A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease

Wun, Ted; Soulières, Denis; Frelinger, Andrew L.; Krishnamurti, Lakshmanan; Novelli, Enrico M.; Kutlar, Abdullah; Ataga, Kenneth I.; Knupp, Charles; McMahon, Lillian; Strouse, John J.; Zhou, Chunmei; Heath, Lori E.; Nwachuku, Chuke; Jakubowski, Joseph A.; Riesmeyer, Jeffrey S.; Winters, Kenneth J.

doi:10.1186/1756-8722-6-17

Cited by 65 publications

(59 citation statements)

References 30 publications

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“…Phase 2 randomized, double-blind, placebo-controlled studies to examine safety were completed in adults. 42 There were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rates (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo.…”

Section: Antiplatelet Therapymentioning

confidence: 88%

Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies

Manwani

Frenette

2013

Blood

293

183

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Recurrent and unpredictable episodes of vaso-occlusion are the hallmark of sickle cell disease. Symptomatic management and prevention of these events using the fetal hemoglobin–reactivating agent hydroxyurea are currently the mainstay of treatment. Discoveries over the past 2 decades have highlighted the important contributions of various cellular and soluble participants in the vaso-occlusive cascade. The role of these elements and the opportunities for therapeutic intervention are summarized in this review.

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Section: Antiplatelet Therapymentioning

confidence: 88%

Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies

Manwani

Frenette

2013

Blood

293

183

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“…Some novel agents that are currently in clinical trials induce HbF production (decitabine and HQK-1001), 26,27 inhibit the activation and adhesive function of neutrophils (GMI-1070) 28 and platelets (Prasugrel), 29 impair blood coagulation (Tinzaparin), 30 and decrease oxidative stress (omega-3 fatty acids and N-acetyl cysteine). 31,32 In particular, the randomized phase II study with GMI-1070 (Rivipansel), a pan selectin inhibitor, has shown that when given to SCD patients early in their hospitalization for treatment of vaso-occlusive events, it reduces the requirement for parenteral opioid analgesia and displays a trend toward decreased time to resolution as indicated by the patient's readiness for discharge from hospital.…”

Section: Discussionmentioning

confidence: 99%

Hydroxyurea with AKT2 inhibition decreases vaso-occlusive events in sickle cell disease mice

Barazia¹,

Li²,

Shabrani³

et al. 2015

Blood

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Key Points• Coadministration of HU and an AKT2 inhibitor has beneficial effects on acute vaso-occlusive events and survival in SCD mice.Heterotypic cell-cell adhesion and aggregation mediate vaso-occlusive events in patients with sickle cell disease (SCD). Although hydroxyurea (HU), an inducer of fetal hemoglobin, is the main therapy for treatment of SCD, it is unclear whether it has immediate benefits in acute vaso-occlusive events in SCD patients. Using real-time fluorescence intravital microscopy, we demonstrated that short-term coadministration of HU and Akti XII, an AKT2 inhibitor, efficiently reduced neutrophil adhesion and platelet-neutrophil aggregation in venules of Berkeley (SCD) mice challenged with tumor necrosis factor a (TNF-a) or hypoxia/reoxygenation. Importantly, compared with HU or Akti XII treatment alone, short-term treatment with both agents significantly improved survival in those mice. We found that the level of plasma nitric oxide species was elevated by HU but not Akti XII, AKT2 phosphorylation levels in activated neutrophils and platelets were reduced by Akti XII but not HU, and the expression of endothelial E-selectin and intercellular adhesion molecule 1 was decreased by either agent. Our results suggest that short-term coadministration of HU and Akti XII has immediate benefits for acute vaso-occlusive events and survival in SCD mice exceeding those seen for single therapy. (Blood. 2015;126(22):2511-2517 IntroductionSickle cell disease (SCD), an inherited blood disorder, results from a homozygous mutation at the 6th position (Glu6Val) of the b-globin chain (hemoglobin S [HbS]) or from compound heterozygous forms such as HbSC and HbS-b-thalassemia.1 HbS tends to polymerize in the deoxygenated state, and this leads to the sickling and hemolysis of red blood cells.2,3 Importantly, decreased nitric oxide (NO) bioavailability and increased oxidative stress contribute to the pathophysiology of SCD, including activation of endothelial cells (ECs), inflammation, and organ damage. 4 Recurrent vaso-occlusive events, the hallmark of SCD, are mediated by adhesion and aggregation of red blood cells, leukocytes, and platelets on activated ECs 5,6 and cause pain crises in SCD patients. 7 Hydroxyurea (HU), the only drug approved by the US Food and Drug Administration for treatment of SCD, stimulates HbF production,8 serves as an NO donor, 9,10 and inhibits tissue factor expression in leukocytes.11 Although the mechanism by which HU acts is still not fully understood, previous studies showed that treatment of SCD patients with HU is associated with the production of NO and increases HbF levels in an NO-dependent manner. 9,10 Studies that use a humanized SCD (Berkeley) mouse model have consistently shown that short-term treatment with HU can have immediate benefits in vaso-occlusive events, independently of HbF production. 12The authors further demonstrated that combination therapy of HU and a phosphodiesterase 9 inhibitor efficiently inhibits acute vasoocclusion in SCD mice. 12Intravital microscopic ...

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“…Platelet surface P-selectin and plasma soluble P-selectin, both biomarkers of platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. This study showed a decrease in platelet activation biomarkers and a trend toward decreased pain [75]. A phase II trial to determine dosing was completed in children and results are pending (NCT01476696).…”

Section: Beneficial Effects In the Scd Animal Model Have Led To A Phamentioning

confidence: 90%

“…When looking at combining therapies, potential for hazardous side effects can be preventative. For example, bleeding risk is increased with antiplatelet therapy such as prasugrel, in combination with anticoagulation, such as heparin [13,60,75]. …”

Section: Potential Development Issuesmentioning

confidence: 99%

Emerging drugs for sickle cell anemia

Singh¹,

Ballas²

2014

Expert Opinion on Emerging Drugs

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A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease

Cited by 65 publications

References 30 publications

Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies

Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies

Hydroxyurea with AKT2 inhibition decreases vaso-occlusive events in sickle cell disease mice

Emerging drugs for sickle cell anemia

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