com­bi­na­tion with three addi­tional agents in models of MM: immuno­modu­la­tory drug (IMiD), poma­lido­mide (Pomalyst®), and pro­te­a­some inhibitors, car­filz­o­mib (Kyprolis®) and ixazomib. Acetylon also presented data on the discovery of HDAC6 bio­­markers, which could serve to guide further clin­i­cal devel­op­ment of ricolinostat.

“Ricolinostat’s great synergy with IMiDs and pro­te­a­some inhibitors is exemplified by the early signs of clin­i­cal activity in our current clin­i­cal studies with lena­lido­mide and bor­tez­o­mib, and we believe this profile is en­hanced by these pre­clin­i­cal studies with the next-generation com­­pounds, poma­lido­mide, car­filz­o­mib and ixazomib,” commented Catherine A. Wheeler, MD, Vice Pres­i­dent, Clinical Development of Acetylon. “These data underscore our strategy to expand the clin­i­cal exploration of ricolinostat’s poten­tial in addi­tional com­bi­na­tions and indi­ca­tions with the sup­port of our col­lab­o­ration with Celgene. We look forward to an exciting year in 2014, with the initiation of two addi­tional clin­i­cal trials of ricolinostat in MM, and the completion of our current studies.”

Highlights of the Presentations at ASH

ACY-1215, a Selective Histone Deacetylase (HDAC) 6 Inhibitor, in Combination with Lenalidomide and Dexamethasone (dex), is Well Tolerated without Dose Limiting Toxicity (DLT) in Patients (Pts) with Multiple Myeloma (MM) at Doses Demonstrating Biologic Activity: Interim Results of a Phase 1b Trial (poster presentation, Abstract # 3190)

• Ricolinostat has been studied in 22 patients in combination with lenalidomide (Revlimid®) and dexamethasone and has been shown to be well-tolerated, with no maximum tolerated dose (MTD) identified to date
• Of 16 patients evaluable for response, all 16 (100%) of the evaluable patients experienced clinical benefit (disease stabilization or better) and 11 patients (69%) responded to therapy (partial response or better). 1 CR (complete response), 3 VGPRs (very good partial response), 7 PRs (partial response) and 2 MRs (minimal response) were seen and 3 patients achieved SD (stable disease) as their best response
• The most common treatment emergent AEs, including fatigue (50% of patients), upper respiratory infection (39%), neutropenia (27.8%), headache, diarrhea, and muscle spasms (22.2% each) were mild or moderate in severity and there was no relationship to the dose of ricolinostat. Severe events were primarily hematologic, as well as fatigue and asymptomatic laboratory investigations; most were unrelated to ricolinostat

ACY-1215, a Selective Histone Deacetylase (HDAC) 6 Inhibitor: Interim Results of Combination Therapy with Bortezomib in Patients with Multiple Myeloma (MM) (oral presentation, Abstract # 759)

• Ricolinostat has been studied in 37 patients in a Phase 1 trial and has shown to be safe and well-tolerated, with no MTD yet identified
• Of 20 patients treated in Phase 1b with the combination of ricolinostat, bortezomib (Velcade®) and dexamethasone who are evaluable for response, 2 VGPRs, 3 PRs and 2 MRs were seen and 5 patients achieved SD as their best response
• Most adverse events were low grade, and included hematologic changes, elevation of creatinine, fatigue, loss of appetite, diarrhea, and changes in laboratory investigations; these were not increased at higher doses of ricolinostat and most were considered not related to ricolinostat

Preclinical Combination of the Oral Investigational Agents ACY-1215, a Selective HDAC6 Inhibitor, and Ixazomib, a Proteasome Inhibitor, Demonstrates Combination Benefit in Multiple Myeloma Cell Lines and Xenograft Models (poster presentation, Abstract # 4437)

• Ricolinostat in combination with oral proteasome inhibitor, ixazomib, demonstrated increased efficacy similar to combination with bortezomib both in vitro and in vivo
• In vivo, the combination of ricolinostat and ixazomib has striking antitumor activity, with regression of the xenograft tumors below starting volumes, a level maintained throughout the 17-day dosing period

Inhibition of Autophagy by ACY-1215, a Selective HDAC6 Inhibitor Accelerates Carfilzomib-Induced Cell Death in Multiple Myeloma (poster presentation, Abstract # 4431)

• Proteasome inhibition can trigger autophagy, thought to be one of the key mechanisms of cell survival and lead to resistance as is frequently seen with bortezomib
• Combination treatment of ricolinostat and carfilzomib (Kyprolis®) resulted in significant synergistic cytotoxic effects against several MM cell lines through ricolinostat’s ability to potently regulate autophagy through HDAC6 inhibition. This may overcome proteasome inhibitor resistance in the clinic

ACY-1215, a First-In-Class Selective Inhibitor of HDAC6, Demonstrates Significant Synergy with Immunomodulatory Drugs (IMiDs) in Preclinical Models of Multiple Myeloma (MM) (poster presentation, Abstract # 1952)

• Combining ricolinostat with either lenalidomide (Revlimid®) or pomalidomide (Pomalyst®) leads to synergistic decreases in the viability of MM cells in vitro and decreased expression of critical cancer targets Myc and IRF4
• The combination of ricolinostat and either lenalidomide or pomalidomide was well tolerated in vivo

Tubulin Hyper-Acetylation in Blood Lymphocytes: Pharmacodynamic (PD) Biomarker for the Selective Histone Deacetylase (HDAC) 6 Inhibitor ACY-1215 in Multiple Myeloma (MM) Patients (poster presentation, Abstract # 3219)

• Acetylated α-tubulin as a clinical PD biomarker suggests (along with pharmacokinetic data) that ricolinostat reached a pharmacologically relevant level of HDAC6 inhibition at clinical doses ≥80 mg
• These results will aid in the determination of the recommended Phase 2 dose of ricolinostat in combination with proteasome inhibitors and IMiDs

Discovery Histone Deacetylase (HDAC)6 Specific Proteomic Biomarkers in Multiple Myeloma (MM) Using Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC) (poster presentation, Abstract # 1909)

• With administration of ricolinostat, AcK peptides identified in MM cells by the SILAC approach confirmed the critical function of HDAC6 in protein folding, ubiquitination, degradation, cytoskeleton structure and apoptosis, and also suggested other new functional targets for HDAC6 inhibition
• AcK peptide biomarkers could expand knowledge of the role of HDAC6 inhibition, particularly in combination with other MM therapeutic agents and assist in the development of biomarkers of ricolinostat activity in patients with MM

About Ricolinostat

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. 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 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

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 1b clin­i­cal devel­op­ment for the treat­ment of multiple myeloma. The Company recently 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 the Harvard University, the Dana-Farber Cancer Institute, the Massachusetts General Hospital, and Harvard Medical School. www.acetylon.com

Revlimid® and Pomalyst® are registered trademarks of Celgene Corpo­ra­tion. Velcade® is a registered trademark of Millennium Pharma­ceu­ticals, Inc. Kyprolis® is a registered trademark of Onyx Pharma­ceu­ticals, Inc.

Source: Acetylon Pharma­ceu­ticals.