Pan-Selectin Antagonist GMI-1070 Affects Biomarkers of Adhesion, Activation and the Coagulation Cascade in Sickle Cell Adults At Steady State

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 87-87
Author(s):  
John L. Magnani ◽  
Frans A Kuypers ◽  
John T. Patton ◽  
Sandra K Larkin ◽  
Lori Styles ◽  
...  
Keyword(s):  
Steady State ◽  
Tissue Factor ◽  
Sickle Cell ◽  
Research Funding ◽  
Thrombus Formation ◽  
Small Sample ◽  
Coagulation Cascade ◽  
Loading Dose ◽  
Employment Equity ◽  
Equity Ownership

Abstract Abstract 87 Introduction: Engagement of selectins by their ligands leads to cellular activation and adhesion and plays a role in thrombus formation. In sickle cell disease (SCD), the selectins underlie vaso-occlusion, which results in vaso-occlusive crisis (VOC). In SCD patients high levels of soluble E-selectin (sEsel) are associated with increased mortality (Kato, BJH 2005). In addition, SCD patients exhibit chronic activation of the coagulation cascade and of leukocytes. Previously, we showed in animal models of SCD VOC that pan-selectin antagonist GMI-1070 reduced arrested RBC/WBC aggregates and improved blood flow and survival. In a Phase 1 study of SCD adults at steady state (not in VOC), GMI-1070 inhibited neutrophil activation and platelet/neutrophil aggregate formation and increased circulating neutrophils. Herein we report on the effect of GMI-1070 on biomarkers of monocyte, endothelial cell, and coagulation cascade activation; and on the effect of hydroxycarbamide (hydroxyurea or HU) on these biomarkers for patients on this trial. Methods: SCD adults at steady state (n=15) received an IV loading dose of GMI-1070 (20 mg/kg) and a second dose ten hours later (10 mg/kg). Safety and PK were reported elsewhere. HU use was noted. Biomarker blood samples were drawn prior to treatment, and at 4, 8, 24 and 48 hrs after the loading dose. Analytes measured included: soluble adhesion molecules sEsel, soluble P-selectin (sPsel) and intracellular adhesion molecule-1 (ICAM-1) by multiplex ELISA; tissue factor and thrombin-antithrombin complexes (TF and TAT) by ELISA; and, surface expression of monocyte b2 integrins MAC-1 & LFA-1; and platelet-monocyte aggregates (PMA) by flow cytometry. Expression levels were compared against pre-treatment, and stratified by HU use. Analysis was by ANOVA F-test from mixed effects model. Data are reported for 11 subjects (biomarkers) and 15 subjects (neutrophils). Results: Soluble adhesion markers were reduced after 8 hrs (sEsel), or 4 and 8 hrs (sPsel; ICAM-1). Tissue factor (TF) was reduced at 4 and 8 hrs. Thrombin-antithrombin complex (TAT) levels and expression of MAC-1 and LFA-1 were reduced at all time points. The percentage of PMA was reduced at 8 hrs. (Table) When HU use was considered (HU–No; HU–Yes), the levels of sEsel, sPsel, ICAM-1, TF, TAT, MAC-1, and neutrophil counts were higher and more variable at baseline in the HU-No group, significantly so for ICAM-1 (p=0.048) and MAC-1 (p=0.001). After GMI-1070, significant reduction from baseline was seen in both groups: in the HU-No group for ICAM-1, TF, PMA, LFA-1, and in the HU-Yes group for sEsel, MAC-1, TF, TAT. Neutrophil counts increased at 24 hours in the HU-No group only (p=0.001). Conclusion: In this small sample of adults with SCD at steady state, selectin inhibition by treatment with GMI-1070 resulted in reduction in soluble adhesion markers, leukocyte activation, PMA, and markers of coagulation activation. This suggests that selectin inhibition affects downstream processes in vivo, continuing after plasma clearance of >97% of the drug. This may represent interference in the processes that lead to VOC in SCD. A phase 2 study is underway to further explore the effect of this experimental drug on these markers and in the treatment of VOC. Disclosures: Magnani: GlycoMimetics: Employment, Equity Ownership. Kuypers:GlycoMimetics: Research Funding. Patton:GlycoMimetics: Employment. Larkin:GlycoMimetics: Research Funding. Styles:GlycoMimetics: Research Funding. DeCastro:GlycoMimetics: Research Funding. Telen:GlycoMimetics: Research Funding. Wun:GlycoMimetics: Research Funding. Thackray:GlycoMimetics: Employment, Equity Ownership.

Steady-State Imatinib Trough Levels as Well as Dose Interruptions Are Associated with Clinical Response (CCyR and MMR) and Adverse Events (AEs) in Patients with Chronic Myeloid Leukemia (CML) Receiving IM as Frontline Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2213-2213
Author(s):  
Richard A. Larson ◽  
Yen Lin Chia ◽  
Camille Granvil ◽  
François Guilhot ◽  
Brian J. Druker ◽  
...  
Keyword(s):  
Steady State ◽  
Clinical Response ◽  
Cumulative Dose ◽  
Research Funding ◽  
Risk Scores ◽  
Employment Equity ◽  
Risk Patients ◽  
Equity Ownership ◽  
Grade 3 ◽  
Trough Levels

