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 300
adult and pediatric patients, with manageable side effects often associated with drugs of this class, such as fatigue. The results of these studies suggest that Pracinostat has potential best-in-class pharmacokinetic properties when compared to the two approved 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), with the responses enduring for more than 206 and 362 days, respectively. These results were presented at the American Society of Hematology (ASH) Annual Meeting in December 2010. In addition, 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.

Myelodysplastic Syndrome

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 study of Pracinostat in combination with azacitidine in patients with advanced MDS were presented at the ASH Annual Meeting. Data from nine patients treated at the MD Anderson Cancer Center showed an overall response rate of 89%. Combined with the results from an additional patient treated at the University of Wisconsin-Madison, a 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 Phase II clinical study of Pracinostat in combination with azacitidine in intermediate-2 and high-risk patients with previously untreated MDS. The double-blind, placebo-controlled study enrolled 102 evaluable patients, randomized one-to-one, at 19 sites in the U.S. 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. We announced top-line data from this study in March 2015.

We reached a clinical response milestone in an open-label Phase II study of Pracinostat in hypomethylating agent (HMA)-refractory MDS in December 2014. Of the first 28 patients who received Pracinostat in combination with azacitidine or decitibine (marketed as Dacogen®) after progressing while being treated with the same HMA alone, three have now achieved clinical responses -- one partial response (PR) and two marrow complete responses (mCR) -- exceeding the pre-specified clinical improvement rate for expansion of study enrollment. We have now completed enrollment in this study and will continue to follow patients for response and survival. The combination of Pracinostat and azacitidine or decitabine has been generally well-tolerated in the study, with no unexpected toxicities. The most common treatment-emergent adverse events include anemia, fatigue and gastrointestinal disorders.

Acute Myeloid Leukemia

We completed enrollment in an open-label Phase II study of Pracinostat in combination with azacitidine in elderly patients with newly diagnosed AML in December 2014. The study enrolled a total of 50 patients at 15 clinical sites in the U.S. We presented interim data at the ASH Annual Meeting later that month. At that time 45% of patients (15 out of 33) evaluable for efficacy achieved the primary endpoint in the study, including nine who achieved a CR, four who achieved a complete response with incomplete blood count recovery (CRi) and two who achieved a morphologic leukemia-free state (MLFS). No patient who achieved a response has progressed. The combination of Pracinostat and azacitidine has been generally well-tolerated in the study, with no unexpected toxisities; six patients discontinued due to treatment-emergent adverse events. The most common treatment-emergent adverse events are neutropenia/neutropenic fever, thrombocytopenia, nausea, fatigue and anemia.

Based on these interim data and recent discussions with the FDA, we are now preparing for a registration-oriented study using CR as the primary endpoint to potentially support accelerated approval for this indication and overall survival as the endpoint for full approval. We expect to initiate this randomized, double-blind, placebo-controlled Phase III clinical trial of Pracinostat in combination with azacitidne in elderly patients with newly diagnosed AML in mid-2015.

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 also intend to seek orphan drug designation for Pracinostat in combination with azacitidine for the treatment of AML.

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

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