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GALE-401 - Galena Biopharma

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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.
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