Abstract Abstract 2213 Poster Board II-190 Background: Correlations between IM trough plasma levels (Cmin) and clinical response have been previously reported [Picard et al. Blood 2007; Larson et al. (IRIS) Blood 2008; Guilhot et al. (TOPS) ASH 2008]. This analysis correlates IM Cmin on Day 29 of initial treatment with complete cytogenetic response (CCyR) and major molecular responses (MMR) at 12 months and with cumulative Grade 3&4 toxicity over 12 months based on data pooled from 2 studies, IRIS (400 mg qd) and TOPS (400 mg bid (800 mg/daily) vs 400 mg qd), in newly diagnosed, previously untreated, Ph+ CML-CP. Methods: Steady-state Cmin was defined as predose blood level collected within ±3 hours of the scheduled dosing time on Day 29 without any dose interruptions within 5 days prior to PK sampling. The correlation between IM Cmin and CCyR and MMR at 12 months was studied by two approaches: 1) analysis of outcomes by quartile groups based on patients' IM Cmin levels; 2) logistic regression analysis with Cmin as a continuous variable plus Sokal risk scores and cumulative days with any dose interruptions during the initial 12 months. Safety parameters included Grade 3&4 AEs, as well as all frequently-occurring (>10%) AEs of any grade that occurred during the 12 months. Patients with missing covariates were excluded. Results: Steady-state IM Cmin trough levels were available in 526 patients: 319 in IRIS and 207 from TOPS. At the time of assessment most patients received either 400 mg or 800 mg; 8 patients received reduced doses (6 at 300 mg; 2 at 600 mg). The median IM Cmin [25-75% quartiles] for 400 mg in the pooled dataset was 943 ng/mL [688-1280 ng/mL], and that for 800 mg was 2910 ng/mL [2333-3900 ng/mL]. IM Cmin showed large inter-patient variability for both 400 mg and 800 mg dose groups (52.7% and 39.9%, respectively). Both CCyR and MMR rates at 12 months were significantly correlated with IM Cmin on Day 29. Besides Cmin on Day 29, Sokal risk scores and cumulative dose interruptions (due either to treatment-related toxicities or non-adherence) were significant covariates for 12 month CCyR and MMR. Patients with high Sokal scores (H) had lower CCyR and MMR rates than those with low Sokal scores (L), 64% (H), 69% (intermediate (I)), and 83% (L), respectively, for CCyR, and 37%, 48%, and 59%, respectively, for MMR. Response rates at 12 months were significantly lower for patients with cumulative dose interruptions > 28 days (in the first 12 months): 45% vs 76% for CCyR, and 27% vs 48% for MMR. Modeling predicts that at a Cmin level of 1000 ng/mL and assuming no or minimal dose interruptions, the CCyR at 12 months would be 85%, 78%, and 68% for L, I, and H Sokal risk patients, respectively, and for MMR 55%, 45% and 36%, respectively. If the Cmin were 2000 ng/mL, the CCyR at 12 months would be 93%, 89%, and 83% for L, I, and H Sokal risk patients, respectively, and for MMR 65%, 55% and 44%, respectively. The predicted CCyR and MMR would be lower if there were dose interruptions. Patients who had Grade 3&4 AEs over first 12 months period (n=136) had a higher IM Cmin on Day 29 (median [25-75% quartiles], 1985 [982-2943] ng/mL vs 1010 [728-1468] ng/mL, P<0.001), than those without (n=390) as well as longer cumulative dose interruptions (20 [8-41] days vs 0 [0-2] days, P<0.001), lower CCyR rate (66%; 77/117 vs 75%; 277/369, P=0.05), and lower MMR rate (37%; 49/131 vs 48%; 155/323, P=0.006). Most Grade 3&4 AEs were treatment-related hematologic AEs with median times to onset between 50-63 days. Regression analysis showed the correlation between hematologic Grade 3&4 AEs and IM Cmin level for the population (Figure). Among all-grade non-hematologic AEs, rash and vomiting were associated with higher IM Cmin levels. Conclusion: IRIS+TOPS pooled data confirmed earlier findings that higher steady-state IM levels correlate with better CCyR and MMR responses but also with more Grade 3&4 treatment-related toxicities. Dose interruptions compromise CCyR and MMR rates at 12 months. IM Cmin levels provide additional information together with clinical response and tolerability to inform dose changes for individual patients. Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding. Chia:Novartis: Employment. Granvil:Novartis: Employment. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. O'Brien:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Wyeth: Research Funding. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Nedelman:Novartis: Employment, Equity Ownership. Wang:Novartis: Employment, Equity Ownership.

Effects of Selectin Antagonist GMI-1070 on the Activation State of Leukocytes In Sickle Cell Patients Not In Crisis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2672-2672
Author(s):  
Scott I Simon ◽  
Shannon Chase ◽  
Sandra K Larkin ◽  
Frans Kuypers ◽  
Lori Styles ◽  
...  
Keyword(s):  
Steady State ◽  
Sickle Cell ◽  
Fold Increase ◽  
Employment Equity ◽  
Blood Samples ◽  
High Affinity ◽  
Equity Ownership ◽  
First Time ◽  
Time Point

