Pracinostat is an orally available histone deacetylase (HDAC) inhibitor that is being developed for advanced hematologic diseases such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). HDACs belong to a larger set of proteins collectively known as epigenetic regulators that can alter gene expression by chemically modifying DNA or its associated chromosomal proteins. Abnormal activity of these regulators is believed to play an important role in cancer and other diseases. There are currently two HDAC inhibitors, one oral and one injectable, approved by the FDA – both for the treatment of T-cell lymphoma.

Pracinostat has been tested in multiple Phase I and Phase II clinical trials in hematologic and solid tumor indications. Pracinostat has been generally well tolerated in more than 200
adult and pediatric patients and found to be generally well tolerated with readily manageable side effects often associated with drugs of this class, including fatigue. The results of these studies suggest that Pracinostat has potential best-in-class pharmacokinetic properties when compared to other oral HDAC inhibitors.

Pracinostat has demonstrated clinical evidence of single-agent activity in patients with AML and myelofibrosis. In a Phase I dose-escalation study, two out of 14 evaluable patients with AML (14%) achieved a complete remission (CR) lasting for more than 206 and 362 days, respectively. The results from this study were presented at the American Society of Hematology Annual Meeting in December 2010. In addition, data from a Phase II clinical trial of Pracinostat showed that eight out of 22 patients with intermediate or high-risk myelofibrosis (36%) demonstrated a clinical response, including two patients showing a clinical improvement (anemia response) and six patients experiencing some reduction in splenomegaly. These results were published in the September 2012 issue of Leukemia Research.

Pracinostat has also shown evidence of synergistic activity when used in combination with the hypomethylating agent Vidaza® (azacitidine) in patients with MDS. In December 2012, data from a pilot Phase II clinical trial of Pracinostat in combination with Vidaza in patients with advanced MDS were presented at the American Society of Hematology Annual Meeting. Data from nine patients treated at the MD Anderson Cancer Center showed an overall response rate (CR+CRi+PR) of 89%, including seven CRs. Combined with the results from an additional patient treated at the University of Wisconsin-Madison, another CR, the trial showed an overall response rate of 90% (nine out of 10). The combination of Pracinostat and Vidaza was well tolerated in the study. The most frequent side effects were nausea and fatigue.

We initiated a double-blinded, placebo-controlled Phase II clinical trial of Pracinostat in combination with Vidaza in intermediate-2 and high-risk patients with previously untreated MDS in June 2013. The multi-center trial is expected to enroll 100 patients with a one-to-one randomization. Completion of enrollment is anticipated by the third quarter of 2014, with topline data expected in the first quarter of 2015. The primary endpoint of the study is CR. Secondary endpoints include overall response rate, hematologic improvement, duration of response, progression-free survival, rate of leukemic transformation, overall survival and safety.

In addition, we have initiated two open-label, single-armed Phase II trials of Pracinostat, one in combination with Vidaza in elderly patients with AML who are not suited for intensive chemotherapy, and the other in combination with Vidaza or Dacogen® (decitabine) in patients with MDS who either failed to respond or maintain a response to a hypomethylating agent alone. Preliminary data from both open-label trials are anticipated by December 2014.

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