Abstract #3178 Phase 1 Study Results of a Novel Controlled-Release Formulation of Anagrelide (GALE-401) for the Treatment of Thrombocytosis Robert J. Laliberte, MS, Paul F. Glidden, PhD and Brian L. Hamilton, MD, PhD Galena Biopharma, Inc., Portland, OR 56th ASH Annual Meeting and Exposition, Dec. 6-9, 2014 Introduction Phase 1 Trials in Healthy Adult Subjects Ongoing Phase 2 Trial in MPN-Related Thrombocytosis Despite recent advances in the diagnosis and management of myeloproliferative neoplasms (MPNs), treatment of essential thrombocythemia (ET) has remained largely unchanged since the introduction of anagrelide in the US during 1997. Anagrelide is indicated for the treatment of thrombocythemia, to reduce the elevated platelet count and risk of thrombosis, and to ameliorate symptoms including thrombohemorrhagic events. Summary of Trial Designs PD Results: Effect on Platelet Count Study Objective & Design • 98 healthy adult subjects were enrolled among 5 Phase 1 clinical trials of Anagrelide CR, including 12 placebo-control subjects and 86 subjects who received single or multiple doses ranging from 0.2 to 0.6 mg twice daily (b.i.d.) for up to 41 days. • Platelet lowering effect was evident in the multiple dose studies. • Primary Objective: Estimate response rate in terms of platelet reduction in subjects with an MPN-related thrombocytosis. The primary pharmacological effect of anagrelide is inhibition of megakaryocyte hypermaturation leading to reduced platelet production. Anagrelide also inhibits cyclic AMP phosphodiesterase III (PDE3), and common drug related adverse events (AEs; e.g., headache, palpitations, fluid retention, nausea and diarrhea) are believed to be due to this mechanism. Although initiating treatment at low doses and slowly increasing the dose to reach a target decreased platelet count may mitigate AEs, over 20% of patients still withdraw from treatment due to poor tolerability. • The trials included an open-label, single dose developmental study to select a formulation; two placebo-controlled multiple dose ranging studies; a food effect study; and a comparative crossover PK study vs. IR reference product. As the currently marketed anagrelide product is an immediate release (IR) formulation with peak plasma concentrations (Cmax) that may exceed that needed for platelet reduction and cause unwanted PDE3 inhibition and AEs, an alternate formulation that modifies this pharmacokinetic (PK) profile may improve patient tolerability, adherence and treatment outcomes. This has led to the development and study of a controlled-release (CR) formulation of anagrelide (GALE-401). • Anagrelide CR demonstrated dose proportional PK characteristics. Here we present the results of Phase 1 clinical trials of GALE-401 in healthy volunteers and preliminary results from an ongoing Phase 2 trial in patients with MPN-related thrombocytosis. o Total daily dose and treatment duration is limited by expected platelet lowering effects. • Anagrelide CR (GALE-401) is a promising, novel formulation of anagrelide that exhibited the desired PK profile of a significantly reduced Cmax, while maintaining plasma exposure to induce platelet count reductions. • The product was well tolerated with an AE profile that was not distinguishable from placebo at the doses studied in the Phase 1 trials in healthy adult subjects. • Safety assessed by frequency and severity of AEs using NCI CTCAE v4.03. Key Eligibility Criteria • Age ≥18 yrs with any of the following MPN diagnosis: Chronic myelogenous leukemia (CML), Polycythemia vera (PV), Primary myelofibrosis (PMF) or ET. • Baseline platelet count ≥600 x 109/L as determined on two occasions. • Requirement for platelet reduction therapy as assessed by the Investigator. PK Results • Currently not receiving therapy specifically intended to reduce platelet counts. GALE-401 Study Drug Administration • Plasma exposure was higher when CR was administered in the fed state, as demonstrated by the ratio of least-squares mean values for Cmax and AUC0-t, which were increased by 100% and 60%, respectively. • Starting dose: 0.5 mg b.i.d. (1.0 mg/day). • Titrate dose (0.5 mg/day/wk) to maintain platelet count of 150 - 400 x 109/L. • Following a 0.5 mg dose of Anagrelide CR in the fasted state: Preliminary Results* o Mean time to maximum plasma