A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease

Vichinsky, Elliott; Hoppe, Carolyn; Ataga, Kenneth I.; Ware, Russell E.; Nduba, Videlis; El‐Beshlawy, Amal; Hassab, Hoda; Achebe, Maureen; Alkindi, Salam; Brown, Robert C.; Diuguid, David L.; Telfer, Paul; Tsitsikas, Dimitris A.; Elghandour, Ashraf; Gordeuk, Victor R.; Kanter, Julie; Abboud, Miguel R.; Lehrer‐Graiwer, Joshua; Tonda, Margaret; Intondi, A.; Tong, Barbara; Howard, Jo

doi:10.1056/nejmoa1903212

Cited by 457 publications

(526 citation statements)

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“…[26][27][28] Global Blood Therapeutics published the results of a phase III trial (NCT03036813) known as the HOPE trial in 2019. 29 It reported on the efficacy and safety of voxelotor at two dose levels (1500 and 900 mg) for improvements in hemoglobin response from baseline over 24 weeks. Data were analyzed for 274 patients.…”

Section: Discussionmentioning

confidence: 99%

Systematic Review of l‐glutamine for Prevention of Vaso‐occlusive Pain Crisis in Patients with Sickle Cell Disease

et al. 2019

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l‐glutamine was approved by the U.S. Food and Drug Administration (FDA) for sickle cell disease (SCD) in 2017. A vaso‐occlusive crisis (VOC) occurs in persons with SCD and is associated with acute pain episodes. This systematic review summarizes the evidence for l‐glutamine in the prevention of VOC and associated pain in patients with SCD. Medline, Embase, and International Pharmaceutical Abstracts were searched for records reporting on l‐glutamine use in persons with SCD. Eligibility criteria identified primary reports of investigations conducted in humans who were administered l‐glutamine, reported on outcomes related to VOC or associated pain, published in English, and were available as full text. All relevant efficacy, safety, participant demographic data, and study method characteristics were extracted and documented. Risk‐of‐bias assessments were conducted using the Risk of Bias in Non‐Randomized Studies‐of Interventions (ROBINS‐I) tool and the revised Cochrane risk‐of‐bias tool for randomized studies. Three studies assessing the effect of exogenous l‐glutamine administration in patients with SCD met eligibility criteria: one prospective nonrandomized controlled study and two prospective randomized controlled trials. Rate of VOC and related hospitalizations were reduced in patients receiving l‐glutamine, although some conflicting results were noted between studies. l‐glutamine was generally well tolerated. Limitations of one or more of the eligible studies included small sample size, nonblinding, and study groups that differed at baseline. l‐glutamine has limited high‐quality evidence supporting its use. Although l‐glutamine is FDA approved for the prevention of frequent episodes of VOC pain, only one randomized controlled trial has strong evidence to support this indication. Based on the results of a systematic review, l‐glutamine may be considered for patients unable to receive hydroxyurea or in addition to hydroxyurea for reduction in VOC and associated pain.

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Section: Discussionmentioning

confidence: 99%

Systematic Review of l‐glutamine for Prevention of Vaso‐occlusive Pain Crisis in Patients with Sickle Cell Disease

et al. 2019

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“…2 Risk stratification was according to the International Staging System (ISS) and the Revised International Staging System (R-ISS). 2,3 Granulocyte colonystimulating factor was the preferred agent used for stem cell mobilization,…”

Section: Delayed Neutrophil Engraftment In Patients Receiving Daratummentioning

confidence: 99%

“…recently tested in SCD. 1,3 The joint experience of the authors of this study with the oxygenscan has prompted us to study methodological aspects and pre-analytical factors that could influence key oxygenscan parameters. A better understanding of these aspects and factors will strongly enhance reproducibility of results and will enable interlaboratory comparison of results and collaboration.…”

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Methodological aspects of the oxygenscan in sickle cell disease: A need for standardization

et al. 2019

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“…A number of research attempts have been made to design interventions aimed at modulating the structural properties, aggregation tendencies, and defective O 2 transport properties of sickle hemoglobin. For example, allosteric modulators and covalent modifiers of HbS that stabilize the non-polymer forming R-state Hb conformation have been reported and include the recently FDA approved voxelotor (GBT 440) [53] and derivatives of vanillin [54,55]. Compounds like senicapoc, a Gardos channel blocker, were also reported with the ability to prevent RBC dehydration [56]; clinical assessment in SCD, however, failed to find a correlation between improvements in hemolysis and vaso-occlusive crisis [57].…”

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confidence: 99%

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

2019

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Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the β-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30-40 years ago up to more promising 12-and 15-mers under consideration in recent years.Molecules 2019, 24, 4551 2 of 23 with hemoglobin reduces HbS solubility and promotes polymerization, also called sickling [3,4]. This ultimately leads to hampered O 2 binding and transport, impaired erythrocyte morphology and interaction with endothelial surfaces [5,6], premature erythrocyte rupture and anemia, painful vaso-occlusive crisis, a general poor health, and, in many cases, death [7][8][9][10][11].Despite growing understanding of the polymerization of HbS and its effects on red blood cells (RBCs), until very recently, only two drugs-hydroxyurea and L-glutamine-were approved by the United States (US) Food and Drug Administration (FDA) for the management of SCD [12]. Hydroxyurea is the most widely employed drug treatment of sickle cell anemia in different age groups [13][14][15][16][17][18]. While its clinically observed efficacy has been attributed to different effects at the cellular level [19], the most important mechanism of action relates to its ability to induce the production of fetal hemoglobin (HbF), which does not polymerize, and to increase the total concentration of hemoglobin [20,21]. Hydroxyurea remains a viable treatment option for SCD, and the concern of toxicities associated with its administration has largely been limited to side effects that resolve with medication discontinuation [22][23][24][25][26]. There have, however, been certain reports of associated malignancies [27][28][29][30][31][32], but further investigations are needed to categorically confirm these [33]. L-glutamine is the second approved drug treatment [12,34]. While its mechanism of action is not known, and only suggested to involve a reduction of oxidative stress via elevation of the levels of reduced glutathione [35,36], it is clear that it has no effect on hemo...

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A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease

Cited by 457 publications

References 20 publications

Systematic Review of l‐glutamine for Prevention of Vaso‐occlusive Pain Crisis in Patients with Sickle Cell Disease

Systematic Review of l‐glutamine for Prevention of Vaso‐occlusive Pain Crisis in Patients with Sickle Cell Disease

Methodological aspects of the oxygenscan in sickle cell disease: A need for standardization

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

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