Investigational pharmacologic therapies for sickle cell disease

INTRODUCTION — The major causes of morbidity and mortality in sickle cell disease (SCD) are the acute and long-term consequences of ischemia-reperfusion injury of the organs, leading to cerebral infarcts; heart, lung, and kidney disease; pain that can be severe and debilitating; and other complications.

Hydroxyurea is the primary therapy to prevent these complications in children and adults with Hb SS and Hb S beta⁰ thalassemia. Hydroxyurea provides a myriad of well-documented clinical benefits, making it the first choice for children and adults with Hb SS and Hb S beta⁰ thalassemia. However, hydroxyurea has limitations, and not all individuals with SCD benefit from therapy. Additional therapies are needed for those who cannot take hydroxyurea or for whom hydroxyurea or one of the other disease-modifying therapies is ineffective. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease".)

This topic reviews potential therapies for SCD that are in development or undergoing clinical investigation, including their rationale, preclinical data, and information from early clinical trials. It also discusses when these approaches should be considered and when patients should be referred to be considered for therapy with a curative intent.

Separate topic reviews discuss existing management options in SCD including routine evaluations and treatments, hydroxyurea and other disease-modifying therapies, transfusions, and hematopoietic stem cell transplantation:

●Management overview – (See "Overview of the management and prognosis of sickle cell disease".)

●Comprehensive care for children – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

●Pain management – (See "Acute vaso-occlusive pain management in sickle cell disease".)

●Hydroxyurea – (See "Hydroxyurea use in sickle cell disease".)

●Transfusion – (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

●Stem cell transplantation and gene therapy – (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy".)

OVERVIEW OF SCD DRUG DEVELOPMENT

Timeline of drug development in SCD — Since the initial report of SCD, there have been few approved disease-modifying therapies, with the first drug, hydroxyurea, approved over 80 years later. The timeline of new SCD therapies has accelerated during the previous two decades, with the following history:

●1910 – SCD first reported

●1998 – First drug approved for SCD treatment (hydroxyurea)

●2017 to 2019 – Three additional therapies approved (L-glutamine in 2017; crizanlizumab and voxelotor in 2019)

Limitations of available therapies — The most common and debilitating complication experienced by individuals with SCD is acute vaso-occlusive pain. However, there are other risks for severe morbidity and early mortality due to chronic complications such as stroke, kidney failure, and cardiopulmonary disease [1,2]. Despite the remarkable efficacy of hydroxyurea, there are limitations to its use, and many questions remain unanswered:

●Indications – The efficacy of hydroxyurea in individuals with Hb SC and Hb S beta⁺ thalassemia is unproven. Important clinical trial data have mostly included individuals with Hb SS and Hb S beta⁰ thalassemia. (See "Hydroxyurea use in sickle cell disease", section on 'Evidence for efficacy'.)

●Safety – Hydroxyurea has limited use in individuals planning to have children. It typically is not used in female patients who are attempting to conceive due to presumed teratogenic effects, although definitive evidence of teratogenicity is lacking [3]. It typically is not used in males attempting conception due to its impact on sperm count, although it has no significant impact on spermatogenesis when started during the pre-pubertal period [4,5]. (See "Hydroxyurea use in sickle cell disease", section on 'Adverse effects'.)

●Efficacy – Hydroxyurea reduces vaso-occlusive pain episodes, acute chest syndrome, and red blood cell transfusions by approximately 50 percent in adults with Hb SS and Hb S beta⁰ thalassemia. However, some individuals will continue to have acute pain episodes, other vaso-occlusive events, or both, despite adherence to properly administered hydroxyurea. Morbidity and mortality remain high in adults with SCD, even when treated with hydroxyurea [6]. (See "Overview of the management and prognosis of sickle cell disease", section on 'Survival and prognosis'.)

