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

Clin Transl Sci. 2019 Mar;12(2):180-188. doi: 10.1111/cts.12604. Epub 2018 Dec 31.

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.

Trial registration: ClinicalTrials.gov NCT02114203.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors*
  • Adolescent
  • Adult
  • Aged
  • Anemia, Sickle Cell / blood
  • Anemia, Sickle Cell / diagnosis
  • Anemia, Sickle Cell / drug therapy*
  • Biomarkers / blood
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Administration Schedule
  • Drug Therapy, Combination / adverse effects
  • Drug Therapy, Combination / methods
  • E-Selectin / blood
  • Female
  • Humans
  • Hydroxyurea / administration & dosage
  • Hydroxyurea / adverse effects
  • Male
  • Middle Aged
  • Phosphodiesterase Inhibitors / administration & dosage*
  • Phosphodiesterase Inhibitors / adverse effects
  • Phosphodiesterase Inhibitors / pharmacokinetics
  • Placebos / administration & dosage
  • Placebos / adverse effects
  • Platelet Aggregation / drug effects
  • Pyrazoles / administration & dosage*
  • Pyrazoles / adverse effects
  • Pyrazoles / pharmacokinetics
  • Pyrimidinones / administration & dosage*
  • Pyrimidinones / adverse effects
  • Pyrimidinones / pharmacokinetics
  • Treatment Outcome
  • Young Adult

Substances

  • 6-(4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo(3,4-d)pyrimidin-4-one
  • Biomarkers
  • E-Selectin
  • Phosphodiesterase Inhibitors
  • Placebos
  • Pyrazoles
  • Pyrimidinones
  • SELE protein, human
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • PDE9A protein, human
  • Hydroxyurea

Associated data

  • ClinicalTrials.gov/NCT02114203