Mobilization of hematopoietic stem cells with the novel CXCR4 antagonist POL6326 (balixafortide) in healthy volunteers\u2014results of a dose escalation trial

Hans Martin,Halvard Bonig,Eric Chevalier,Ariane Krämer,Klaus Dembowski,Susanne Bräuninger,Eliza Wiercinska,Darja Karpova,Belinda Stock,Christophe Escot,Garry Douglas,Leon Hooftman,Achim Wach,Jochen Graff,Barbara Romagnoli

doi:10.1186/s12967-016-1107-2

Abstract

BackgroundCertain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. We herein report results of a Phase I dose escalation trial comparing mobilization with a peptidic CXCR4 antagonist POL6326 (balixafortide) vs. G-CSF.MethodsHealthy male volunteer donors with a documented average mobilization response to G-CSF received, following ≥6 weeks wash-out, a 1–2 h infusion of 500–2500 µg/kg of balixafortide. Safety, tolerability, pharmacokinetics and pharmacodynamics were assessed.ResultsBalixafortide was well tolerated and rated favorably over G-CSF by subjects. At all doses tested balixafortide mobilized HSPC. In the dose range between 1500 and 2500 µg/kg mobilization was similar, reaching 38.2 ± 2.8 CD34 + cells/µL (mean ± SEM). Balixafortide caused mixed leukocytosis in the mid-20 K/µL range. B-lymphocytosis was more pronounced, whereas neutrophilia and monocytosis were markedly less accentuated with balixafortide compared to G-CSF. At the 24 h time point, leukocytes had largely normalized.ConclusionsBalixafortide is safe, well tolerated, and induces efficient mobilization of HSPCs in healthy male volunteers. Based on experience with current apheresis technology, the observed mobilization at doses ≥1500 µg/kg of balixafortide is predicted to yield in a single apheresis a standard dose of 4× 10E6 CD34+ cells/kg from most individuals donating for an approximately weight-matched recipient. Exploration of alternative dosing regimens may provide even higher mobilization responses.Trial Registration European Medicines Agency (EudraCT-Nr. 2011-003316-23) and clinicaltrials.gov (NCT01841476)

Highlights

Certain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives
The synthetic protein epitope mimetic (PEM) peptidic CXCR4 antagonist POL5551, a close analogue of the clinical stage compound balixafortide (POL6326), shows a very wide pharmacodynamic range in preclinical models and at optimal doses even mobilizes more efficiently than G-CSF [16]. In this clinical phase I dose escalation trial we evaluated balixafortide with regard to its safety, tolerability, pharmacokinetics and mobilization efficiency in healthy male volunteers in comparison to G-CSF
At the time of follow-up, volunteers were questioned about their subjective rating of G-CSF vs. balixafortide as mobilizing agents; there was an overwhelming preference for balixafortide

Summary

Introduction

Certain disadvantages of the standard hematopoietic stem and progenitor cell (HSPC) mobilizing agent G-CSF fuel the quest for alternatives. Most autologous and 80% of allogeneic hematopoietic stem cell transplantations (HSCT) are currently performed with mobilized peripheral blood stem cells [1]. These can be extracted by apheresis from the circulation after pretreatment of donors with the cytokine G-CSF, currently the most commonly used mobilizing agent [1]. Significant activity has been dedicated to the identification and development of alternative mobilizing agents that would combine predictable, efficient stem cell mobilization with single dose activity and good tolerability for both donor and recipient

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