Voxelotor: A Ray of Hope for Sickle Disease

AlDallal, Salma M

doi:10.7759/cureus.7105

Cited by 9 publications

(10 citation statements)

References 16 publications

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“…Several clinical trials have reported its benefits. 73 Crizanlizumab is a new, FDA-approved drug for the prevention of VOC. It is a humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions with its ligands including P-selectin glycoprotein ligand 1.…”

Section: Hydroxyurea and New Therapeutic Approachesmentioning

confidence: 99%

Complement in Sickle Cell Disease: Are We Ready for Prime Time?

Varelas

Tampaki

Sakellari

et al. 2021

JBM

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Sickle cell disease (SCD) is a widely spread inherited hemoglobinopathy that includes a group of congenital hemolytic anemias, all characterized by the predominance of sickle hemoglobin (HbS). Its features are anemia, predisposal to bacterial infections and complications such as vaso-occlusive crisis (VOC) or delayed hemolytic transfusion reaction (DHTR), which lead to increased rate of morbidity and mortality even in the era of hydroxyurea. The interaction between sickle cells, neutrophils, platelets or endothelial cells in small vessels results in hemolysis and has been considered the disease's main pathophysiological mechanism. Complement activation has been reported in small cohorts of SCD patients, but the governing mechanism has not been fully elucidated. This will be important to predict the patient group that would benefit from complement inhibition. Until now, eculizumab-mediated complement inhibition has shown beneficial effects in DHTR, with limited reports in patients with VOC. In the meantime, several innovative agents are under clinical development Our state-of-the-art review summarizes current data on 1) complement activation in SCD both in steady state and crisis, 2) underlying mechanisms of complement over-activation for the clinician in the context of SCD, 3) actions of hydroxyurea and new therapeutic approaches including indirect involvement in complement activation, and 4) novel paradigms in complement inhibition.

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Section: Hydroxyurea and New Therapeutic Approachesmentioning

confidence: 99%

Complement in Sickle Cell Disease: Are We Ready for Prime Time?

Varelas

Tampaki

Sakellari

et al. 2021

JBM

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“…Acute and chronic manifestations increase with age and these complications lead to early mortality. Approximately 100 000 individuals are affected by SCA within the United States alone and the condition dramatically decreases life expectancy by about 30 years 4 …”

Section: Figurementioning

confidence: 99%

“…Approximately 100 000 individuals are affected by SCA within the United States alone and the condition dramatically decreases life expectancy by about 30 years. 4 Voxelotor (GBT440) is a first-in-class, oral, once-daily drug (Global Blood Product, San Francisco, CA) that binds to the α-chain of haemoglobin S (HbS), which is known to interrupt HbS polymerisation. [5][6][7] This study aimed to conduct a meta-analysis of the efficacy of voxelotor 900 mg in patients with SCA.…”

mentioning

confidence: 99%

The efficacy of voxelotor, 900 mg in patients with sickle cell anaemia: A meta‐analysis of the randomised controlled trials

et al. 2021

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Objective Sickle cell anaemia (SCA), an inherited chronic hematological disease affecting hundreds of thousand people worldwide, causes significant morbidity and reduced life expectancy about two or three decades. This study aimed to conduct a meta‐analysis of the efficacy of voxelotor, 900 mg in patients with SCA. Methods The research protocol was registered at the International Register of Prospective Systematic Reviews (PROSPERO), under the registration number: CRD42020147796. ClinicalTrials.gov, Cochrane Central Register of Controlled Trials, Conference Abstracts, Google Scholar, Ovid Medline, Scopus, Web of Science, and Wiley Online Library from 2015 through July 25, 2019, and bibliographies of review articles and eligible studies. Eleven eligible studies that evaluated the effectiveness of voxelotor, 900 mg in SCA. Based on pre‐specified inclusion and exclusion criteria, 2 randomized, placebo‐controlled studies were included in the meta‐analysis. Results The primary outcome measured was hemoglobin elevation, assessed in a highly similar fashion in both trials. There was a significant difference between voxelotor and placebo in haemoglobin change from baseline (mean difference [MD]: 0.87, 95% confidence interval [CI]: 0.67‐1.06). Voxelotor also reduced markers of haemolysis, MD: −36.79, 95% CI: (−75.05) to 1.48 for unconjugated bilirubin that changes from baseline; MD: −19.09, 95% CI: (−44.06) to 5.88 for the percentage of reticulocytes that change from baseline and MD: −23.29, 95% CI: (−65.14) to 18.55 for LDH that change from baseline) but the difference was not statistically significant. Conclusions As a conclusion, voxelotor, 900 mg use significantly increased hemoglobin levels which of 1 g/dL elevation predicts a reduced risk of stroke (41%), albuminuria (53%), pulmonary arterial hypertension (57%), and mortality (64%) in recent studies. Voxelotor also reduced markers of hemolysis but failed to reach statistically significance in current evidence. Multicenter, randomized, placebo‐controlled studies are on the way and will provide more evidence to see the potential of disease‐modifying effects of voxelotor.

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“…There is a great expectation regarding the use of voxelotor as “it consists the first of its kind,” meaning that it could potentially alter the underlying SCD pathology. After a series of clinical trials (NCT02285088, NCT03041909), this drug has shown great benefits by increasing the affinity between Hb and oxygen resulting in the inhibition of drepanocytosis of the RBCs and therefore, to a significant improvement in patients’ quality of life [ 42 , 43 ]. Subsequently, in phase 3 clinical trial called GBT_HOPE (NCT03036813), voxelotor established efficacy and safety even with concomitant administration of placebo (hydroxyurea), in patients with SCD ( N = 274).…”

Section: Introductionmentioning

confidence: 99%

Genome-based therapeutic interventions for β-type hemoglobinopathies

et al. 2021

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For decades, various strategies have been proposed to solve the enigma of hemoglobinopathies, especially severe cases. However, most of them seem to be lagging in terms of effectiveness and safety. So far, the most prevalent and promising treatment options for patients with β-types hemoglobinopathies, among others, predominantly include drug treatment and gene therapy. Despite the significant improvements of such interventions to the patient’s quality of life, a variable response has been demonstrated among different groups of patients and populations. This is essentially due to the complexity of the disease and other genetic factors. In recent years, a more in-depth understanding of the molecular basis of the β-type hemoglobinopathies has led to significant upgrades to the current technologies, as well as the addition of new ones attempting to elucidate these barriers. Therefore, the purpose of this article is to shed light on pharmacogenomics, gene addition, and genome editing technologies, and consequently, their potential use as direct and indirect genome-based interventions, in different strategies, referring to drug and gene therapy. Furthermore, all the latest progress, updates, and scientific achievements for patients with β-type hemoglobinopathies will be described in detail.

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Voxelotor: A Ray of Hope for Sickle Disease

Cited by 9 publications

References 16 publications

Complement in Sickle Cell Disease: Are We Ready for Prime Time?

Complement in Sickle Cell Disease: Are We Ready for Prime Time?

The efficacy of voxelotor, 900 mg in patients with sickle cell anaemia: A meta‐analysis of the randomised controlled trials

Genome-based therapeutic interventions for β-type hemoglobinopathies

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