Final Results of Anagrelide Controlled-Release (GALE-401) Safety, Efficacy and Pharmacokinetics in Subjects with Myeloproliferative Neoplasms (MPN)-Related Thrombocytosis
Authors: Troung Phu V. , Saltzman Marc , Bessudo Alberto , Jawien William , Lyons Roger M. , Berenzon Dmitriy , Mena Raul , Wingate-Pearse Nasiema , Barriere Olivier , Beeson Hali E. , Glidden Paul F. , Choy Gavin S. , Verstovsek Srdan 
Published: October 2019

Abstract
Introduction: Agrylin® (United States) and Xagrid® (European Union) are immediate release (IR) preparations of anagrelide hydrochloride that block megakaryocyte differentiation and proliferation and inhibit the action of cyclic AMP phosphodiesterase. Anagrelide was developed as an inhibitor of platelet aggregation but was found to reduce platelet count at lower doses than the amount needed for platelet aggregation. This led to the development of a controlled release formulation of anagrelide (GALE-401). Early healthy volunteer results demonstrated platelet lowering activity and a pharmacokinetic profile with lower Cmax compared to anagrelide IR. The current study, GALE-401-201, was undertaken in subjects with MPN-related thrombocytosis and the final safety, efficacy, and pharmacokinetics are reported here.
Methods: GALE-401-201 is a phase 2 open-label, single arm, clinical proof-of-concept study in chronic myelogenous leukemia (CML), polycythemia vera (PV), primary myelofibrosis (PMF) or essential thrombocythemia (ET). Eligible subjects must not be refractory to anagrelide IR and must have a platelet count ≥ 600 K/μL. GALE-401 was administered orally at a starting dose of 0.5 mg twice daily and titrated to a dose that maintained a platelet count of 150-400 K/μL. Platelet response was defined by World Health Organization 2008 (complete response, ≤ 400 K/μL or partial response ≤ 600 k/μL or ≥ 50% reduction from baseline), safety assessments were graded by CTCAE version 4.03, and the pharmacokinetic profile was assessed at the starting dose, weekly sampling during dose titration, and at the final titrated dose using a non-linear mixed effect modeling.
Results: Eighteen subjects were enrolled, median age 64 years (range, 40-79), 10 females/8 males, 14 ET, 3 PV, and 1 PV/ET. Three groups of anagrelide subjects were enrolled: naïve, intolerant and tolerant subjects with 10, 5, and 3 subjects, respectively. Baseline mutation of JAK2 V617F was present in 12 (66.7%) subjects, CALR in 3 (16.7%) subjects, and thrombopoietin receptor gene (MPL) in 1 (5.6%) subject. After a median duration of 7 months on GALE-401, an overall response rate of 14 of 18 subjects (77.8%; 7 CRs and 7 PRs) was observed across the anagrelide subject groups with median GALE-401 dose of 2 mg daily (range, 0-5 mg). The median duration of response (CR or PR) is 6.3 months (ongoing) with a median time to first objective response of 3.1 weeks (range, 1.1-5.0 weeks). JAK2 V617F was present at baseline in 7 (38.9%) and CALR mutation 1 (5.6%) of ET subjects who demonstrated a clinical response. Majority of the AEs, regardless of relationship were of Grade 1/2 in severity. Treatment related Grade 3/4 adverse events occurred in 2 subjects; Grade 3 (anemia, pancreatitis, increased creatinine, headache); Grade 4 (cholestatic jaundice). Grade 3/4 events were not correlated with higher anagrelide doses. A logistical regression evaluating the relationship between adverse events severity versus dose, anagrelide maximum plasma concentration (Cmax occurring between the time of the adverse event occurrence and up to 7 days prior) versus adverse events, did not reveal a clear positive correlation. Further exposure-adverse events analyses in addition to pharmacokinetic parameters will be presented.
Conclusions: In this pilot clinical proof-of-concept study, GALE-401 produces an overall response rate at a dose comparable to anagrelide IR in a diverse group of subjects both treated and untreated with anagrelide IR. The majority of adverse events were mild to moderate in nature, and the adverse events severity was not correlated with dose or plasma concentration. A comparative controlled study evaluating GALE-401 with anagrelide IR in a well-defined MPN population, such as anagrelide treatment naïve ET, will be further needed to fully elucidate the safety and efficacy profile of GALE-401.

Disclosures
Troung: Galena Biopharma, Inc.: Research Funding. Saltzman:Galena Biopharma, Inc.: Research Funding. Jawien:Galena Biopharma, Inc.: Research Funding. Lyons:Galena Biopharma, Inc.: Research Funding; Amgen: Consultancy. Berenzon:Galena Biopharma, Inc.: Research Funding. Mena:Galena Biopharma, Inc.: Research Funding. Wingate-Pearse:Galena Biopharma, Inc.: Employment. Barriere:Galena Biopharma, Inc.: Other: Contract Research Organization. Beeson:Galena Biopharma, Inc.: Other: Contract Research Organization. Glidden:Galena Biopharma, Inc.: Consultancy, Equity Ownership, Patents & Royalties: N/A. Choy:Galena Biopharma, Inc.: Employment.