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ACY-241 in Multiple Myeloma

ACY-241 is a selective histone deacetylase (HDAC) 6 inhibitor which is structurally and biologically very similar to ricolinostat (ACY-1215) but is administered as a tablet. Like ricolinostat, it has low activity against other subtypes of HDAC enzymes.

HDACs are a family of 18 different enzymes which are present in most cells of the human body. The way in which HDAC inhibitors work is very complex, and the current generation of HDAC inhibitors (sometimes called “pan-HDAC” inhibitors) affect indiscriminately many gene functions as well as protein transport within cells, resulting in significant side effects.

Preclinical models suggest that selectively inhibiting HDAC6 (versus other enzymes of the HDAC family) may lead to effective therapy with potentially fewer serious side effects. In preclinical cancer models and safety studies, ACY-241 is as biologically active and as well-tolerated as ricolinostat. Like ricolinostat, ACY-241 may also make cancer cells more susceptible to the effects of other beneficial anti-cancer medications.

Highlights of preclinical data reported at the American Association for Cancer Research 2015 Annual Meeting include:

  • Preclinical treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL) cell lines with ACY-241 in combination with either lenalidomide or pomalidomide synergistically increased cell death
  • Both HDAC6 selective inhibitors and the IMiD® drugs lenalidomide (Revlimid®) and pomalidomide (Pomalyst®) as single agents reduce expression of the oncogenic transcription factors, MYC and IRF4, and this effect was further enhanced by combination treatment in MM and MCL cells
  • Prolonged treatment with the combination of ACY-241 and pomalidomide was well-tolerated in vivo, and significantly delayed tumor growth in a preclinical MM disease model

Our first-in-human clinical trial (ACE-MM-200) with ACY-241 for the treatment of patients with multiple myeloma is currently underway. Initial results suggest that ACY-241, like ricolinostat, is well-tolerated both alone and in combination with pomalidomide and dexamethasone. Interim results from this study will be presented at the Annual Meeting of the American Society of Hematology in Orlando, Florida in December 2015. Previous single-arm clinical studies with ricolinostat in combination with other myeloma drugs have shown potentially superior tolerability for ricolinostat versus non-selective HDAC inhibitors. Clinically significant diarrhea, fatigue, and decreases in platelet count have limited the therapeutic utility of non-selective HDAC inhibitors, where ricolinostat and ACY-241 can be dosed daily without dose-limiting toxicity to date.

NOTE: ACY-241 is currently being evaluated in clinical trials and is not approved for other human use.

Click to find out more about the ACY-241 clinical trial in multiple myeloma.