PF-04447943, a Phosphodiesterase 9A Inhibitor, in Stable Sickle Cell Disease Patients: A Phase Ib Randomized, Placebo-Controlled Study
Robert J Charnigo, David Beidler, Denis Rybin, Debra D Pittman, Beesan Tan, Jo Howard, Alan D Michelson, Andrew L Frelinger , III, Nicholas Clarke, Robert J Charnigo, David Beidler, Denis Rybin, Debra D Pittman, Beesan Tan, Jo Howard, Alan D Michelson, Andrew L Frelinger , III, Nicholas Clarke
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.
Conflict of interest statement
R.J.C., D.B., D.R., D.D.P., and N.C. are employees of Pfizer Inc and may own stock/options in the company. B.T. was an employee of Pfizer, Inc at the time of this study. J.H. is a consultant for Bluebird Bio, GBT, and Pfizer, and a member of the Speakers’ Bureau for Addmedica, Novartis, and Terumo BCT. A.D.M. has served as a consultant for Instrumentation Laboratory; receives research funding from Baxalta, Eisai, GLSynthesis, Ionis, Ironwood, Pfizer, and Sysmex; and is a member of advisory committees for AstraZeneca and Janssen. A.L.F. has received research funding from Baxalta, Eisai, GLSynthesis, Ionis, Ironwood, Pfizer, and Sysmex.
© 2018 Pfizer Inc. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.
Figures
References
- Piel, F.B. , Steinberg, M.H. & Rees, D.C. Sickle cell disease. N. Engl. J. Med. 376, 1561–1573 (2017).
- Almeida, C.B. et al Hydroxyurea and a cGMP‐amplifying agent have immediate benefits on acute vaso‐occlusive events in sickle cell disease mice. Blood 120, 2879–2888 (2012).
- Hassell, K.L. Population estimates of sickle cell disease in the U.S. Am. J. Prev. Med. 38, S512–S521 (2010).
- Piel, F.B. , Hay, S.I. , Gupta, S. , Weatherall, D.J. & Williams, T.N. Global burden of sickle cell anaemia in children under five, 2010‐2050: modelling based on demographics, excess mortality, and interventions. PLoS Med. 10, e1001484 (2013).
- Hoover, R. , Rubin, R. , Wise, G. & Warren, R. Adhesion of normal and sickle erythrocytes to endothelial monolayer cultures. Blood 54, 872–876 (1979).
- Turhan, A. , Weiss, L.A. , Mohandas, N. , Coller, B.S. & Frenette, P.S. Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm. Proc. Natl. Acad. Sci. USA 99, 3047–3051 (2002).
- Belcher, J.D. et al Critical role of endothelial cell activation in hypoxia‐induced vasoocclusion in transgenic sickle mice. Am. J. Physiol. Heart Circ. Physiol. 288, H2715–H2725 (2005).
- Zennadi, R. , Chien, A. , Xu, K. , Batchvarova, M. & Telen, M.J. Sickle red cells induce adhesion of lymphocytes and monocytes to endothelium. Blood 112, 3474–3483 (2008).
- Frenette, P.S. & Atweh, G.F. Sickle cell disease: old discoveries, new concepts, and future promise. J. Clin. Invest. 117, 850–858 (2007).
- Zhang, D. , Xu, C. , Manwani, D. & Frenette, P.S. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood 127, 801–809 (2016).
- Powars, D.R. , Chan, L.S. , Hiti, A. , Ramicone, E. & Johnson, C. Outcome of sickle cell anemia: a 4‐decade observational study of 1056 patients. Medicine 84, 363–376 (2005).
- Platt, O.S. et al Pain in sickle cell disease. Rates and risk factors. N. Engl. J. Med. 325, 11–16 (1991).
- Darbari, D.S. et al Severe painful vaso‐occlusive crises and mortality in a contemporary adult sickle cell anemia cohort study. PLoS One 8, e79923 (2013).
- Canalli, A.A. , Franco‐Penteado, C.F. , Saad, S.T. , Conran, N. & Costa, F.F. Increased adhesive properties of neutrophils in sickle cell disease may be reversed by pharmacological nitric oxide donation. Haematologica 93, 605–609 (2008).
- Cokic, V.P. et al Hydroxyurea induces fetal hemoglobin by the nitric oxide‐dependent activation of soluble guanylyl cyclase. J. Clin. Invest. 111, 231–239 (2003).
- Kleiman, R.J. et al Phosphodiesterase 9A regulates central cGMP and modulates responses to cholinergic and monoaminergic perturbation in vivo. J. Pharmacol. Exp. Ther. 341, 396–409 (2012).
