Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial

Howard, Jo; Ataga, Kenneth I.; Brown, Robert C.; Achebe, Maureen; Nduba, Videlis; El‐Beshlawy, Amal; Hassab, Hoda; Agodoa, Irene; Tonda, Margaret; Gray, Sarah; Lehrer‐Graiwer, Joshua; Vichinsky, Elliott

doi:10.1016/s2352-3026(21)00059-4

Cited by 63 publications

(85 citation statements)

References 21 publications

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“…Considering current drug discovery work for SCD, it is interesting to note that the compound GBT1118 is structurally related to Voxelotor, an approved drug recently shown in the HOPE Phase III clinical trial to be effective in increasing SCD patient hemoglobin concentrations, which in turn correlated with reduced incidence of vaso-occlusive crises ( Howard et al, 2021 ). GBT1118 reduces RBC sickling, increases oxygen affinity, stabilizes HbS structure, and decreases cation fluxes mediated by Psickle, Gardos and KCC pathways ( Al Balushi et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Aquaporin-1 Cation Conductance by Selected Furan Compounds Reduces Red Blood Cell Sickling

et al. 2022

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In sickle cell disease (SCD), the pathological shift of red blood cells (RBCs) into distorted morphologies under hypoxic conditions follows activation of a cationic leak current (Psickle) and cell dehydration. Prior work showed sickling was reduced by 5-hydroxylmethyl-2-furfural (5-HMF), which stabilized mutant hemoglobin and also blocked the Psickle current in RBCs, though the molecular basis of this 5-HMF-sensitive cation current remained a mystery. Work here is the first to test the hypothesis that Aquaporin-1 (AQP1) cation channels contribute to the monovalent component of Psickle. Human AQP1 channels expressed in Xenopus oocytes were evaluated for sensitivity to 5-HMF and four derivatives known to have differential efficacies in preventing RBC sickling. Ion conductances were measured by two-electrode voltage clamp, and osmotic water permeability by optical swelling assays. Compounds tested were: 5-HMF; 5-PMFC (5-(phenoxymethyl)furan-2-carbaldehyde); 5-CMFC (5-(4-chlorophenoxymethyl)furan-2-carbaldehyde); 5-NMFC (5-(2-nitrophenoxymethyl)-furan-2-carbaldehyde); and VZHE006 (tert-butyl (5-formylfuran-2-yl)methyl carbonate). The most effective anti-sickling agent, 5-PMFC, was the most potent inhibitor of the AQP1 ion conductance (98% block at 100 µM). The order of sensitivity of the AQP1 conductance to inhibition was 5-PMFC > VZHE006 > 5-CMFC ≥ 5-NMFC, which corresponded with effectiveness in protecting RBCs from sickling. None of the compounds altered AQP1 water channel activity. Combined application of a selective AQP1 ion channel blocker AqB011 (80 µM) with a selective hemoglobin modifying agent 5-NMFC (2.5 mM) increased anti-sickling effectiveness in red blood cells from human SCD patients. Another non-selective cation channel known to be expressed in RBCs, Piezo1, was unaffected by 2 mM 5-HMF. Results suggest that inhibition of AQP1 ion channels and capacity to modify hemoglobin are combined features of the most effective anti-sickling agents. Future therapeutics aimed at both targets could hold promise for improved treatments for SCD.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the Aquaporin-1 Cation Conductance by Selected Furan Compounds Reduces Red Blood Cell Sickling

et al. 2022

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“…We recommend considering the addition of voxelotor for patients ≥12 years of age who are adherent to hydroxyurea with suboptimal hemoglobin concentrations (<9 g/dl) with careful ongoing hemoglobin surveillance, given that up to 20% of individuals in the HOPE trial treated with the 1500 mg dose experienced a dramatic increase in hemoglobin of >3 g/dl by the full 72 weeks of the study. 48 Although no increase in VOE was reported for those who achieved Hb >12 g/dl, the long-term consequences of an elevated hemoglobin concentration with predominance of HbS on whole blood viscosity and clinical outcomes are still unknown and need further investigation. Given the evidence for the prevention of SCD-related complications with hydroxyurea, which was not seen with voxelotor, 47,48 our personal approach and recommendation is to first prescribe hydroxyurea rather than to replace hydroxyurea with voxelotor as a monotherapy, unless there is a clear contraindication to hydroxyurea.…”