concentration (Tmax) and terminal elimination half-life (t1/2) were 2.0±1.5 hrs and 10.4±9.3 hrs (mean ± SD), respectively. Cmax and total plasma exposure (AUC0-inf) were reduced to 26% and 59% of IR. o Steady-state PK following 6 daily 0.5 mg b.i.d. doses of Anagrelide CR or IR showed similar AUC0-inf values, while Cmax with CR remained nearly unchanged (29% of IR). • 18 subjects enrolled: 13 ET, 4 PV, 1 PMF • Anagrelide CR did not have a relevant impact on platelet function as assessed by template bleeding time. • In a cross-over, multiple dose study of Anagrelide CR and IR (0.5mg b.i.d., N=20 subjects), similar reductions in platelet counts were observed despite differences in PK exposure (see PK results). o First subject initiated study treatment on 06 Sep 2014. • Prior Treatments: Hydroxyurea (n=8), Anagrelide IR (n=6), None (n=7) • Rapid reductions in platelet counts observed with dose titration: Mean Platelet Count (± SD) 1600 Mean Platelet Count Anagrelide Plasma PK CR Ratio of Arithmetic Mean CR : IR IR (GALE-401) Day 7-9 CR 350 Ratio of Arithmetic Mean CR : IR IR (GALE-401) Cmax (pg/mL) 722 2800 25.8% 633 2210 29% AUC0-12 or τ (pg*h/mL) 3066 6919 44% 2960 5503 54% AUC0-t (pg*h/mL) 3660 6878 53% 4409 5456 81% AUC0-inf (pg*h/mL) 4079 6960 59% 5542 5586 99.2% t1/2 (h) 10.4 1.4 -- 19.6 1.6 -- 1400 1200 Platelet Count (x109/L) 300 800 250 600 400 200 200 Study Day: 3000 -1 Study Drug (0.5mg): AM PM 1 2 3 4 5 6 7 X X X X X X X X X X X 8 9 10 11 12 13 14 21 Anagrelide (CR: GALE-401) 2500 0 Study Day: 1 8 15 22 29 36 43 50 57 64 Week: 1 2 3 4 5 6 7 8 9 10 Number** of subjects: 18 18 17 17 13 10 8 4 4 3 Average dose (mg/day): 1.0 1.4 1.9 1.9 1.8 2.1 2.3 2.4 2.3 3.0 Anagrelide (IR capsule) Safety Results 3-OH Anagrelide (CR: GALE-401) 2000 Plasma conc. (pg/mL) Anagrelide IR 150 Mean Plasma Levels Following 0.5 mg b.i.d. Dosing (Day 7) 1000 Platelet Count (x109/L) Anagrelide CR 3-OH Anagrelide (IR capsule) • Single doses of Anagrelide CR were well tolerated, and the only drugrelated AE reported in 2 or more subjects was headache. 1500 • In the b.i.d. dose-ranging studies, the frequency and severity of AEs were similar between Anagrelide CR and placebo groups, with the exception of decreased platelet counts in subjects receiving anagrelide CR. 500 RJL, BLH: Galena Biopharma, Inc.: Employment, Equity Ownership PFG: Galena Biopharma Inc.: Consultancy, Equity Ownership, Patents & Royalties • Up-to 20 subjects to be enrolled/treated. • Safety assessments included laboratory, ECG, and clinical evaluations. 1000 CONFLICT OF INTEREST DISCLOSURE o Partial response (PR): ≤600 x 109/L or a ≥50% reduction from baseline for ≥4 weeks • Open-label, single-arm, multicenter, exploratory Phase 2 study. • Pharmacodynamic (PD) activity was assessed by daily platelet count determinations in the multiple dosing studies. • Dose-related reductions in platelet counts were observed and was similar to IR formulation in a crossover, multiple dose study. • These data support the importance of an ongoing Phase 2 study in patients with MPN-related thrombocytosis, including ET. o Complete response (CR): ≤400 x 109/L for ≥4 weeks o Nonresponse: failure to meet CR or PR criteria • PK was assessed by measurements of plasma anagrelide and its active metabolite (3-hydroxy anagrelide) by HPLC-MS/MS. Day 1-2 Conclusions • In a placebo-controlled study of 0.2 to 0.6 mg b.i.d. dosing for up to 21 days (n=8 subjects/cohort randomized 2:1 to anagrelide or placebo), a dose-related decrease in platelet counts was observed, and the 0.6 mg cohort was halted early due to excessive platelet reductions. 0 0 2 4 6 8 10 12 14 Time Post-Dose (Hours) 16 18 20 22 24 • All AEs were transient, mild or moderate in severity, and no severe or serious AEs were reported. • Platelet responses to-date include confirmed and unconfirmed CRs and PRs among 9 subjects. • AEs reported in 2 or more subjects regardless of relationship to study drug: headache (5 subjects), abdominal pain (3), fatigue (3), nausea (3), AST elevation (2), diarrhea (2), edema (2), and tachycardia (2), all Grade 1 or 2. • 1 subject withdrew at Week 7 for personal reasons (subject request). -------------------------------* Preliminary data available in the study database as of 01DEC2014. ** Number of subjects with platelet data as of the data cut-off date.