Voxelotor (<scp>GBT</scp>440), a first‐in‐class hemoglobin oxygen‐affinity modulator, has promising and reassuring preclinical and clinical data

Estepp, Jeremie H.

doi:10.1002/ajh.25042

Cited by 21 publications

(11 citation statements)

References 10 publications

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“…Blyden et al have reported the compassionate use of voxelotor, at the dosage of 900 mg/d up to 1500 mg/d for 24 weeks in a small group of subjects with severe untreatable SCD. Voxelotor beneficially impacts SCD patient well-being with a reduction in number of hospitalization for severe VOC compared to patient’s clinical history 63. These data further support the on-going phase III clinical trial on voxelotor in a larger population of SCD patients (HOPE; #NCT03036813).…”

Section: Novel Therapeutic Approaches To Treat Sickle Cell Diseasesupporting

confidence: 58%

New Therapeutic Options for the Treatment of Sickle Cell Disease

Mattè

Zorzi

Mazzi

et al. 2019

Mediterr J Hematol Infect Dis

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Sickle cell disease (SCD; ORPHA232; OMIM # 603903) is a chronic and invalidating disorder distributed worldwide, with high morbidity and mortality. Given the disease complexity and the multiplicity of pathophysiological targets, development of new therapeutic options is critical, despite the positive effects of hydroxyurea (HU), for many years the only approved drug for SCD.New therapeutic strategies might be divided into (1) pathophysiology-related novel therapies and (2) innovations in curative therapeutic options such as hematopoietic stem cell transplantation and gene therapy. The pathophysiology related novel therapies are: a) Agents which reduce sickling or prevent sickle red cell dehydration; b) Agents targeting SCD vasculopathy and sickle cell-endothelial adhesive events; c) Anti-oxidant agents.This review highlights new therapeutic strategies in SCD and discusses future developments, research implications, and possible innovative clinical trials.

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Section: Novel Therapeutic Approaches To Treat Sickle Cell Diseasesupporting

confidence: 58%

New Therapeutic Options for the Treatment of Sickle Cell Disease

Mattè

Zorzi

Mazzi

et al. 2019

Mediterr J Hematol Infect Dis

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“…Voxelotor is the first FDA‐approved agent in this class. Voxelotor binds HbS and stabilizes the oxygenated conformation, inhibits HbS polymerization, and reduces the red blood cell sickling process 6, 7 . The use of voxelotor inhibits destruction of sickle erythrocytes and improves the Hb level 18 .…”

Section: Discussionmentioning

confidence: 99%

“…Voxelotor inhibits hemoglobin polymerization by increasing the oxygen affinity to HbS 6, 7 . There is a theoretical concern that this increased oxygen binding capacity of Hb may actually decrease its ability to transport oxygen to peripheral tissues and that the rise in Hb may not be sufficient to compensate for a functional loss of oxygen delivery 31 .…”

Section: Discussionmentioning

confidence: 99%

“…Because polymerization of deoxygenated HbS is a major driver for the pathogenesis of SCD, a HbS polymerization inhibitor can potentially mitigate erythrocyte sickling and have a disease‐modifying effect. Voxelotor, previously called GBT440, is an Hb modulator that binds to the α‐globin chain of HbS and increases the affinity of oxygen to the hemoglobin molecule by causing an allosteric change that stabilizes the oxygenated state of HbS and consequently interrupts the polymerization process 6, 7 . Voxelotor partitions highly selectively into erythrocytes in vitro, allowing the achievement of therapeutic concentrations within the red blood cell in the presence of low serum concentrations 8 .…”

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confidence: 99%

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Systematic Review of Voxelotor: A First‐in‐Class Sickle Hemoglobin Polymerization Inhibitor for Management of Sickle Cell Disease

Han

Saraf

2020

Pharmacotherapy

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Voxelotor, a sickle hemoglobin polymerization inhibitor, was approved by the U.S. Food and Drug Administration to treat sickle cell disease (SCD) in November 2019. This article reviews published data about voxelotor treatment of SCD based on a search of MEDLINE, Embase, and International Pharmaceutical Abstracts. In a phase I/II trial, voxelotor demonstrated a dose‐dependent pharmacokinetic and pharmacodynamic response and was well tolerated in healthy volunteers and patients with SCD. In a multi‐center, randomized, double‐blind, phase III trial (HOPE trial), a significantly higher percentage of patients randomized to voxelotor had increased hemoglobin (> 1 g/dl from baseline) compared to placebo. A greater reduction of hemolytic markers was also observed in the voxelotor‐treated group, whereas the incidence of adverse effects was comparable. Three case series or reports also demonstrated the efficacy and safety of voxelotor use in a limited number of SCD patients in the real‐world situation, although one patient with SCD, severe anemia, and a history of autoantibody‐mediated hemolysis failed to respond to voxelotor. An ongoing trial (HOPE‐KIDS) is designed to establish the use of voxelotor in younger pediatric patients with SCD. There is a theoretical concern that voxelotor may impair oxygen delivery, due to modification of the oxygen affinity of hemoglobin, which needs to be further evaluated. As a first‐in‐class hemoglobin modulator, voxelotor offers a new treatment option targeting the root cause of SCD.

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“…Voxelotor (GBT-440) was created by Global Blood Therapeutics from HOPE (Hemoglobin Oxygen Affinity Modulation to inhibit HbS PolymErization) study. It improves blood oxygen saturation and reduces hospitalization-induced vaso-occlusive crisis [43]. LG BB305 (Lenti Globin) is a therapeutic regimen which acts as gene therapy.…”

Section: Regular and Novel Regimens/investigational Drugsmentioning

confidence: 99%

Beyond the Legislation for Sickle Cell Disease Prevention - Getting the Right Outcomes

Nwabuko¹

2019

AJIM

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This study aimed at highlighting benefits derivable from legislation for Sickle cell disease (SCD) prevention using the three levels of health legislative power (primary, secondary and tertiary). It was an evidence-based integrative review of 54 references related to SCD, epidemiology, management, and legislation for its control over the past three decades . Two keywords (SCD and Legislation/Policy) were used as search strategy to identify the problem, intervention, and outcome evaluation of the research questions. MeSH, Medline, CINAHL, PubMed, Cochrane Database Systematic Review, Google Scholar and African Journal Online were search databases reviewed. The expected outcomes were categorized into three levels of benefits. They were primary, secondary and tertiary categories of benefit. While the primary category would institutionalize pre-genetic counseling in the health institutions, the secondary and tertiary groups would establish screening (prenatal and newborn)/comprehensive care and curative interventions (i.e., investigational therapies and stem cell transplantation) respectively for people living with SCD. These interventions will enhance SCD surveillance, screening, auditing, health needs assessment, treatment, control, and prevention in the target audience. Conclusions The legislation for Sickle Cell Disease prevention in the target population would promote early disease detection, treatment, and prevention. We expect that with an increase in case ascertainment, the disability-adjusted life year (DALY) would reduce so also other complications. This legislation will diffuse new innovations in SCD management and research which will ultimately improve the health indices of people living with the disease globally.

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Voxelotor (GBT440), a first‐in‐class hemoglobin oxygen‐affinity modulator, has promising and reassuring preclinical and clinical data

Cited by 21 publications

References 10 publications

New Therapeutic Options for the Treatment of Sickle Cell Disease

New Therapeutic Options for the Treatment of Sickle Cell Disease

Systematic Review of Voxelotor: A First‐in‐Class Sickle Hemoglobin Polymerization Inhibitor for Management of Sickle Cell Disease

Beyond the Legislation for Sickle Cell Disease Prevention - Getting the Right Outcomes

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