The newer FDA-approved therapies may further reduce vaso-occlusive complications, improve anemia, and/or reduce hemolysis, but none of them have been demonstrated to abate progressive heart, lung, kidney, or central nervous system disease or to provide a cure for the disease. Additionally, some carry high costs and burdens such as the requirement for intravenous administration. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Disease-modifying medications'.)

Regular blood transfusion therapy, with a goal to decrease the Hb S level <30 percent or 50 percent, is indicated in some individuals, but transfusions also carry significant costs and burdens. (See 'Transfusions' below.)

New therapies and multi-modality approaches are needed to prevent acute vaso-occlusive pain episodes, attenuate progressive organ damage (including brain, heart, lung, and kidney), and increase life expectancy, as well as therapies that can be used in individuals with other compound heterozygous SCD (including sickle beta⁺ thalassemia and hemoglobin SC disease). Further, no disease-modifying therapy, other than monthly blood transfusion therapy, can be used for pregnant women, a period with the highest incidence rates of acute pain and acute chest syndrome [7]. As new therapies are being considered, strategies should be included that can be used during pregnancy.

Categories of SCD therapies — Therapies for SCD can be categorized as pharmacologic or curative.

●Pharmacologic – Pharmacologic therapies are medications that must be taken on a regular basis. There are several steps in the vaso-occlusion process that can be targeted. Many of these are under investigation, as summarized in the discussions below. Examples include:

•Fetal hemoglobin induction – (See 'Increasing Hb F' below.)

•Inhibiting sickle hemoglobin polymerization – (See 'Reducing Hb S polymerization' below.)

•Reducing interactions between sickle cells, neutrophils, and/or vasculature – (See 'Decreasing cell adhesion' below.)

•Decreasing oxidative stress – (See 'Decreasing oxidative stress (cathepsin B inhibitor, arginine)' below.)

In some cases it may be possible to target several of these processes simultaneously, which might produce additive or synergistic effects.

●Curative – Curative therapy refers to hematopoietic stem cell transplant, including allogeneic HSCT from a matched sibling donor, haploidentical donor, or matched unrelated donor; or autologous transplantation using autologous hematopoietic stem cells that have been treated with gene therapy or gene editing techniques. These are discussed separately. (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy".)

How to select and sequence therapies

FDA-approved agents — US Food and Drug Administration (FDA)-approved agents, along with indications for use, supporting data, and appropriate sequence, are summarized below and discussed in detail in separate topic reviews:

●Hydroxyurea – Should be offered to all adults and children with Hb SS and Hb S beta⁰ thalassemia at nine months of age. (See "Hydroxyurea use in sickle cell disease".)

●L-glutamine – May be offered to children ≥5 years or adults who continue to have pain episodes despite hydroxyurea or who cannot take hydroxyurea. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'L-glutamine (pharmaceutical grade)'.)

●Crizanlizumab – May be offered to adolescents ≥16 years or adults who continue to have pain episodes despite hydroxyurea or who cannot take hydroxyurea. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Crizanlizumab'.)

●Voxelotor – May be offered to children ≥4 years or adults who have symptomatic or severe anemia related to their SCD.

Transfusions — Transfusions can be used to treat acute anemia or as prophylaxis against complications, as summarized briefly here and in detail separately. The goal of chronic (regular) transfusion therapy or exchange transfusions is to keep the percent of Hb S <30 percent. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Indications for transfusion'.)

●Acute vaso-occlusive events – Transfusions are used in the acute setting for stroke, acute chest syndrome, multi-organ failure, symptomatic anemia, hepatic sequestration, or splenic sequestration.

●Prophylaxis – Transfusions are used preoperatively and during pregnancy. Chronic transfusions are used for stroke prevention in at-risk individuals, and for certain other recurrent vaso-occlusive complications (eg, acute chest syndrome) if they continue despite hydroxyurea and the individual is eligible for therapy.