Abstract Abstract 2672 It is hypothesized that activated leukocytes play key roles in sickle cell vaso-occlusion by adhering to inflamed venules and capturing circulating platelets and sickle red blood cells. GMI-1070 is a small molecule selectin antagonist which was recently reported to reverse acute vascular occlusion in a humanized sickle cell disease (SCD) mouse model (Chang et al, Blood 2010) presumably by inhibiting E-selectin and its effects on downstream signaling of leukocyte activation. Sickle cell patients express elevated levels of soluble E-selectin (Kato et al, Brit J Haem 2005) activated polymorphonuclear neutrophils (PMN) (Lum et al Amer J Hem 2004) and platelet/monocyte aggregates (PMA) (Wun et al Clin Lab Haem 2002). In this study, the activation state of leukocytes from whole blood samples of sickle cell patients not in crisis before and after infusion of GMI-1070 was evaluated ex vivo. Isolated PMN from normal, healthy volunteers were strongly activated by binding soluble E-selectin/hIg in vitro as determined by a 7-fold increase of the integrin MAC1 (CD11b) and an 8-fold increase in expression of the high affinity form of CD18 detected by antibody 327C. Addition of GMI-1070 completely blocked upregulation of MAC1 and 327C at 50μg/ml and showed pronounced inhibition (79% MAC1; 75% 327C) at 10μg/ml. These in vitro concentrations are consistent with blood levels of GMI-1070 found in sickle cell patients 4 and 8 hours after dosing. A phase 1/2 study was conducted on 10 adult subjects with SCD at steady state. GMI-1070 was given IV at 20mg/kg as a loading dose and at 10 hours a final dose of 10mg/kg was given. Blood samples were drawn from these adults pre-infusion and at 8, 24, and 48 hours after the initial infusion. In some subjects, a blood sample was also drawn at 4 hours post infusion. Activation of PMN's in whole blood samples from subjects was assessed by upregulation of MAC-1, expression of the high affinity CD18 and the loss of CD62L due to shedding of L-selectin determined by flow cytometric analysis of cell surface labeling with fluorescently conjugated antibodies. Of 4 subjects tested, 3 showed increased surface expression of L-selectin, 3 showed decreased expression of MAC-1, and 2 showed decreased expression of high affinity CD11b at the first time point tested (4 or 8hr) after dosing with GMI-1070 suggesting an inhibition of PMN activation in these patients. A functional consequence of monocyte activation is the formation of platelet/monocyte aggregates due to expression of high affinity integrins. Platelet-monocytes aggregates (PMA) in blood were detected using anti-CD11c for monocytes and anti-CD41a for platelets. Treatment of samples with lipopolysaccharide (LPS) was used for positive controls. Intracellular IL-1β was used as a marker of activated monocytes. In 5 patients out of 6 tested with this assay, PMA in the subject's blood were decreased at the first time point after dosing (8hr). These results are consistent with an effect of GMI-1070 on inhibition of activation given its IC50 value for E-selectin (4.3μM), the blood concentration in subjects after dosing, and the serum half life (7.7hr) in steady state sickle cell adults. Conclusions: GMI-1070 significantly inhibited E-selectin-mediated activation of PMNs in vitro as determined by expression of the integrin MAC-1 and high affinity CD18 at 10μg/ml. Similar concentrations of GMI-1070 in sickle cell subjects' blood at 4 and 8 hours after dosing also resulted in a lowered activation state of PMNs identified by reduced expression of cell surface integrin molecules as well as the inhibition of shedding of L-selectin in some cases. A more functional measure of leukocyte activation is the aggregation of platelets on monocyte cell surfaces. In 5 of 6 subjects tested, GMI-1070 reduced PMA 8 hours after dosing. Thus, GMI-1070 not only inhibits E-selectin, but also blocks the expression of downstream integrin adhesion molecules that together play crucial roles in vaso-occlusion by promoting the adhesion to platelets and erythrocytes in the formation of occlusions that block blood flow. The effects of GMI-1070 on the activation state of leukocytes via the inhibition of functional adhesion molecules in steady state sickle cell subjects supports the further evaluation of treatment with GMI-1070 during vaso-occlusive episodes. Disclosures: Simon: GlycoMimetics: Research Funding. Chase:GlycoMimetics:.Kuypers:GlycoMimetics Inc.: Research Funding. Styles:GlycoMimetics: Consultancy, clinical trial sponsorship. Wun:GlycoMimetics Inc.: Consultancy, clinical trial sponsorship. Thackray:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership. Off Label Use: The drug (GMI-1070) is not approved for any clinical indication.

A Phase 1 Study of Prasugrel in Subjects with Sickle Cell Disease: Effects on In Vivo Markers of Platelet Activation and of Coagulation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1049-1049
Author(s):  
Joseph A. Jakubowski ◽  
Chunmei Zhou ◽  
David S. Small ◽  
Kenneth J. Winters ◽  
D. Richard Lachno ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Platelet Activation ◽  
Sickle Cell ◽  
Research Funding ◽  
Blood Platelet ◽  
Cell Disease ◽  
Employment Equity ◽  
Equity Ownership ◽  
Adp Receptor

Abstract Abstract 1049 Introduction: Evidence suggests that platelets are activated in sickle cell disease (SCD) and this appears to increase further during painful crises caused by vascular occlusions from sickled red blood cells. Antiplatelet therapy may be useful in reducing the frequency and severity of acute pain episodes and reducing the risk of thrombotic complications. Prasugrel, an ADP receptor antagonist, irreversibly inhibits the P2Y12 ADP receptor, blocking ADP-stimulated platelet activation and aggregation and reducing downstream procoagulant activities. Here we present the first evaluation of prasugrel's effects on markers of in vivo platelet activation and of coagulation in subjects with SCD. Methods: Twenty-six adult subjects were enrolled and 25 completed the study: 12 with SCD and 13 well-matched healthy controls. Subjects were examined before and after 12±2 days of treatment with oral prasugrel (5.0 mg/day for subjects weighing <60 kg and 7.5 mg/day for subjects weighing ≥60 kg). Markers of platelet activation and coagulation included whole-blood platelet-monocyte and -neutrophil aggregates, and whole blood platelet-associated P-selectin and platelet CD40L, all measured by flow cytometry and presented as percent (%) of marker positive cells. Plasma soluble (s) P-selectin, CD40L, and plasma prothrombin fragment 1.2 (F1.2) were evaluated by ELISA. Results: Results from the biomarkers are presented in the table. Prior to prasugrel administration (baseline), subjects with SCD had significantly higher levels of the following biomarkers compared to healthy subjects: Platelet-monocyte aggregates, platelet-neutrophil aggregates, platelet CD40L, and plasma F1.2. In addition, subjects with SCD had numerically higher values of sCD40L, as well as platelet-associated and sP-selectin. Prasugrel treatment resulted in numerical decreases in levels of all biomarkers (with the exception of platelet-associated CD40L for control subjects), most notably in SCD subjects with elevated baseline levels. Prasugrel was safe and well tolerated with no serious adverse events observed during the study. No subject discontinued the study due to an adverse event (AE) and the majority of AEs were mild. No subjects with SCD reported any bleeding-related AEs. Conclusion: In this study, compared to healthy controls, baseline elevation of several platelet-activation and coagulation markers among adult subjects with SCD is consistent with that seen in previous studies of both children and adults with SCD. The decrease in platelet activation biomarkers following 12 days of prasugrel treatment in subjects with SCD suggests prasugrel interrupts SCD-related platelet activation in vivo and raises the possibility that prasugrel may modulate the frequency and/or severity of painful crises associated with SCD. These data support additional studies of the safety and efficacy of prasugrel in the treatment of vascular complications associated with SCD. Disclosures: Jakubowski: Eli Lilly and Company: Employment, Equity Ownership. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Small:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Lachno:Eli Lilly and Company: Employment, Equity Ownership. Frelinger:Takeda: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Consultancy, Research Funding; GLSynthesis: Research Funding. Howard:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Payne:Eli Lilly and Compnay: Employment, Equity Ownership.