- Hutson, P.H. et al The selective phosphodiesterase 9 (PDE9) inhibitor PF‐04447943 (6‐[(3S,4S)‐4‐methyl‐1‐(pyrimidin‐2‐ylmethyl)pyrrolidin‐3‐yl]‐1‐(tetrahydro‐2H‐py ran‐4‐yl)‐1,5‐dihydro‐4H‐pyrazolo[3,4‐d]pyrimidin‐4‐one) enhances synaptic plasticity and cognitive function in rodents. Neuropharmacology 61, 665–676 (2011).
- Verhoest, P.R. et al Design and discovery of 6‐[(3S,4S)‐4‐methyl‐1‐(pyrimidin‐2‐ylmethyl)pyrrolidin‐3‐yl]‐1‐(tetrahydro‐2H‐pyr an‐4‐yl)‐1,5‐dihydro‐4H‐pyrazolo[3,4‐d]pyrimidin‐4‐one (PF‐04447943), a selective brain penetrant PDE9A inhibitor for the treatment of cognitive disorders. J. Med. Chem. 55, 9045–9054 (2012).
- Vardigan, J.D. , Converso, A. , Hutson, P.H. & Uslaner, J.M. The selective phosphodiesterase 9 (PDE9) inhibitor PF‐04447943 attenuates a scopolamine‐induced deficit in a novel rodent attention task. J. Neurogenet. 25, 120–126 (2011).
- Wu, L.C. , Sun, C.W. , Ryan, T.M. , Pawlik, K.M. , Ren, J. & Townes, T.M. Correction of sickle cell disease by homologous recombination in embryonic stem cells. Blood 108, 1183–1188 (2006).
- Jasuja, R. , Patel Hett, S. , Fruebis, J. & Pittman, D. PDE‐9 inhibition combined with hydroxyurea is beneficial in vaso‐occlusive crisis in mouse model of sickle cell disease [abstract]. Blood 124, 2694 (2014).
- Jasuja, R. , Parks, E. , Murphy, J.E. & Pittman, D.D. Chronic administration of the PDE9 inhibitor PF‐04447943 reduces leukocyte‐platelet aggregates and markers of endothelial activation in a mouse model of sickle cell disease [abstract]. Blood 128, 1293 (2016).
- Evans, R.M. et al Safety and pharmacokinetics of PF‐04447943, a PDEA inhibitor, in single and multiple dose phase 1 studies in healthy volunteers [abstract O3‐05‐04]. Alzheimers Dement. 6, S135 (2010).
- Nicholas, T. et al PF‐04447943, a novel PDE9A inhibitor, increases CGMP levels in cerebrospinal fluid: translation from non‐clinical species to healthy human volunteers [abstract P2‐240]. Alzheimers Dement. 5, P330–P331 (2009).
- Schwam, E.M. et al A multicenter, double‐blind, placebo‐controlled trial of the PDE9A inhibitor, PF‐04447943 Alzheimer's disease. Curr. Alzheimer Res. 11, 413–421 (2014).
- Michelson, A.D. , Barnard, M.R. , Krueger, L.A. , Frelinger, A.L. III & Furman, M.I. Evaluation of platelet function by flow cytometry. Methods 21, 259–270 (2000).
- Gerrits, A.J. , Frelinger, A.L. III & Michelson, A.D. Whole blood analysis of leukocyte‐platelet aggregates. Curr. Protoc. Cytom. 78, 6.15.1–6.15.10 (2016).
- R Core Team . R: a language and environment for statistical computing. R Foundation for Statistical Computing <>. (2016) Accessed: October 9, 2018.
- Xie, R. , Tan, B. & Harnisch, L.O . Population pharmacokinetics of PF‐04447943 in health volunteers and adult patients with Alzheimer's disease or sickle cell disease [poster]. Presented at: Annual Meeting of the Population Approach Group in Europe; June 6–9, 2017; Budapest, Hungary.
- Chang, J. , Patton, J.T. , Sarkar, A. , Ernst, B. , Magnani, J.L. & Frenette, P.S. GMI‐1070, a novel pan‐selectin antagonist, reverses acute vascular occlusions in sickle cell mice. Blood 116, 1779–1786 (2010).
- Wun, T. et al Phase 1 study of the E‐selectin inhibitor GMI 1070 in patients with sickle cell anemia. PLoS One 9, e101301 (2014).
- Telen, M.J. et al Randomized phase 2 study of GMI‐1070 in SCD: reduction in time to resolution of vaso‐occlusive events and decreased opioid use. Blood 125, 2656–2664 (2015).
Source: PubMed