Highlights
- •Disease-modifying drug therapies for sickle cell disease are rapidly emerging.
- •Three new drugs have been approved by the FDA in addition to hydroxyurea.
- •Over 30 clinical trials are ongoing to test new drugs or drug indications.
Abstract
Keywords
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- Sickle-cell disease.Lancet. 2010; 376 (2018-31)
National instututes of Health. ClinicalTrials.gov. Accessed July 7, 2022.
- Sickle cell disease.New Engl J Med. 2017; 376 (1561-73)
- Treating sickle cell disease by targeting HbS polymerization.Blood. 2017; 129 (2719-26)
- Fetal hemoglobin in sickle cell anemia.Blood. 2011; 118: 19-27
- Discovery of GBT440, an orally bioavailable R-state stabilizer of sickle cell hemoglobin.ACS Med Chem Lett. 2017; 8: 321-326
- GBT440 increases haemoglobin oxygen affinity, reduces sickling and prolongs RBC half-life in a murine model of sickle cell disease.Br J Haematol. 2016; 175: 141-153
- Safety, pharmacokinetics, and pharmacodynamics of etavopivat (FT-4202), an allosteric activator of pyruvate kinase-R, in healthy adults: a randomized, placebo-controlled, double-blind, first-in-human phase 1 trial.Clin Pharm Drug Dev. 2022; 11 (654-65)
- A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease.Blood. 2022;
- Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia.Blood. 2008; 111: 3991-3997
- Novel sickle cell disease therapies: targeting pathways downstream of sickling.Semin Hematol. 2018; 55: 68-75
- Crizanlizumab for the prevention of pain crises in sickle cell disease.New Engl J Med. 2017; 376 (429-39)
- Crizanlizumab: first approval.Drugs. 2020; 80: 79-84
- Randomized phase 2 study of GMI-1070 in SCD: reduction in time to resolution of vaso-occlusive events and decreased opioid use.Blood. 2015; 125: 2656-2664
- Early initiation of treatment with rivipansel for acute vaso-occlusive crisis in sickle cell disease (SCD) achieves earlier discontinuation of IV opioids and shorter hospital stay: reset clinical trial analysis.Blood. 2020; 136: 18-19
- Recent advances in the treatment of sickle cell disease.Front Physiol. 2020; 11: 435
- The evolving pharmacotherapeutic landscape for the treatment of sickle cell disease.Mediterr J Hematol Infect Dis. 2020; 12e2020010
- Role of the coagulation system in the pathogenesis of sickle cell disease.Blood Adv. 2019; 3 (3170-80)
- The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease.JAMA. 2005; 293: 1653-1662
- Therapeutic strategies for sickle cell disease: towards a multi-agent approach.Nat Rev Drug Disco. 2019; 18 (139-58)
- A phase 3 trial of l-glutamine in sickle cell disease.New Engl J Med. 2018; 379 (226-35)
- Intravascular hemolysis and the pathophysiology of sickle cell disease.J Clin Invest. 2017; 127 (750-60)
- Arginine supplementation of sickle transgenic mice reduces red cell density and Gardos channel activity.Blood. 2002; 99: 1103-1108
- Impact of arginine therapy on mitochondrial function in children with sickle cell disease during vaso-occlusive pain.Blood. 2020; 136: 1402-1406
- Riociguat use in sickle cell related chronic thromboembolic pulmonary hypertension: A case series.Pulm Circ. 2018; 8 (2045894018791802)
- Olinciguat, a stimulator of soluble guanylyl cyclase, attenuates inflammation, vaso-occlusion and nephropathy in mouse models of sickle cell disease.Br J Pharmacol. 2021; 178 (3463-75)
- Hydroxyurea enhances fetal hemoglobin production in sickle cell anemia.J Clin Invest. 1984; 74: 652-656
- Hydroxyurea for the treatment of sickle cell anemia.New Engl J Med. 2008; 358: 1362-1369
- Reticulocyte parameters and hemoglobin F production in sickle cell disease patients undergoing hydroxyurea therapy.J Clin Lab Anal. 2003; 17: 66-72
- The influence of hydroxyurea on oxidative stress in sickle cell anemia.Rev Bras Hematol Hemoter. 2012; 34: 421-425
- Inflammatory molecule reduction with hydroxyurea therapy in children with sickle cell anemia.Haematologica. 2018; 103 (e50-e4)
- Investigators of the multicenter study of hydroxyurea in sickle cell A. Rheological properties of sickle erythrocytes in patients with sickle-cell anemia: the effect of hydroxyurea, fetal hemoglobin, and alpha-thalassemia.Eur J Haematol. 2018; 101: 798-803
