| Reference | 1. Cancer Res. 2016 Aug 15;76(16):4841-4849. doi: 10.1158/0008-5472.CAN-15-3062.
Epub 2016 Jun 10.
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Pexmetinib: A Novel Dual Inhibitor of Tie2 and p38 MAPK with Efficacy in
Preclinical Models of Myelodysplastic Syndromes and Acute Myeloid Leukemia.
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Bachegowda L(#)(1), Morrone K(#)(1), Winski SL(#)(2), Mantzaris I(#)(1),
Bartenstein M(1), Ramachandra N(1), Giricz O(1), Sukrithan V(1), Nwankwo G(1),
Shahnaz S(1), Bhagat T(1), Bhattacharyya S(1), Assal A(1), Shastri A(1),
Gordon-Mitchell S(1), Pellagatti A(3), Boultwood J(3), Schinke C(1), Yu Y(1),
Guha C(1), Rizzi J(2), Garrus J(2), Brown S(2), Wollenberg L(2), Hogeland G(2),
Wright D(2), Munson M(2), Rodriguez M(2), Gross S(2), Chantry D(2), Zou Y(1),
Platanias L(4), Burgess LE(2), Pradhan K(1), Steidl U(1), Verma A(1).
<br>
Author information: <br>
(1)Albert Einstein College of Medicine, Bronx , NY.
(2)Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80304 USA.
(3)LLR Molecular Haematology Unit, NDCLS, John Radcliffe Hospital, and NIHR
Biomedical Research Centre, Oxford, UK.
(4)Northwestern University, Chicago, IL.
(#)Contributed equally
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Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) suppress normal
hematopoietic activity in part by enabling a pathogenic inflammatory milieu in
the bone marrow. In this report, we show that elevation of angiopoietin-1 in
myelodysplastic CD34(+) stem-like cells is associated with higher risk disease
and reduced overall survival in MDS and AML patients. Increased angiopoietin-1
expression was associated with a transcriptomic signature similar to known
MDS/AML stem-like cell profiles. In seeking a small-molecule inhibitor of this
pathway, we discovered and validated pexmetinib (ARRY-614), an inhibitor of the
angiopoietin-1 receptor Tie-2, which was also found to inhibit the
proinflammatory kinase p38 MAPK (which is overactivated in MDS). Pexmetinib
inhibited leukemic proliferation, prevented activation of downstream effector
kinases, and abrogated the effects of TNFα on healthy hematopoietic stem cells.
Notably, treatment of primary MDS specimens with this compound stimulated
hematopoiesis. Our results provide preclinical proof of concept for pexmetinib as
a Tie-2/p38 MAPK dual inhibitor applicable to the treatment of MDS/AML. Cancer
Res; 76(16); 4841-9. ©2016 AACR.
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2. Clin Pharmacol. 2015 Sep 30;7:87-95. doi: 10.2147/CPAA.S83871. eCollection 2015.
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An exploratory, randomized, parallel-group, open-label, relative bioavailability
study with an additional two-period crossover food-effect study exploring the
pharmacokinetics of two novel formulations of pexmetinib (ARRY-614).
<br>
Wollenberg LA(1), Corson DT(2), Nugent CA(1), Peterson FL(1), Ptaszynski AM(1),
Arrigo A(2), Mannila CG(2), Litwiler KS(1), Bell SJ(3).
<br>
Author information: <br>
(1)Array BioPharma, Boulder, CO, USA.
(2)Array BioPharma, Longmont, CO, USA ; Avista Pharma Solutions, Longmont, CO,
USA.
(3)Array BioPharma, Boulder, CO, USA ; Mallinckrodt Pharmaceuticals, Ellicott
City, MD, USA.
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BACKGROUND: Pexmetinib (ARRY-614) is a dual inhibitor of p38 mitogen-activated
protein kinase and Tie2 signaling pathways implicated in the pathogenesis of
myelodysplastic syndromes. Previous clinical experience in a Phase I
dose-escalation study of myelodysplastic syndrome patients using pexmetinib
administered as neat powder-in-capsule (PIC) exhibited high variability in
pharmacokinetics and excessive pill burden, prompting an effort to improve the
formulation of pexmetinib.<br>
METHODS: A relative bioavailability assessment encompassed three parallel
treatment cohorts of unique subjects comparing the two new formulations (12
subjects per cohort), a liquid oral suspension (LOS) and liquid-filled capsule
(LFC) and the current clinical PIC formulation (six subjects) in a fasted state.
The food-effect assessment was conducted as a crossover of the LOS and LFC
formulations administered under fed and fasted conditions. Subjects were divided
into two groups of equal size to evaluate potential period effects on the
food-effect assessment.<br>
RESULTS: The geometric mean values of the total plasma exposures based upon
area-under-the-curve to the last quantifiable sample (AUClast) of pexmetinib were
approximately four- and twofold higher after administration of the LFC and LOS
formulations, respectively, than after the PIC formulation, when the formulations
were administered in the fasted state. When the LFC formulation was administered
in the fed state, pexmetinib AUClast decreased by <5% compared with the fasted
state. After administration of the LOS formulation in the fed state, pexmetinib
AUClast was 34% greater than observed in the fasted state.<br>
CONCLUSION: These results suggest that the LFC formulation of pexmetinib may
achieve greater exposures with lower doses due to the greater bioavailability
compared to the PIC, and remain unaffected by coadministration with food.
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