Page 116 - Haematologica March 2020

J.G. McArthur et al.
ment could trigger cognitive modulation of unknown con- sequences with chronic therapy.
Discussion
Previous groups have described that reticulocytes and neutrophils from SCD patients express elevated levels of PDE9 and that exposure to a PDE9 inhibitor reduced the adhesive properties and extravagation of neutrophils in sickle cell models.38,39 They also reported the ability of this PDE9i to increase HbF mRNA levels in K562 cells. We describe a novel non-brain penetrant PDE9i, IMR- 687, and its ability to increase HbF protein expression in human cell lines, patient-derived cells, and mouse mod- els of SCD, and reduce many of the associated disease pathologies, including reduced RBC sickling and hemol- ysis, and normalization of WBC counts. Normalization of hemolysis is one of the major key improvements in SCD pathophysiology, having the potential to impact hemolytic-related complications. This is the first demon- stration of the reduction in hemolysis by a PDE9i. IMR- 687 treatment was also efficacious in a model of vaso- occlusive crisis, preventing in vivo microvascular occlu- sion following a transient hypoxic insult. These effects were similar to the benefits seen with a high dose of HU, associated with mortality in the mouse model that was associated with some lethality in mice and cellular toxic- ity in vitro.
Hydroxyurea has been associated with activity in mul- tiple pathways beyond cGMP, including cAMP, c-Jun kinases, epigenetic modification, and regulation of miRNA.56 It is, therefore, intriguing that many of the ben- eficial RBC and WBC effects of HU therapy in models of SCD are recapitulated by inhibitors to a PDE9 enzyme at daily doses that were safe and well tolerated. This sug- gests that an optimized dose of IMR-687 may be useful as a single agent therapy for SCD. That said, IMR-687 may also have a role in combination with low-dose HU in refractory patients. This may open the way for a new
group of patients to see the full benefits of HU. Data in the Townes mouse model suggested that IMR-687 and HU together had an additive effect in reducing vaso- occlusion. This effect did not seem to be mediated by an additive effect on induction of HbF or reduction in RBC sickling. It may have been through an additive effect in NO modulation; this remains hypothetical, although not unexpected, given the robust reduction in hemolysis seen with IMR-687 which would reduce the release of heme, an NO scavenger. Clinically, IMR-687 is being tested in adult SCD patients both as a solo therapy and in those taking HU.
IMR-687 was purposefully developed for SCD, selected not only for its potency and selectivity, but also its low brain exposure to avoid concerns about modulating cogni- tive function, especially in children with SCD. The data presented in this report indicate that, in the context of SCD models, IMR-687 has many of the beneficial in vitro and in vivo properties of HU without its attendant toxici- ties. Furthermore, many of the positive changes associated with HU are sufficiently recapitulated by selective target- ing of the PDE9 pathway, which acts through increases in cGM, culminates in increased HbF and ameliorates RBC pathology. This offers significant advantages over drugs that increase cGMP systemically, impacting cells that are not necessarily suitable targets, and mediating side effects such as hypotension. The clinical development of a safe, well-tolerated, orally available drug like IMR-687, with low CNS exposure, acting through the PDE9 pathway, may offer an improved single treatment option for patients living with SCD. In the light of these findings, clinical studies are underway to determine if IMR-687 might offer a safe, well-tolerated and efficacious alterna- tive to HU therapy for SCD patients.
Acknowledgments
PDE selectivity assays were performed by SB Drug Discovery (Glasgow, UK). We thank Dr. Michael Dussiot for his assis- tance on Amnis Imaging Flow Cytometer experiment and data analysis.
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