Pracinostat is an orally available histone deacetylase (HDAC) inhibitor that is being developed for advanced hematologic diseases such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and myelofibrosis (MF). 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.
The results of these studies suggest that Pracinostat has potential best-in-class pharmacokinetic properties when compared to other oral HDAC inhibitors, with side effects often associated with drugs of this class, the most frequent of which are fatigue and myelosuppression.

Pracinostat has demonstrated clinical evidence of single-agent activity in patients with AML and MF. 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 a Phase II clinical trial in intermediate or high-risk MF, 36% of patients (eight of 22) demonstrated a clinical response from Pracinostat treatment, with 9% of patients (two of 22) having a clinical improvement (anemia response) and 27% (six of 22) 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 (HMA) azacitidine (marketed as Vidaza®) in patients with advanced MDS. Results from a pilot Phase II study presented at the ASH Annual Meeting in December 2012 showed an overall response rate of 89% (eight of nine). The combination of Pracinostat and Vidaza was generally well tolerated in the study; the most frequent side effects were nausea and fatigue.

In March 2015, we announced top-line data from a randomized, double-blind, placebo-controlled Phase II clinical study of Pracinostat in combination with azacitidine in intermediate-2 or high-risk patients with previously untreated MDS. The study enrolled 102 evaluable patients, randomized one-to-one, at 19 sites in the U.S. The top-line data showed the addition of Pracinostat to azacitidine did not increase the overall CR rate, the study's primary endpoint, compared to azacitidine alone. Data from event-driven endpoints, including event and progression-free survival and overall survival are currently immature and will require longer follow-up in order to achieve meaningful conclusions. There were no new toxicities observed in the study. Fatigue, gastrointestinal toxicities and myelosuppresion occurred more frequently in the combination group and resulted in a higher rate of drug discontinuations compared to azacitidine alone, predominantly within the first two cycles of treatment. Exploratory follow-up data suggest that patients receiving Pracinostat plus azacitidine for more than four cycles may receive clinical benefit compared to azacitidine alone. These data have been accepted for oral presentation at the ASH Annual Meeting in December 2015.

In December 2014, we reached the clinical response milestone in our open-label Phase II study of Pracinostat in HMA-refractory MDS. 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 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 completed enrollment with 39 patients in this arm and will continue to follow these patients for response and survival. A second arm, patients with stable disease following initial HMA therapy, was closed due to insufficient enrollment. There were no new or unexpected toxicities in the study. The most common treatment-emergent adverse events include anemia, fatigue and gastrointestinal disorders.

Acute Myeloid Leukemia

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 in the U.S. and Europe for Pracinostat in combination with azacitidine for the treatment of AML.

In November 2014, we completed enrollment in our open-label Phase II study of Pracinostat in combination with azacitidine in elderly patients with newly diagnosed AML. The study enrolled a total of 50 patients at 15 clinical sites in the U.S. Interim data from the study were presented at the European Hematology Association (EHA) Annual Congress in June 2015. Updated response and overall survival data have been accepted for oral presentation at the ASH Annual Meeting in December 2015. As of the ASH abstract on August 4, 2015, 54% of patients (27 of 50) have achieved the primary endpoint of CR + CRi + MLFS, including 42% (21 of 50) who achieved a CR. Most responses occurred within the first two cycles and many continued to improve with ongoing therapy. Median overall survival has not been reached. The one-year survival rate was approximately 60%. The 60-day mortality rate was 10% (five of 50). Pracinostat in combination with azacitidine was generally well tolerated in this population of elderly AML patients. The most common treatment-emergent adverse events included febrile neutropenia, thrombocytopenia, nausea and fatigue.

We continue to follow patients for overall survival. We believe this survival analysis will be important in determining the development path forward for Pracinostat in combination with azacitidine in AML.

Pracinostat has shown evidence of activity when used in combination with a wide range of therapies in clinical and pre-clinical studies. Pre-clinical data published in the May 2012 issue of Blood Cancer Journal demonstrated synergistic activity when Pracinostat was combined with pacritinib, an experimental JAK2 inhibitor. In addition to our Phase II clinical studies in AML and MDS, Pracinostat is currently being evaluated in a Phase II study in combination with ruxolitinib (marketed as Jakafi® and Jakavi®) in patients with myelofibrosis. The goal of this study is to learn if Pracinostat, when given in combination with ruxolitinib, can help to control myelofibrosis. The study, sponsored by the M.D. Anderson Cancer Center, began enrollment in early 2015.

View related publications