Dataset Information

PF-04447943, a Phosphodiesterase 9A Inhibitor, in Stable Sickle Cell Disease Patients: A Phase Ib Randomized, Placebo-Controlled Study.

ABSTRACT: This phase Ib study randomized patients with stable sickle cell disease (SCD) aged 18-65 years to twice-daily PF-04447943 (a phosphodiesterase 9A inhibitor; 5 or 25 mg) or placebo, with/without hydroxyurea coadministration, for up to 29 days. Blood samples were collected at baseline and various posttreatment time points for assessments of PF-04447943 pharmacokinetics (PKs)/pharmacodynamics (PDs). Change from baseline in potential SCD-related biomarkers was evaluated. Of 30 patients, 15 received hydroxyurea and 28 completed the study. PF-04447943, with/without hydroxyurea, was generally well tolerated, with no treatment-related serious adverse events. Plasma PF-04447943 exposure was dose proportional. Twice-daily PF-04447943 25 mg significantly reduced the number and size of circulating monocyte-platelet and neutrophil-platelet aggregates and levels of circulating soluble E-selectin at day 29 vs. baseline (adjusted P < 0.15). PF-04447943 demonstrated PK/PD effects suggestive of inhibiting pathways that may contribute to vaso-occlusion. This study also provides guidance regarding biomarkers for future SCD studies.

SUBMITTER: Charnigo RJ

PROVIDER: S-EPMC6440678 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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PF-04447943, a Phosphodiesterase 9A Inhibitor, in Stable Sickle Cell Disease Patients: A Phase Ib Randomized, Placebo-Controlled Study.

Charnigo Robert J RJ Beidler David D Rybin Denis D Pittman Debra D DD Tan Beesan B Howard Jo J Michelson Alan D AD Frelinger Andrew L AL Clarke Nicholas N

Clinical and translational science 20181231 2

This phase Ib study randomized patients with stable sickle cell disease (SCD) aged 18-65 years to twice-daily PF-04447943 (a phosphodiesterase 9A inhibitor; 5 or 25 mg) or placebo, with/without hydroxyurea coadministration, for up to 29 days. Blood samples were collected at baseline and various posttreatment time points for assessments of PF-04447943 pharmacokinetics (PKs)/pharmacodynamics (PDs). Change from baseline in potential SCD-related biomarkers was evaluated. Of 30 patients, 15 received ...[more]

PMID: 30597771

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Project description:BackgroundLow myocardial cGMP-PKG (cyclic guanosine monophosphate-protein kinase G) activity has been associated with increased cardiomyocyte diastolic stiffness in heart failure with preserved ejection fraction. Cyclic guanosine monophosphate is mainly hydrolyzed by PDE (phosphodiesterases) 5a and 9a. Importantly, PDE9a expression has been reported to be upregulated in human heart failure with preserved ejection fraction myocardium and chronic administration of a PDE9a inhibitor reverses preestablished cardiac hypertrophy and systolic dysfunction in mice subjected to transverse aortic constriction (TAC). We hypothesized that inhibiting PDE9a activity ameliorates diastolic dysfunction.MethodsTo examine the effect of chronic PDE9a inhibition, 2 diastolic dysfunction mouse models were studied: (1) TAC-deoxycorticosterone acetate and (2) Leprdb/db. PDE9a inhibitor (5 and 8 mg/kg per day) was administered to the mice via subcutaneously implanted osmotic minipumps for 28 days. The effect of acute PDE9a inhibition was investigated in intact cardiomyocytes isolated from TAC-deoxycorticosterone acetate mice. Atrial natriuretic peptide together with PDE9a inhibitor were administered to the isolated intact cardiomyocytes through the cell perfusate.ResultsFor acute inhibition, no cellular stiffness reduction was found, whereas chronic PDE9a inhibition resulted in reduced left ventricular chamber stiffness in TAC-deoxycorticosterone acetate, but not in Leprdb/db mice. Passive cardiomyocyte stiffness was reduced by chronic PDE9a inhibition, with no differences in myocardial fibrosis or cardiac morphometry. PDE9a inhibition increased the ventricular-arterial coupling ratio, reflecting impaired systolic function.ConclusionsChronic PDE9a inhibition lowers left ventricular chamber stiffness in TAC-deoxycorticosterone acetate mice. However, the usefulness of PDE9a inhibition to treat high-diastolic stiffness may be limited as the required PDE9a inhibitor dose also impairs systolic function, observed as a decline in ventricular-arterial coordination, in this model.

Dataset Information

PF-04447943, a Phosphodiesterase 9A Inhibitor, in Stable Sickle Cell Disease Patients: A Phase Ib Randomized, Placebo-Controlled Study.

Publications

PF-04447943, a Phosphodiesterase 9A Inhibitor, in Stable Sickle Cell Disease Patients: A Phase Ib Randomized, Placebo-Controlled Study.

Similar Datasets

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