Page 109 - Haematologica March 2020

Red Cell Biology & its Disorders
A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease
Ferrata Storti Foundation
Haematologica 2020 Volume 105(3):623-631
James G. McArthur,1 Niels Svenstrup,2 Chunsheng Chen,3 Aurelie Fricot,4 Caroline Carvalho,4 Julia Nguyen,3 Phong Nguyen,3 Anna Parachikova,2 Fuad Abdulla,3 Gregory M. Vercellotti,3 Olivier Hermine,4 Dave Edwards,5 Jean-Antoine Ribeil,6 John D. Belcher3 and Thiago T. Maciel4
1Imara Inc., 2nd Floor, 700 Technology Square, Cambridge, MA, USA; 2H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark; 3Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA; 4INSERM UMR 1163, CNRS ERL 8254, Imagine Institute, Laboratory of Excellence GR-Ex, Paris Descartes - Sorbonne Paris Cité University, Paris, France; 5Kinexum, 8830 Glen Ferry Drive, Johns Creek, GA, USA and 6Departments of Biotherapy, Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris Descartes- Sorbonne Paris Cité University, Paris, France
ABSTRACT
The most common treatment for patients with sickle cell disease (SCD) is the chemotherapeutic hydroxyurea, a therapy with pleiotropic effects, including increasing fetal hemoglobin (HbF) in red blood cells and reducing adhesion of white blood cells to the vascular endothelium. Hydroxyurea has been proposed to mediate these effects through a mechanism of increasing cellular cGMP levels. An alternative path to increasing cGMP levels in these cells is through the use of phospho- diesterase-9 inhibitors that selectively inhibit cGMP hydrolysis and increase cellular cGMP levels. We have developed a novel, potent and selective phosphodiesterase-9 inhibitor (IMR-687) specifically for the treatment of SCD. IMR-687 increased cGMP and HbF in erythroid K562 and UT-7 cells and increased the percentage of HbF positive erythroid cells generated in vitro using a two-phase liquid culture of CD34+ progenitors from sickle cell blood or bone marrow. Oral daily dosing of IMR-687 in the Townes transgenic mouse SCD model, increased HbF and reduced red blood cell sickling, immune cell activation and microvascular stasis. The IMR-687 reduction in red blood cell sickling and immune cell activation was greater than that seen with physiological doses of hydroxyurea. In contrast to other described phosphodiesterase-9 inhibitors, IMR-687 did not accumulate in the central nervous system, where it would inhibit phosphodiesterase-9 in neurons, or alter rodent behavior. IMR-687 was not genotoxic or myelotox- ic and did not impact fertility or fetal development in rodents. These data suggest that IMR-687 may offer a safe and effective oral alternative for hydroxyurea in the treatment of SCD.
Introduction
Sickle cell disease (SCD) is a genetic disease arising from a point mutation in the HBB gene that leads to the polymerization of hemoglobin S (HbS) during deoxy- genation.1-5 HbS forms long chains of polymers that deform red blood cells (RBC) into a sickle shape, which impairs RBC transit in smaller blood vessels and renders them prone to hemolysis.6,7 Increased RBC lysis and release of free HbS scavenges nitric oxide (NO) and promotes vasoconstriction, which further alters vascular biol- ogy.8-10 This process in turn promotes the activation and mobilization of white blood cells (WBC), increasing their adhesiveness to activated endothelium.11-16 These pathological manifestations in RBC and WBC in SCD ultimately result in painful vaso-occlusive crises, end-organ damage, and, in many cases, premature death.17-19
Correspondence:
JAMES G. MCARTHUR
jmcarthur@cydanco.com
Received: December 7, 2018. Accepted: May 27, 2019. Pre-published: May 30, 2019.
doi:10.3324/haematol.2018.213462
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/3/623
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