- The effects of hydroxycarbamide on the plasma proteome of children with sickle cell anaemia.Br J Haematol. 2019; 186 (879-86)
- How I use hydroxyurea to treat young patients with sickle cell anemia.Blood. 2010; 115: 5300-5311
- Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the multicenter study of hydroxyurea in sickle cell anemia.New Engl J Med. 1995; 332: 1317-1322
- Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment.JAMA. 2003; 289: 1645-1651
- Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group.Blood. 1999; 94: 1550-1554
- Effect of hydroxyurea on growth in children with sickle cell anemia: results of the HUG-KIDS Study.J Pediatr. 2002; 140: 225-229
- Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease.Blood. 2004; 103: 2039-2045
- Long-term hydroxyurea treatment in children with sickle cell disease: tolerance and clinical outcomes.Haematologica. 2006; 91: 125-128
- The safety and efficacy of hydroxycarbamide in infants with sickle cell anemia.Expert Rev Hematol. 2011; 4: 407-409
- Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia.Blood. 2011; 118: 4985-4991
- Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.Lancet. 2016; 387 (661-70)
- Novel use of hydroxyurea in an african region with malaria (NOHARM): a trial for children with sickle cell anemia.Blood. 2017; 130 (2585-93)
- Hydroxyurea for Children with Sickle Cell Anemia in Sub-Saharan Africa.New Engl J Med. 2019; 380 (121-31)
National instututes of Health. Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014. https://www.nhlbi.nih.gov/health-topics/evidence-based-management-sickle-cell-disease. Accessed July 7, 2022.
- Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia.Blood. 1992; 79: 2555-2565
- A bioavailability and pharmacokinetic study of oral and intravenous hydroxyurea.Blood. 1998; 91: 1533-1541
- Optimizing hydroxyurea therapy for sickle cell anemia.Hematol Am Soc Hematol Educ Program. 2015; 2015: 436-443
- The risks and benefits of long-term use of hydroxyurea in sickle cell anemia: A 17.5 year follow-up.Am J Hematol. 2010; 85: 403-408
- Adverse effect of hydroxyurea on spermatogenesis in patients with sickle cell anemia after 6 months of treatment.Blood. 2017; 130: 2354-2356
- Hydroxyurea therapy contributes to infertility in adult men with sickle cell disease: a review.Expert Rev Hematol. 2014; 7: 767-773
- Reproductive issues in sickle cell disease.Blood. 2014; 124: 3538-3543
- Exposure to hydroxyurea and pregnancy outcomes in patients with sickle cell anemia.J Natl Med Assoc. 2009; 101: 1046-1051
- National institutes of health consensus development conference statement: hydroxyurea treatment for sickle cell disease.Ann Intern Med. 2008; 148: 932-938
- Hydroxyurea therapy for sickle cell disease in community-based practices: a survey of Florida and North Carolina hematologists/oncologists.Am J Hematol. 2005; 79: 107-113
- Hydroxyurea adherence and associated outcomes among Medicaid enrollees with sickle cell disease.Am J Hematol. 2011; 86: 273-277
- Examining the characteristics and beliefs of hydroxyurea users and nonusers among adults with sickle cell disease.Am J Hematol. 2011; 86: 85-87
- Patient-focused inquiry on hydroxyurea therapy adherence and reasons for discontinuation in adults with sickle cell disease.Am J Hematol. 2022; 97: E93-e5
- Spectrum of fetal hemoglobin responses in sickle cell patients treated with hydroxyurea: the National Institutes of Health experience.Semin Oncol. 1992; 19: 67-73
- Effects of hydroxyurea treatment for patients with hemoglobin SC disease.Am J Hematol. 2016; 91 (238-42)
- Hydroxyurea treatment of children with hemoglobin SC disease.Pediatr Blood Cancer. 2013; 60: 323-325
- Interorgan amino acid transport and its regulation.J Nutr. 2003; 133: 2068s-2072ss
- A phase 3 trial of l-glutamine in sickle cell disease.N Engl J Med. 2018; 379 (226-35)
- Decreased erythrocyte nicotinamide adenine dinucleotide redox potential and abnormal pyridine nucleotide content in sickle cell disease.Blood. 1988; 71: 512-515
- Oral L-glutamine therapy for sickle cell anemia: I. Subjective clinical improvement and favorable change in red cell NAD redox potential.Am J Hematol. 1998; 58: 117-121
U.S. Food and Drug Administration. L-Glutamine orphan drug designation and approval.
