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
Sickle cell disease is an inherited blood disorder afflicting an estimated 100,000
individuals in the United States and over 20 million people worldwide. The disease
is heralded as the first molecular disease. However, despite its genetic simplicity,
the pathophysiologic processes leading to its clinical sequelae are complex, heterogeneous
and interrelated, making drug development to treat the disease challenging. For over
two decades only one drug, hydroxyurea, had been used as disease-modifying therapy.
New pharmacologic agents are rapidly evolving with three new drugs, with different
mechanisms of action, approved by the United States Food and Drug Administration in
recent years (L-glutamine, crizanlizumab and voxelotor). Several therapeutic approaches targeting
different pathways in the disease pathophysiology are being investigated. These include
inhibition of hemoglobin S polymerization such as by fetal hemoglobin induction or
by increasing hemoglobin oxygen affinity, as well as intervention of downstream pathways
including inhibiting cellular adhesion, reducing inflammation and oxidant stress,
modulating platelet activation and coagulation abnormalities, and targeting nitric
oxide signaling. This review will provide an overview of these therapeutic strategies,
discuss the four currently approved drugs in detail, and summarize ongoing clinical
trials of new drugs or drug indications for the treatment of sickle cell disease in
different phases of development excluding those related to cellular therapies.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Transfusion and Apheresis ScienceAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- 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)
Article Info
Publication History
Published online: August 28, 2022
Identification
Copyright
© 2022 Elsevier Ltd. All rights reserved.
