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.

Trial registration: ClinicalTrials.gov NCT02114203.

Figure 1

Schematic of the study design. Cohort 1 received 25 mg PF‐04447943 or placebo twice a day for 29 days (n = 15,^a 3:1 active‐placebo ratio). Cohort 2 received 5 mg PF‐04447943 or placebo twice a day for 29 days (n = 7, 3:1 active‐placebo ratio). CI, confidence interval; HU, hydroxyurea; ICAM, intercellular adhesion molecule; RBC, red blood cell; VCAM, vascular adhesion molecule. ^aOne patient discontinued after randomization (n=16) but before receiving study drug.

Figure 2

Percent change from baseline at day 29 in biomarkers with PF‐04447943 25 mg twice daily. The percent changes from baseline to day 29 in adhesion, aggregates, microparticle, coagulation, and hematology biomarkers are depicted in the forest plot. Estimates and 95% confidence intervals are based on repeated measures model. Statistically significant (P < 0.15 after multiplicity correction using Holm‐Bonferroni stepdown procedure) changes from baseline are indicated by an asterisk. CI, confidence interval; ICAM, intercellular adhesion molecule; MPA, monocyte‐platelet aggregates; NPA, neutrophil‐platelet aggregate; RBC, red blood cell; TAT, thrombin‐antithrombin; VCAM, vascular adhesion molecule.

Figure 3

Percent change from baseline at day 29 in cellular aggregates and soluble P‐selectin and E‐selectin levels. (a) Change in monocyte‐platelet aggregates, number, and size. (b) Change in neutrophil‐platelet aggregates, number, and size. (c) Change in plasma‐soluble E‐selectin and P‐selectin. Bars and whiskers represent estimates and 95% confidence intervals (CIs), based on repeated measures model. The P values of statistically significant (P < 0.15 after multiplicity correction using Holm‐Bonferroni stepdown procedure) changes from baseline are reported above corresponding estimates. MPA, monocyte‐platelet aggregates; NPA, neutrophil‐platelet aggregate.

Figure 4

Analysis of biomarkers by hydroxyurea (HU) use and fetal hemoglobin (HbF) levels. (a) Box and whiskers plot of HbF baseline levels (%) in patients (n = 27) with and without HU treatment. Boxes present area between 25th and 75th percentile values. Whiskers extend 1.5 of interquartile range from the box. Line within each box is the median value. The circles represent individual observations that could be considered outliers. (b) The percent changes from baseline at day 29 for biomarkers in subgroups of patients (PF‐04447943 25 mg twice daily), with vs. without HU cotreatment, and low vs. high baseline HbF levels. Low HbF levels were defined as < 10%, and high baseline HbF levels were 10% or higher, based on median of the sample distribution. Forest plot presents estimates and 95% confidence intervals, based on repeated measures model.