Open AccessPF ‐04447943, a Phosphodiesterase 9A Inhibitor, in Stable Sickle Cell Disease Patients: A Phase Ib Randomized, Placebo‐Controlled Study
Author(s) -
Charnigo Robert J.,
Beidler David,
Rybin Denis,
Pittman Debra D.,
Tan Beesan,
Howard Jo,
Michelson Alan D.,
Frelinger Andrew L.,
Clarke Nicholas
Publication year - 2019
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/cts.12604
Subject(s) - medicine , placebo , pharmacodynamics , adverse effect , pharmacokinetics , randomization , pharmacology , sickle cell anemia , platelet , hydroxycarbamide , gastroenterology , randomized controlled trial , disease , pathology , alternative medicine
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 ( PK s)/pharmacodynamics ( PD s). 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.