scholarly journals Correlation of Voxelotor Exposure with Hemoglobin Response and Measures of Hemolysis in Patients from the HOPE Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1020-1020 ◽  
Author(s):  
Jo Howard ◽  
Elliott Vichinsky ◽  
Jennifer Knight-Madden ◽  
Margaret Tonda ◽  
Carla Washington ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Research Funding ◽  
Organ Damage ◽  
Advisory Board ◽  
Pharmacodynamic Modeling ◽  
Employment Equity ◽  
Double Blind ◽  
Hydroxyurea Treatment ◽  
Travel Grant ◽  
Equity Ownership

Background: Sickle cell disease (SCD) is an inherited disorder in which pathology is driven by hemoglobin (Hb) polymerization and red blood cell sickling, leading to chronic hemolysis and anemia as well as episodic vaso-occlusion. These manifestations of SCD contribute to the cumulative organ damage that leads to disability and accelerated mortality. Voxelotor is a first-in-class therapy in development for the treatment of SCD that has been shown to increase Hb levels and reduce markers of hemolysis, consistent with inhibition of sickle Hb polymerization. The objective of this analysis was to evaluate the association between Hb response and markers of hemolysis in voxelotor-treated patients. Methods: The HOPE trial is a phase 3, randomized, placebo-controlled, double-blind, multicenter study comparing the efficacy and safety of voxelotor (1500 mg and 900 mg daily) versus placebo for ≥24 weeks in patients aged 12 to 65 years with SCD. The primary endpoint is the percentage of patients with a Hb response at week 24, defined as a >1.0 g/dL increase in Hb. Secondary endpoints include change in markers associated with hemolysis: absolute reticulocyte count and percentage of reticulocytes, indirect bilirubin level, and lactate dehydrogenase (LDH) level. The per-protocol population was defined as those who completed the week 24 visit of the assigned treatment regimen and who did not initiate hydroxyurea treatment between baseline and week 24. Pharmacokinetic/pharmacodynamic modeling was used to correlate voxelotor exposure with Hb response and measures of hemolysis. Results: A total of 229 patients (n=74, voxelotor 1500 mg; n=79, voxelotor 900 mg; n=76, placebo) were included in the per-protocol analysis. Among patients receiving voxelotor 1500 mg, all measures of hemolysis were consistently lower for those with changes in Hb of >1 g/dL compared with those with changes of ≤1 g/dL (Table 1). In the 900 mg group, percentage of reticulocytes, bilirubin, and LDH were lower for those with changes in Hb of >1 g/dL compared with those with changes of ≤1 g/dL; this pattern was not seen for absolute reticulocytes in this cohort. Generally, the degree of reduction in hemolysis markers was greater in the 1500 mg arm compared with the 900 mg arm. Linear relationships between voxelotor exposure and Hb and LDH response were observed. In addition, saturable relationships between reticulocytes and bilirubin were also observed. Conclusions: Among patients treated with voxelotor, those with Hb changes of >1.0 g/dL had the greatest reductions in the markers of hemolysis. In addition, patients with Hb changes of >1 g/dL and who received voxelotor 1500 mg had lower hemolytic markers than those who received voxelotor 900 mg, suggesting that exposure to a higher dose of voxelotor results in a greater decrease in hemolysis markers. Taken together, these results suggest that the mechanism by which voxelotor raises Hb is related to a reduction in hemolysis, which may modify the morbidity of SCD by improving hemolytic anemia. Disclosures Howard: Imara: Consultancy, Other: Travel grant; Global Blood Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant; Resonance Health: Other: Travel grant. Vichinsky:Global Blood Therapeutics: Consultancy; Agios: Research Funding; Pfizer: Research Funding. Knight-Madden:Global Blood Therapeutics: Research Funding; Nova Laboratories: Advisory Board on SCD 2017, Research Funding; Global Blood Therapeutics: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Addmedica: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; BlueBird Bio: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Abbott Nutrition: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Abbot International: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Nova Laboratories: Other: Sponsor of a conference held by Sickle Cell Unit in 2017; Pfizer: Other: Advisory Board on SCD 2017. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Washington:Global Blood Therapeutics: Employment, Equity Ownership. Tong:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Gordeuk:Emmaus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Imara: Research Funding; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Ironwood: Research Funding; Inctye: Research Funding; Pfizer: Research Funding; Inctye: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Modus Therapeutics: Consultancy, Honoraria; Global Blood Therapeutics: Consultancy, Honoraria, Research Funding; Emmaus: Consultancy, Honoraria; Ironwood: Research Funding; Modus Therapeutics: Consultancy, Honoraria; Imara: Research Funding; Pfizer: Research Funding.

scholarly journals Genotype-Response Correlation in DRIVE PK, a Phase 2 Study of AG-348 in Patients with Pyruvate Kinase Deficiency

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3621-3621
Author(s):  
Charles Kung ◽  
Penelope A. Kosinski ◽  
Heidi Mangus ◽  
Lei Hua ◽  
Gary Connor ◽  
...  
Keyword(s):  
Sample Size ◽  
Mechanism Of Action ◽  
Research Funding ◽  
Small Sample Size ◽  
Small Sample ◽  
Missense Mutations ◽  
Phase 2 ◽  
Employment Equity ◽  
Protein Levels ◽  
Equity Ownership