●Pain control – We consider a defined period of chronic transfusions (typically 6 to 12 months) in adolescents and adults with recurrent acute pain episodes that are not improved with disease-modifying therapy. Transfusion therapy is often coupled with mental health counseling for assessment of the presence and treatment of depression and anxiety. However, transfusions carry risks and burdens, as discussed separately. We agree with a 2020 guideline from the American Society of Hematology (ASH) that suggests monthly (regular) transfusions not be used as a first-line strategy to prevent or reduce recurrent acute pain episodes [8]. (See "Transfusion in sickle cell disease: Management of complications including iron overload".)

When to consider investigational therapies — Individuals whose disease is well controlled with available therapies, who have good quality of life, and who wish to avoid the burdens and unknown risks of investigational therapies, may continue their current treatment. For others, the question of investigational therapies may be further explored.

Investigational therapies that have not been approved by the FDA or a comparable regulatory agency are administered as part of a clinical trial. FDA-approved therapies may be administered for an off-label indication that is considered investigational. The decision to participate in a clinical trial depends on what clinical trials are available at the time and the expert opinion of an SCD specialist.

Clinicians and patients should familiarize themselves with the details of the trial (or off-label use) before participating, including available alternatives, possible benefits, possible risks, and trial design and oversight. In some cases, individuals and their families may need to travel to specialized SCD centers that are conducting research to receive investigational therapies.

The risk-benefit calculation differs substantially between pharmacologic therapies, which can be discontinued if unhelpful or for side effects, versus curative therapies, which carry a much higher up-front risk and the possibility for cure. Considerations for each type of therapy are discussed below.

●Pharmacologic – Pharmacologic therapies include a number of drugs directed at various biologic targets to improve disease outcomes, typically focused on decreasing the incidence of acute vaso-occlusive pain. Our approach is to reserve investigational pharmacologic therapies for children and adults who want to participate in clinical trials and where the potential risk-benefit ratio favors trial participation. Drug trials for the most part focus on painful episodes as an endpoint, although drugs that reduce vaso-occlusive pain may also reduce other vaso-occlusive complications.

●Curative – We believe all patients with SCD should have the opportunity to discuss risks and benefits of curative therapies with their physicians. Details of the indications and risk-benefit calculations are discussed separately. (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy".)

Resources for determining which trials are available as well as recruiting, entry criteria, and other aspects of trial oversight are limited. The clinicaltrials.gov website is the best resource for trial review. Referral to an expert center that conducts high-quality clinical trials in SCD, including curative therapies, may be the best approach to ensuring that patients and their families/caregivers receive the most comprehensive and balanced information about available trials.

INCREASING HB F — Fetal hemoglobin (hemoglobin F [Hb F]) is comprised of alpha globin chains and gamma globin chains, which do not contain the sickle cell variant (present only in beta globin chains). Increases in Hb F reduce the proportion of sickle hemoglobin, and this reduction in turn reduces the abnormal polymerization of hemoglobin molecules. (See 'Reducing Hb S polymerization' below.)

Increasing Hb F was initially thought to be the primary mechanism of action of hydroxyurea in SCD, although other contributing mechanisms have subsequently been proposed. (See 'FDA-approved agents' above and "Hydroxyurea use in sickle cell disease", section on 'Mechanism of action'.)

Other drugs are under development to increase Hb F by a variety of mechanisms:

●Epigenetic changes – Drugs that de-repress gamma globin gene expression via epigenetic mechanisms (deoxyribonucleic acid [DNA] methyltransferase [DNMT] inhibitors, histone deacetylase [HDAC] inhibitors) [9-14]. Of these, decitabine appears the most promising, but data are very limited [13]. A trial including combination treatment with decitabine and the pharmacokinetic enhancer tetrahydrouridine (THU) is ongoing [15]. Other epigenetic drugs including sodium dimethyl butyrate, vorinostat, and an inhibitor of lysine-specific demethylase (LSD-1) did not significantly elevate Hb F or were terminated early. (See "Principles of epigenetics".)