Section: Voxelotormentioning

confidence: 97%

“…47 The initial results from HOPE and recently published long-term follow-up, however, have not demonstrated any statistical differences between treatment and placebo groups in the annualized incidence of VOE, nor patient-reported outcome measures such as quality of life. 48 Based on meeting the primary endpoint of increased hemoglobin concentration, voxelotor received accelerated FDA approval for adults and children with all genotypes of SCD at least 12 years old in November 2019.…”

Section: Voxelotormentioning

confidence: 99%

How I approach disease‐modifying therapy in children with sickle cell disease in an era of novel therapies

Karkoska

McGann

2021

Pediatric Blood & Cancer

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Finally,after decades of stagnation, the therapeutic landscape for sickle cell disease (SCD) is changing with an increasing number of novel therapeutics. Hydroxyurea remains the primary disease-modifying therapy and, when started early in life with maintenance of an optimal dose, can reduce many SCD-related complications. To complement hydroxyurea, there are a growing number of pharmacologic options with additional efforts focused on the development and optimization of curative therapies. Here, we review current treatment options and provide recommendations as to how to approach the treatment of children and adolescents within this evolving therapeutic landscape to allow for full and healthy lives.

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“…16 Even though decreasing 2,3-DPG increases oxygen affinity, the left shift in the ODC is considerably less because, unlike voxelotor, it binds and dissociates rapidly 51 (supplemental Figure 2). After all of our calculations were completed and the original manuscript submitted, we became aware of the results of the extension of the phase 3 clinical trial from 24 to 72 weeks reported by Howard et al, 52 a trial supported by Global Therapeutics, the producer of voxelotor. Although the drug increased hemoglobin levels via amelioration of hemolysis, there was no reduction in painful episodes except in a small fraction of patients with SCD with hemoglobin levels .12 g/dL.…”

Section: Increase Hbfmentioning

confidence: 99%

Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin

Henry

Metaferia

et al. 2021

Blood

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The issue of treating sickle cell disease with drugs that increase hemoglobin oxygen affinity has come to the fore with the FDA approval in 2019 of voxelotor, the only anti-sickling drug approved since hydroxyurea in 1998. Voxelotor reduces sickling by increasing the concentration of the non-polymerizing, high oxygen affinity R (oxy) conformation of HbS. Treatment of sickle cell patients with voxelotor increases Hb levels and decreases indicators of hemolysis, but with no indication as yet that it reduces the frequency of pain episodes. Here we use the allosteric model of Monod, Wyman, and Changeux to simulate whole blood oxygen dissociation curves and red cell sickling in the absence and presence of voxelotor under the in vivo conditions of rapid oxygen pressure decreases. Our modeling agrees with experiments using a new robust assay, which shows the very large, expected decrease in sickling from the drug. The modeling indicates, however, that the increase in oxygen delivery from reduced sickling is largely offset by the increase in oxygen affinity. The net result is that the drug increases overall oxygen delivery only at the very lowest oxygen pressures. Reduction of sickling does, however, mitigate against red cell damage and explains the observed decrease in hemolysis. More importantly, our modeling of in vivo oxygen dissociation, sickling, and oxygen delivery suggests that drugs that increase fetal hemoglobin or decrease MCHC, should be more therapeutically effective than drugs that increase oxygen affinity.

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Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial

Cited by 63 publications

References 21 publications

Inhibition of the Aquaporin-1 Cation Conductance by Selected Furan Compounds Reduces Red Blood Cell Sickling

Inhibition of the Aquaporin-1 Cation Conductance by Selected Furan Compounds Reduces Red Blood Cell Sickling

How I approach disease‐modifying therapy in children with sickle cell disease in an era of novel therapies

Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin

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