Pracinostat

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.



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 250
adult and pediatric patients and found to be generally well tolerated with readily manageable side effects often associated with drugs of this class, the most frequent of which is 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 azacitidine (marketed as Vidaza®). In December 2012, data from a pilot Phase II clinical trial of Pracinostat in combination with azacitidine 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 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.

In August 2014, we completed enrollment in a randomized, double-blind, placebo-controlled Phase II clinical trial of Pracinostat in combination with azacitidine in intermediate-2 and high-risk patients with previously untreated MDS. The multi-center trial enrolled 108 patients with a one-to-one randomization. We expect to unblind this study after a six-month follow-up period and report topline data 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, two open-label Phase II trials of Pracinostat are ongoing: one in combination with azacitidine or decitibine (marketed as Dacogen®) in patients with MDS who either failed to respond or maintain a response to a hypomethylating agent alone, and the other in combination with azacitidine in elderly patients with newly diagnosed AML who are not suited for intensive chemotherapy.

In June 2014, we announced preliminary data from the front line AML trial. Of the first nine patients enrolled in the study, three achieved a CR or CRi, each following one or two treatment cycles. In addition, three patients achieved a partial response (PR) or partial response with incomplete blood count recovery (PRi) after their initial or second treatment evaluation, for an overall response rate of 67%. We expect to report additional data from this open-label study at a scientific conference in December 2014.

In February 2014, the U.S. Food & Drug Administration (FDA) granted orphan drug designation to Pracinostat for the treatment of AML. The designation provides orphan status to drugs defined by the FDA as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases that affect fewer than 200,000 people in the U.S. Orphan designation qualifies us for certain development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions and seven-year marketing exclusivity upon FDA approval.

We own exclusive worldwide rights to all of our drug candidates, including Pracinostat.

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