- L-glutamine therapy reduces endothelial adhesion of sickle red blood cells to human umbilical vein endothelial cells.BMC Blood Disord. 2005; 5: 4
European Medicines Agency. EU/3/12/1011: Orphan designation for the treatment of sickle cell disease. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3121011. Accessed July 7, 2022.
- L-glutamine therapy reduces hospitalization for sickle cell anemia and sickle β°-thalassemia patients at six months – a phase II randomized trial.Clin Pharm Biopharm. 2014; 3: 116
- L-glutamine use in adults with sickle cell disease: clinical trials where success meets reality.Am J Hematol. 2020;
Bradt P.S.E., Synnott P.G., Chapman R., Beinfeld M., Rind D.M., Pearson S.D.Crizanlizumab, voxelotor, and L-glutamine for sickle cell disease: effectiveness and value. ICER (Institute for Clinical and Economic Review); 2020.
- l-Glutamine for sickle cell anemia: more questions than answers.Blood. 2018; 132 (689-93)
European Medicines Agency. Xyndari: Withdrawal of the marketing authorisation application. https://www.ema.europa.eu/en/medicines/human/withdrawn-applications/xyndari. Accessed July 7, 2022.
- Platelet activation and platelet-erythrocyte aggregates in patients with sickle cell anemia.J Lab Clin Med. 1997; 129: 507-516
- Platelet-neutrophil-interactions: linking hemostasis and inflammation.Blood Rev. 2007; 21: 99-111
- P-selectin mediates the adhesion of sickle erythrocytes to the endothelium.Blood. 2001; 98: 1955-1962
- Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation.Nat Rev Immunol. 2004; 4: 325-335
- The contribution of endothelial cell P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo.Blood. 2004; 104: 3378-3385
Turhan A., Weiss L.A., Mohandas N., Coller B.S., Frenette P.S. Primary role for adherent leukocytes in sickle cell vascular occlusion: A new paradigm. Proceedings of the National Academy of Sciences. 2002;99:3047–3051.
U.S. Food and Drug Administration. Crizanlizumab orphan drug designation and approval. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=259708. Accessed July 7, 2022.
- P-selectin–mediated platelet-neutrophil aggregate formation activates neutrophils in mouse and human sickle cell disease.Arterioscler Thromb Vasc Biol. 2010; 30: 2392-2399
- Inhibition of cell adhesion by anti–P-selectin aptamer: a new potential therapeutic agent for sickle cell disease.Blood. 2011; 117: 727-735
- A potent oral P-selectin blocking agent improves microcirculatory blood flow and a marker of endothelial cell injury in patients with sickle cell disease.Am J Hematol. 2012; 87: 536-539
European Medicines Agency. EU/3/12/1034: Orphan designation for the treatment of sickle cell disease. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3121034. Accessed July 7, 2022.
- Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis.Am J Hematol. 2019; 94: 55-61
U.S. Food, Drug Administration. FDA approves crizanlizumab-tmca for sickle cell disease. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizanlizumab-tmca-sickle-cell-disease. Accessed July 7, 2022.
U.S. Food, Drug Administration. Voxelotor orphan drug designation and approval. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=499715. Accessed July 7, 2022.
European Medicines Agency. EU/3/16/1769: Orphan designation for the treatment of sickle cell disease. https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3–16-1769. Accessed July 7, 2022.
- GBT440 improves red blood cell deformability and reduces viscosity of sickle cell blood under deoxygenated conditions.Clin Hemorheol Micro. 2018; 70: 95-105
- A phase 1/2 ascending dose study and open-label extension study of voxelotor in patients with sickle cell disease.Blood. 2019; 133 (1865-75)
- Pharmacokinetics and pharmacodynamics of voxelotor (GBT440) in healthy adults and patients with sickle cell disease.Br J Clin Pharmacol. 2019; 85 (1290-302)
- A phase 3 randomized trial of voxelotor in sickle cell disease.N Engl J Med. 2019; 381 (509-19)
- 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.Lancet Haematol. 2021; 8 (e323-e33)
U.S. Food, Drug Administration. FDA approves voxelotor for sickle cell disease. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-voxelotor-sickle-cell-disease. Accessed July 7, 2022.
- Safety and efficacy of voxelotor in pediatric patients with sickle cell disease aged 4 to 11 years.Pedia Blood Cancer. 2022; 69e29716
- Curative vs targeted therapy for SCD: does it make more sense to address the root cause than target downstream events?.Blood Adv. 2020; 4 (3457-65)