●Immunomodulatory changes – In mouse models, the immunomodulatory agent, pomalidomide, led to modest increases of Hb F similar to hydroxyurea, with preserved bone marrow function and enhanced erythropoiesis [16]. One phosphodiesterase-9 inhibitor (IMR-687) also increased Hb F and decreased hemolysis [17]. Cilostazol (OPC-13013) is a reversible type III phosphodiesterase inhibitor with antiplatelet and vasodilating properties. In vitro, cilostazol induced red blood cell (RBC) differentiation and Hb F production [18]. In a murine model, it led to gamma globin mRNA upregulation and an increase in Hb F-producing RBCs.

Curative therapies that increase Hb F levels are also being pursued. (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy", section on 'Gamma globin upregulation (including exa-cel, Casgevy)'.)

REDUCING HB S POLYMERIZATION — Normal hemoglobin remains soluble in the cytoplasm of RBCs during repeated cycles of oxygenation and deoxygenation. In contrast, Hb S polymerizes when deoxygenated, leading to precipitation and gel formation within the cell. The rate of polymerization depends on the intracellular Hb S concentration. These polymers dramatically reduce RBC deformability and cause damage to the RBC membrane.

Once polymerization occurs, polymerization-induced membrane damage leads to cellular dehydration, which in turn further increases the Hb S concentration, resulting in a cycle of worsening polymerization. This creates a population of very dense cells that are much more prone to sickling and contribute disproportionately to vaso-occlusion. (See "Pathophysiology of sickle cell disease", section on 'Effects on the RBC'.)

Several agents are under investigation to inhibit Hb S polymerization, through one or more of the following mechanisms [19]:

●Increasing Hb F production – (See 'Increasing Hb F' above.)

●Activating pyruvate kinase – (See 'Pyruvate kinase activation (mitapivat, etavopivat)' below.)

●Directly interfering with polymerization – (See 'Increasing O2 affinity of Hb S' below.)

●Improving cellular hydration – (See 'Increasing RBC hydration (senicapoc, memantine)' below.)

●Improving oxygen delivery to RBCs – (See 'Increasing oxygen delivery' below.)

●Decreasing intracellular hemoglobin concentration – (See 'Decreasing intracellular Hb concentration' below.)

Voxelotor is a US Food and Drug Administration (FDA)-approved agent that directly inhibits Hb S polymerization. (See 'FDA-approved agents' above.)

Pyruvate kinase activation (mitapivat, etavopivat) — The pathophysiology of SCD involves sickle hemoglobin polymerization upon deoxygenation. (See 'Reducing Hb S polymerization' above.)

RBCs with sickle hemoglobin are prone to deoxygenation; they have decreased oxygen affinity due to increased 2,3-diphosphoglycerate (2,3-DPG). (See "Pathophysiology of sickle cell disease", section on 'Effects on the RBC'.)

Thus, increasing oxygen affinity by manipulating 2,3-DPG levels might reduce Hb S polymerization. This is feasible because 2,3-DPG levels are controlled by the RBC enzyme pyruvate kinase (PK), and small molecule activators of PK are under study. (See "Pyruvate kinase deficiency", section on 'PK enzymatic function'.)

Two agents that increase PK activity and decrease 2,3-DPG levels are under study:

●Mitapivat (MAG-348)

●Etavopivat (FT-4202)

A phase 1 dose-escalation study of mitapivat in 16 patients reported that at the 50 mg twice daily dose level, mean hemoglobin increased by 1.2 g/dL compared with baseline [20]. There were dose-dependent increases in ATP and decreases in 2,3-DPG levels and improvements in hemolysis markers, with a tolerable safety profile. These results were confirmed in a study involving an additional nine patients [21].

Mitapivat can also be used to treat PK deficiency because it can increase the activity of dysfunctional variants of PK. (See "Pyruvate kinase deficiency", section on 'Treatment'.)

Etavopivat has shown promise in decreasing 2,3-DPG levels and increasing oxygen affinity in nonhuman primates and healthy volunteers [22,23]. RBCs collected from patients treated with etavopivat displayed increased Hb-oxygen affinity and reduced sickling under deoxygenation. Clinical trials are ongoing.