Abstract Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia caused by mutations in the PKLR gene, leading to a deficiency of the glycolytic enzyme red cell PK (PK-R). AG-348 is an orally available small-molecule allosteric activator of PK-R that activates the wild type and a range of mutant PK-R enzymes associated with PK deficiency (Kung et al. Blood 2017;130:1347-56). In a phase 2 clinical study in patients with PK deficiency (DRIVE PK, NCT02476916), 26 of 52 patients (50%) experienced a maximum hemoglobin (Hb) increase of >1.0 g/dL (mean maximum increase, 3.4 g/dL; range, 1.1-5.8 g/dL). In most cases, Hb increases were rapid and sustained, and seen across a wide dose range from 5 to 300 mg twice daily. Hemolysis markers (reticulocytes, indirect bilirubin, haptoglobin) improved in patients who experienced a maximum Hb increase of >1.0 g/dL. Hb increases were observed in patients with a variety of PKLR mutations and were associated with the presence of at least 1 missense mutation. As PK deficiency is a genetically heterogeneous disease, with over 200 described mutations, we sought to understand in greater detail the molecular parameters that were associated with Hb increases in AG-348-treated patients. Here, we have analyzed the relationship between Hb increase and patient genotype, biochemical response to AG-348 treatment, and baseline PK-R protein level. The results are consistent with the proposed mechanism of action of AG-348 through binding and activation of residual mutant PK-R enzyme. Of the 106 PKLR mutations in the 52 subjects (2 subjects carried 3 mutations), there were 47 unique mutations, including 28 missense and 19 non-missense. Of these mutations, only 10 were present in at least 2 patients, highlighting the intrinsic limitations of findings from this small sample size. That notwithstanding, among these 10 mutations, we observed that some were more likely to be associated with Hb increases (e.g. increases were observed in 5/5 patients with at least 1 R486W mutation and 4/4 patients with at least 1 T384M mutation). Other mutations, including V134D (0/3), E241stop (1/6), and R510Q (5/14), were associated with a lack of Hb increase. Notably, 1/10 patients who had 2 non-missense mutations and 0/5 patients who were homozygous for the R479H "Amish" mutation had Hb increases. We have previously reported that, in biochemical assays, AG-348 could efficiently activate recombinantly expressed R479H and R510Q mutant enzymes. Although both of these are technically missense mutations, it is well understood that R510Q results in severely decreased protein stability (Wang et al. Blood 2001;98:3113-20), and the R479H mutation, occurring at the splice junction between 2 exons, can deleteriously affect mRNA splicing (van Wijk et al. Br J Haematol 2004;125:253-63). Therefore, as AG-348 works by directly binding and stimulating the activity of residual mutant PK-R enzyme, we explored the hypothesis that PK-R protein levels in patients with these mutations might be too low to allow for adequate target engagement at clinically tested doses. Using antibody-based capture and detection, we quantitated baseline PK-R protein levels of DRIVE PK subjects. Analysis of these data revealed that patients with Hb increases had, on average, higher PK-R protein levels (49% of reference control compared to 13% in patients without Hb increases). All 10 patients with non-missense/non-missense mutations had nearly undetectable PK-R protein levels (average of 3.7% of reference control), consistent with and confirming the predicted effect of these mutations on protein expression. Baseline PK-R protein levels were also lower in patients with at least 1 R510Q (18% of reference control) or R479H (19% of reference control) mutation compared to patients with other missense mutations (59% of reference control). Taken together, these analyses demonstrate that Hb increases upon AG-348 treatment are associated with the presence of at least 1 missense PK-R mutant enzyme with residual protein for AG-348 to bind and activate. These data strongly suggest that the hematological effects of AG-348 come from the proposed mechanism of action of restoration of glycolytic pathway activity in PK-deficient red cells. The genetic complexity of PK deficiency, combined with the relatively small sample size, limit extrapolation of these findings to the entire PK deficiency patient population, but may help to inform future studies. Disclosures Kung: Agios: Employment, Equity Ownership. Kosinski:Agios: Employment, Equity Ownership. Mangus:Agios: Employment, Equity Ownership. Hua:Agios: Employment, Equity Ownership. Connor:Agios: Employment, Equity Ownership. Mobilia:Agios: Employment, Equity Ownership. Sullivan:Agios: Employment, Equity Ownership. Frye:Agios: Employment, Equity Ownership. Jouvin:Agios: Employment, Equity Ownership. Grace:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Consultancy. Glader:Agios: Consultancy, Research Funding. Bowden:Agios: Employment, Equity Ownership.

A Randomized, Double-Blind, Adaptive Phase 2 Multi-Center Study of Prasugrel Compared to Placebo in Adults with Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 847-847 ◽  
Author(s):  
Ted Wun ◽  
Denis Soulieres ◽  
Lakshmanan Krishnamurti ◽  
Abdullah Kutlar ◽  
Kenneth Ataga ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Research Funding ◽  
Study Drug ◽  
Medical Attention ◽  
Phase 2 ◽  
Cell Disease ◽  
Employment Equity ◽  
Double Blind ◽  
Equity Ownership

Abstract Abstract 847FN2 Introduction: Platelet activation may play a role in the pathogenesis of various complications related to sickle cell disease (SCD). Older studies of antiplatelet agents in reducing the frequency and severity of pain in SCD have been inconclusive. Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndrome undergoing percutaneous coronary intervention. We undertook a study to determine the safety, pharmacodynamics and possible efficacy of prasugrel in adult patients with SCD. Methods: This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo randomization ratio. Study drug was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Secondary endpoints included pain frequency and severity assessed by pain diary and pharmacodynamic effects measured by VerifyNow” P2Y12 reactivity units (VN PRU) and vasodilator stimulated phosphoprotein (VASP) phosphorylation platelet reactivity index (PRI). If interim analysis of pharmacodynamic data revealed insufficient platelet inhibition in the first 16 patients randomized to 5 mg daily prasugrel, the dose was to be escalated to 7.5 mg. Results: Forty-one patients were randomized to the prasugrel arm and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients (44%) in the prasugrel and 9 (43%) in the placebo arm were on hydroxyurea prior to study drug initiation. These characteristics were balanced between the treatment arms, as was baseline pain intensity (average pain score on a scale of 0 to 9 over 7 days prior to study drug). No hemorrhagic event required medical attention. Eight (20%) of patients in the prasugrel arm had hemorrhagic adverse events of which 6 (15%) were possibly related to study drug versus 1 (5%) in the placebo arm; all were mild except one moderate menorrhagia in a prasugrel-treated patient. There were numerical decreases in median and mean pain rate (% of days with pain) and intensity in the prasugrel arm compared to placebo but this did not reach statistical significance (Figure 1). The proportion of pain episodes requiring medical attention was also numerically lower: 23% prasugrel versus 37% placebo. There was measurable platelet inhibition as assessed by both VerifyNow” PRU and VASP PRI such that no dose escalation was necessary (Figure 2). Conclusions: Prasugrel, 5 mg once daily for 30 days, had anticipated pharmacodynamic effect on platelets in adult patients with SCD, was well tolerated, and was not associated with serious hemorrhagic events. Despite the small size and short duration of this phase 2 study, there was a suggestion of decreased days with pain. These data provide a rationale for a Phase 3 study of prasugrel adequately powered to determine effects on relevant clinical outcomes such as pain rate, severity, and frequency of vaso-occlusive crisis. Disclosures: Wun: Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Krishnamurti:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Kutlar:Celgene: Research Funding; Novartis: Research Funding; Hemaquest: Research Funding; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Ataga:Adventrx: Consultancy; Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership.

