Acute Myeloid Leukemia
Newly diagnosed, unfit for intensive chemotherapy
High & very high risk
Front line & relapsed/refractory
Pracinostat is an orally available histone deacetylase (HDAC) inhibitor that is being developed for advanced hematologic diseases such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). 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 malignancies 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.
Acute Myeloid Leukemia
Pracinostat has demonstrated clinical evidence of single-agent activity in patients with AML. 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 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. The median age in the study was 76 years. Patients received 60 mg of Pracinostat orally three times a week for three weeks followed by one week of rest and 75 mg/m2 of azacitidine via subcutaneous injection or intravenous infusion for the first seven days of each 28-day cycle. Results from the study were presented at the ASH Annual Meeting in December 2016. According to the oral presentation by principal investigator Dr. Guillermo Garcia-Manero, MD Anderson Cancer Center, 28 of the 50 patients in the study (56%) achieved the primary endpoint of CR plus complete response with incomplete blood count recovery (CRi) plus morphologic leukemia-free state (MLFS), including 21 patients (42%) who achieved a CR. Median overall survival for all 50 patients in the study was reached at 19.1 months. These data compare favorably to a recent international Phase III study of azacitidine (AZA-001), which showed a median overall survival of 10.4 months with azacitidine alone and a CR rate of 19.5% in a similar patient population. Median survival among patients with high-risk cytogenetics in this study (n=21) was 13.3 months, more than double the median survival of the high-risk population in the AZA-001 study (6.4 months). The combination of Pracinostat and azacitidine was generally well tolerated in the study, with no unexpected toxicities. The most common grade 3/4 treatment-emergent adverse events reported in >10% of all patients included febrile neutropenia, thrombocytopenia, anemia and fatigue.
In August 2016, we announced that the FDA granted Breakthrough Therapy Designation for Pracinostat in combination with azacitidine for the treatment of patients with newly diagnosed AML who are ≥75 years of age or unfit for intensive chemotherapy. In addition, agreement has been reached with the FDA on the proposed Phase III study design. According to the FDA, Breakthrough Therapy Designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for Breakthrough Therapy Designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. A Breakthrough Therapy Designation has all the benefits of the fast track program together with more intensive guidance on an efficient drug development program and an organizational commitment involving senior managers.
In August 2016, we entered into an exclusive license, development and commercialization agreement with Helsinn, a Swiss pharmaceutical corporation, for Pracinostat in AML and other potential indications. Under the terms of the agreement, Helsinn is granted a worldwide exclusive license to develop, manufacture and commercialize Pracinostat, and is responsible for funding its global development and commercialization. As compensation for such grant of rights, we received payments of $20 million, including a $15 million upfront payment in August 2016 and a $5 million payment in March 2017. In addition, we will be eligible to receive up to $444 million in potential regulatory and sales-based milestones, along with royalty payments on the net sales of Pracinostat, which, in the U.S., are tiered and begin in the mid-teens.
Pracinostat has also shown evidence of clinical activity when used in combination with azacitidine 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 azacitidine was generally well tolerated in the study; the most frequent side effects were nausea and fatigue.
In June 2013, we initiated 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. In March 2015, we announced top-line data from the study, which showed that the addition of Pracinostat to azacitidine failed to improve the overall CR rate, the study’s primary endpoint, compared to azacitidine alone. There were no new toxicities observed in the study; however fatigue, gastrointestinal toxicities and myelosuppression 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 analysis of patients able to tolerate Pracinostat plus azacitidine for at least four cycles suggest superior activity of the combination compared to azacitidine alone, with hazard ratios for overall survival (0.59) and duration of response (0.48) both favoring the Pracinostat plus azacitidine arm. These data were presented at the ASH Annual Meeting in December 2015.
As part of our license, development and commercialization agreement, we will work with Helsinn to determine an optimal dosing regimen of Pracinostat in combination with azacitidine for the treatment of high and very high risk MDS. The cost of this study will be shared by Helsinn and us and enrollment is anticipated to commence in the second quarter of 2017.
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 a Phase II clinical trial in intermediate or high-risk myelofibrosis, 36% of patients (eight of 22) derived benefit 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.
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 investigator-sponsored study is being conducted at the M.D. Anderson Cancer Center.