scholarly journals Clinical and Correlative Results of a Phase 1 Study of Cerdulatinib (PRT062070) a Dual SYK/JAK Inhibitor in Patients with Relapsed/Refractory B Cell Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3929-3929 ◽  
Author(s):  
Paul A Hamlin ◽  
Ian Flinn ◽  
Nina wagner-Johnston ◽  
Jan A Burger ◽  
Glenn Michelson ◽  
...  
Keyword(s):  
Steady State ◽  
B Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Employment Equity ◽  
Once Daily ◽  
Markers Of Inflammation ◽  
Equity Ownership ◽  
Grade 3

Abstract Background: Background: Subsets of B cell lymphomas demonstrate a reliance on B-cell receptor (BCR) and/or cytokine JAK/STAT signaling for survival. SYK is positioned upstream of BTK, PI3Kδ, and PLCγ2 on the BCR signaling pathway, making it a potential therapeutic target. Additional survival support appears to be mediated by cytokine-induced JAK/STAT pathways, which can be activated by tumor autocrine signaling loops or by pro-inflammatory cytokines originating from non-malignant infiltrating leukocytes present in the tumor microenvironment. Pre-clinical models demonstrate broad anti-tumor activity with combined SYK and JAK inhibition relative to selective inhibition of these targets alone. Methods: This is a 3+3 dose escalation study with 28-day cycles and doses studied ranging from 15mg to 65mg once daily. PK, PD, and safety were monitored. Clinial response was assessed by standard criteria. The level of inhibition of SYK and JAK was determined by multiple whole blood assays measuring signaling via BCR and receptors for the B-cell antigen, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden - CCL3, CCL4, and other markers of inflammation, were also measured. Results: A total of 36 patients (pt) with CLL/SLL or B cell NHL were dosed. Median age was 67 years (range 23-85) and median prior therapies (tx) was 3 (range 1-8). Treatment emergent AEs of ≥ grade 3 observed deemed related to study drug were: neutropenia (n=2), anemia (n=1), and pneumocystis pneumonia (grade 5, n=1) at 30mg; anemia, AST increase, hypotension, thrombocytopenia (n=1 for each), and fatigue (n=2) at 45mg; anemia, neutropenia, abdominal pain, pneumonia, and fatigue (n=1 for each) at 50mg, and diarrhea and fatigue (n=1 for each) at 65mg. The patient with grade 3 AST had tumor progression to the liver. No dose-limiting toxicities (DLT) have been reported to date and cerdulatinib is generally well tolerated. Saturating inhibition of SYK and JAK in circulating lymphocytes (>80% inhibition) and serum inflammation markers (e.g., β2M,CRP, CCL4; 50-90% inhibition) occurs at plasma concentrations achieved at Cmin of the 40mg dose ( 0.6-1µM) at steady state. At the 65mg dose, these parameters were 80-90% inhibited on day 1 of cycle 1 indicating a more immediate effect compared to lower doses. At the 65mg dose, steady state Cmin and Cmax concentrations are approximately 1 and 2µM, respectively, sufficient to induce apoptosis in the majority of B cell lymphoma cell lines tested. PK is suitable for once daily dosing with a half-life of 12-16 hours and a 2:1 peak-trough ratio. Partial responses (n=4) were observed at 30mg in a pt with del 17p CLL who had relapsed after 6 prior tx; at 45mg a pt with CLL who had received 4 prior tx, and another pt with FL who had received 3 prior tx; and at 65mg in a pt with a transformed DLBCL (MYC, BCL2, and BCL6 expression by IHC) who had relapsed approximately 1 year after 1 prior tx. Responses occurred after 2 cycles of tx. Seven total patients have remained on cerdulatinib for over 200 days, including 2 who have been on for a year or more. Conclusions: Cerdulatinib continues to demonstrate a favorable PK profile and good tolerability at high levels of SYK and JAK inhibition. The clinical responses seen to date support further development and dose escalation continues to identify the MTD. Phase II expansion cohorts are open or planned for CLL, FL, aggressive NHL (DLBCL), and a combination with rituximab. Disclosures Michelson: Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Pandey:Portola Pharmaceuticals Inc: Employment. Birrell:Portola Pharmaceuticals Inc: Employment. Coffey:Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Leeds:Portola Pharmaceuticals Inc: Employment. Curnutte:Portola Pharmaceuticals Inc: Employment.

scholarly journals Successful Plerixafor-Mediated Mobilization, Apheresis, and Lentiviral Vector Transduction of Hematopoietic Stem Cells in Patients with Severe Sickle Cell Disease

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 990-990
Author(s):  
John F Tisdale ◽  
Francis J. Pierciey ◽  
Rammurti Kamble ◽  
Julie Kanter ◽  
Lakshmanan Krishnamurti ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Ex Vivo ◽  
Cell Disease ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Abstract Background Patients with severe sickle cell disease (SCD) may benefit from β-globin gene transfer into autologous hematopoietic stem cells (HSC). Successful HBB gene transfer requires vector-mediated transduction of primitive HSCs. Steady-state bone marrow (BM) is the default HSC source in patients with SCD. Normal human BM contains up to 30% CD34+CD19+ pro-B cells and other lineage-committed cell types (CD34dim) that will not contribute to improved long-term erythropoiesis via gene therapy; these cells mobilize at low rates. CD34+ cell yields from BM harvest (BMH) are typically lower than those after mobilization and peripheral blood (PB) apheresis; multiple rounds of BMH may be required to obtain adequate cell doses for autologous gene therapy (GT) protocols. As G-CSF can cause life-threatening SCD complications and is contraindicated, plerixafor, a CXCR4 receptor antagonist, may accomplish HSC mobilization without the neutrophil or endothelial activation that elicit vaso-occlusion. We modified the protocol for the HGB-206 phase 1 study of LentiGlobin GT in severe SCD (NCT02140554) to assess HSC mobilization with plerixafor alone, followed by apheresis and transduction of mobilized cells. We also characterized BM-derived and plerixafor-mobilized HSC populations from patients with SCD. Methods HGB-206 is a phase 1 study of LentiGlobin Drug Product (DP), which contains autologous HSCs transduced ex vivo with the betibeglogene darolentivec (BB305) lentiviral vector, in patients with severe SCD (defined as a history of recurrent vaso-occlusive crisis [VOC], acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of &gt;2.5 m/s). Patients in group B receive 240 µg/kg plerixafor followed 4-6 hours later by apheresis, processing ~3 total blood volumes to collect backup HSCs. If &lt; 1.5 x 106 CD34+ cells are collected, patients undergo a second day of apheresis. Cells collected in excess of those required for backup in case of graft failure are transduced with BB305 lentiviral vector for exploratory analyses. Group B patients then proceed to BMH to obtain cells for clinical DP manufacture. Group C will receive DP manufactured from mobilized PB. Mass cytometry (CyTOF) was used to analyze ex vivo cultured CD34+ cells with over 35 cell surface markers. Results To date, 3 patients have undergone plerixafor mobilization. Patients had a transient 1.5- to 3-fold increase in peak white blood cell and absolute neutrophil levels after plerixafor. Peak absolute CD34+ cell counts in PB were 170, 58, and 160 x 106 CD34+ cells/liter. A total of 15.3, 5.6, and 9.0 x 106 CD34+ cells/kg were collected in a single day of apheresis, and no subsequent apheresis or mobilization was required. In the same study, a mean of 5.0 (range 0.3-10.8) x 106 CD34+ cells/kg were collected per BMH (N=21). The mobilization and apheresis procedures had an acceptable toxicity profile. No dose-limiting toxicities were observed after plerixafor dosing. One patient had a single VOC approximately 48 hours after receiving plerixafor; this patient also experienced VOCs of similar severity after BMH. In contrast, after 21 BMHs in 9 patients, 18 ≥ grade 3 AEs were reported in 6 patients, primarily pain. Ex vivo cultured CD34+ cells isolated from BMH consisted of an average of 41.0% (17.3%-50.7%) CD34dim cells, with 16%-50% of the CD34dim cells expressing lymphoid markers. In contrast, ex vivo cultured CD34+ cells isolated from plerixafor mobilized PB contained an average of 8.2% (1.5-19.5%) CD34dim cells. Similar drug product vector copy numbers were obtained after research-scale transduction of CD34+ cells from marrow and PB from the same patient. Conclusion Initial results suggest that obtaining adequate doses of CD34+ cells from plerixafor-mobilized PB of patients with SCD may be safe and feasible, without the life-threatening complications associated with G-CSF, and with fewer, less invasive procedures compared with BMH. PB-derived CD34+ cells may contain lower proportions of lineage-committed CD34+ cells than BM-derived cells from patients with SCD. Cells collected by BMH and PB mobilization/apheresis appear to have an equivalent transduction efficiency. Together these results indicate that it may be possible to use plerixafor-only mobilization in clinical studies of autologous HSC GT in SCD. Results of mobilization, apheresis, and DP manufacturing at clinical scale for additional patients will be available for presentation. Disclosures Pierciey: bluebird bio: Employment. Kanter: American Society of Hematology (Sickle Cell Disease Guideline Panel): Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MUSC: Other: The site PI for sponsored research conducted at MUSC who receives funds from: Novartis, bluebird bio, GBT, Sancillo, Apopharma, Pfizer; NHLBI (sickle cell disease research advisory committee): Membership on an entity's Board of Directors or advisory committees, Research Funding; Sancillo: Research Funding; Apopharma: Research Funding; Pfizer: Research Funding; GBT: Research Funding; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kwiatkowski: Novartis: Research Funding; Bluebird Bio: Research Funding; Apopharma: Research Funding; Agios: Consultancy, Honoraria; Ionis: Consultancy, Honoraria. Thompson: Novartis: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Baxalta: Research Funding; Celgene: Consultancy, Research Funding. Shestopalov: bluebird bio: Employment, Equity Ownership. Bonner: bluebird bio: Employment, Equity Ownership. Joseney-Antoine: bluebird bio: Employment, Equity Ownership. Asmal: bluebird bio: Employment, Equity Ownership. Walters: bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; Sangamo Therapeutics: Consultancy; AllCells, Inc: Other: Medical Director.

scholarly journals Edx-17: A Novel, Safe and Efficacious Treatment for Sickle Cell Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1357-1357
Author(s):  
Robert H. Broyles ◽  
Sunil K. Joshi ◽  
Carol D. Curtis ◽  
Austin C. Roth ◽  
Patrick A. Floyd ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
Employment Equity ◽  
Advisory Committees ◽  
Erythroid Precursor ◽  
Gamma Globin ◽  
Equity Ownership

Abstract Gene regulation of developmental hemoglobin switching holds the potential for therapeutic relief from all symptoms associated with Sickle Cell Disease (SCD). Reactivation of fetal gamma-globin expression (HbF) can replace mutant betaS-globin (HbS) to produce functional hemoglobin tetramers and eliminate the hemoglobin polymerization that is characteristic of sickled red blood cells. We have discovered a protein that regulates this developmental switch, and have identified a compound that stimulates expression of this protein. EdX-17 promotes expression of the anti-stress factor ferritin heavy chain (FtH), which enters the nucleus of erythroid precursor cells and activates expression of fetal gamma-globin, producing HbF (PNAS 98:9145-50, 2001; Blood 108:790a, 2006). Mononuclear cells were isolated from SCD patient blood and matured in vitro to the advanced erythroblast stage using a 28-day, 2-phase culture system (Methods in Molecular Biology 482:127-40, 2009; Blood 119:6296-306, 2012). Treatment with EdX-17 for 24h resulted in a dose-responsive induction of gamma-globin gene expression and a concomitant dose-responsive increase in HbF was observed after 28 days in culture. These studies demonstrate that EdX-17 doses in the picomolar range are sufficient to significantly enhance HbF. Furthermore, EdX-17 treatment reconstitutes fetal hemoglobin (HbF) in transgenic betaYAC mice to levels above 25-30% - the range thought to be sufficient to ameliorate symptoms of SCD – with no detectable ill effects. In fact, mice treated with EdX-17 tend to have shinier coats, are more alert and stronger than age-matched, untreated mice. Development of this novel therapeutic is expected to ameliorate SCD symptoms, decrease pain and morbidity, increase life-span, greatly improve patient quality of life, and significantly reduce treatment costs. Supported in part by The Sickle Cell Cure Foundation, Inc., the Bill & Melinda Gates Foundation, and EpimedX, LLC. Disclosures Broyles: EpimedX, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Curtis:EpimedX, LLC: Employment, Equity Ownership, Research Funding. Roth:EpimedX, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Floyd:EpimedX, LLC: Employment, Equity Ownership, Research Funding. Belegu:EpimedX, LLC: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Floyd:EpimedX, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Biomarkers of Hemostatic Activation in a Randomized, Double-Blind, Phase 2 Study of Prasugrel Compared to Placebo in Adults with Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2127-2127
Author(s):  
Ted Wun ◽  
Charles L. Knupp ◽  
Lillian E. McMahon ◽  
John J. Strouse ◽  
Chunmei Zhou ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Platelet Activation ◽  
Sickle Cell ◽  
Research Funding ◽  
Study Drug ◽  
Phase 2 ◽  
Cell Disease ◽  
Employment Equity ◽  
Double Blind ◽  
Equity Ownership

Abstract Abstract 2127 Introduction: Activation of the hemostatic cascade and platelet activation in particular, has been implicated in the pathogenesis of sickle cell disease (SCD). Prasugrel is a third generation thienopyridine antiplatelet agent, an oral P2Y12 ADP receptor antagonist that is FDA-approved for use in patients with acute coronary syndromes undergoing percutaneous coronary revascularization. We evaluated serial biomarkers of hemostatic activation from a trial of prasugrel in adult patients with SCD. Methods: This was a multicenter, randomized, double-blind phase 2 adaptive study design with a 2:1 prasugrel:placebo ratio. Study drug, prasugrel 5 mg or placebo, was given once daily for 30 days. The primary endpoint was safety as measured by hemorrhagic events requiring medical attention. Samples for biomarkers were collected prior to initiation of study drug, on day 10 ± 2, and on day 30 ± 3. Multi-color fluorescent activated cell sorting and monoclonal antibodies were used to determine platelet P-selectin expression, platelet-monocyte aggregates (PMA), and platelet-neutrophil aggregates (PNA) using previously published protocols. Soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L), thromboxane B2 (serum TXB2), and prothrombin fragment F1.2 (F1.2) were determined using standard enzyme-linked immunoassays. Statistical comparison between prasugrel and placebo was performed using a mixed model with treatment, baseline measurement, genotype of SCD, visit and the interaction between visit and treatment as fixed effects and subjects as a random effect. Results: Forty-one patients were randomized to prasugrel 5 mg and 21 to placebo. Mean age was 32 years; 48% were female; 60% HbSS, 5% HbS/b0thalassemia, 10% HbS/b+thalassemia, and 24% HbSC (1 patient was found not to have SCD but to only have b-thalassemia trait). Eighteen patients in the prasugrel and 9 in the placebo arm were on hydroxyurea prior to study drug. Results are shown in the Figure. Compared to placebo, platelet P-selectin (unstimulated), sP-selectin, and sCD40L all achieved or approached significantly lower values in the prasugrel group on day 10 and 30, as did ADP-stimulated platelet P-selectin values (data not shown). TXB2 was significantly lower on day 10 but not on day 30 (Fig. 1), as were PMA/PNA unstimulated, and PMA/PNA in response to ADP ex vivo. F1.2 levels were not different between the groups at either day 10 or 30 (data not shown). Conclusions: As would be predicted by the mechanism of action, prasugrel resulted in decreased cellular and soluble biomarkers of platelet activation. There was no effect on coagulation as assessed by F1.2, a marker of thrombin generation. Clinical results reported elsewhere suggest a decrease in pain rate. Prasugrel 5 mg po daily clearly decreases markers of platelet activation in adult SCD patients. These biomarkers can be incorporated in future studies of prasugrel in SCD to correlate with clinical outcomes. Disclosures: Wun: Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Off Label Use: This abstract discusses prasugrel treatment in patients with sickle cell disease. Please see USPI for most up-to-date information. Knupp:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. McMahon:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Strouse:Daiichi Sankyo Company, Ltd. and Eli Lilly and Company: Research Funding. Zhou:Eli Lilly and Company: Employment, Equity Ownership. Heath:Eli Lilly and Company: Employment, Equity Ownership. Nwachuku:Daiichi Sankyo, Inc.: Employment, Equity Ownership. Jakubowski:Eli Lilly and Company: Employment, Equity Ownership. Winters:Eli Lilly and Company: Employment, Equity Ownership. Riesmeyer:Eli Lilly and Company: Employment, Equity Ownership.

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