Increasing O2 affinity of Hb S — A small molecule that binds noncovalently to Hb S and increases its oxygen affinity was identified using an in-silico screening strategy [24]. In a mouse model, this compound decreased sickling and increased hemoglobin levels [25]. This compound is being pursued clinically, with initial testing in healthy volunteers [26].

Increasing RBC hydration (senicapoc, memantine) — Ion transport channels in the red blood cell (RBC) membrane control hemoglobin concentration by regulating the amount of intracellular solutes and free water. The RBC membrane has channels for potassium (K), sodium (Na), chloride (Cl), and other solutes, as discussed in detail separately. Increasing RBC hydration is a potential means of decreasing Hb S polymerization by decreasing its concentration in the RBC.

The Gardos channel (a calcium-activated K channel) is an attractive target for reducing Hb S concentration because Gardos channel inhibitors are already in clinical use for other indications.

Senicapoc (ICA-17043) is a highly potent Gardos channel inhibitor with good preclinical evidence of efficacy in improving RBC hydration. In a 2011 trial that randomly assigned 289 individuals with SCD to receive placebo or senicapoc, laboratory parameters improved (hemoglobin, cell hydration) but there was no reduction in pain episodes [27]. The hemoglobin response with senicapoc was similar to that with 900 mg voxelotor; although, larger reductions in markers of hemolysis were seen after treatment with senicapoc [28].

The Gardos channel inhibitor clotrimazole was previously studied in five individuals with SCD without clinical improvement [29].

N-methyl D-aspartate (NMDA) receptors are upregulated in RBCs of patients with SCD, and calcium uptake via these non-selective cation channels has a major impact on RBC hydration and Hb S polymerization. In vitro treatment of RBCs from individuals with SCD using the NMDA receptor inhibitor memantine led to RBC hydration and reduced sickling [30]. A study of the safety, tolerability, and efficacy of memantine as a long-term treatment of SCD is ongoing.

Increasing oxygen delivery — Sanguinate (pegylated bovine carboxyhemoglobin) is designed to deliver carbon monoxide as well as oxygen to tissues. Sanguinate has also been shown in vitro to deliver oxygen and carbon monoxide to sickled RBCs, reversing sickling [31]. A study involving 24 adults with homozygous SCD concluded that Sanguinate was safe [32]. A study using Sanguinate to treat vaso-occlusive pain has been completed.

Decreasing intracellular Hb concentration — The tendency of Hb S to polymerize is strongly dependent on the intracellular Hb S concentration; a relatively small decrease in intracellular Hb S concentration may inhibit HbS polymerization and its sequelae. (See "Pathophysiology of sickle cell disease", section on 'Hb S polymerization and fiber formation'.)

Vamifeport is an oral ferroportin inhibitor that restricts intracellular iron and hemoglobin within RBCs, leading to decreased markers of hemolysis in a mouse model of SCD [33]. Vascular cell adhesion molule-1 (VCAM-1), a biomarker of vascular inflammation, was also decreased, and adhesivity of vamifeport-treated blood cells to the endothelium was reduced. A clinical trial is ongoing to evaluate markers of hemolysis in patients with SCD treated with vamifeport [34].

DECREASING INFLAMMATION

Decreasing cell adhesion

Blocking selectin binding (rivipansel) — Selectins are cell-surface adhesion molecules expressed on endothelial cells (E-selectin), white blood cells, and platelets (P [for platelet]-selectin) that may contribute to increased adhesion between blood cells and the microvasculature that promotes vaso-occlusion. (See "Pathophysiology of sickle cell disease", section on 'Adhesion of sickled cells to the vascular endothelium'.)

Crizanlizumab is a P-selectin-blocking monoclonal antibody therapy that was approved by the FDA in late 2019. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Crizanlizumab'.)

Rivipansel (GMI-1070) is a small molecule pan-selectin inhibitor that is administered intravenously. In a randomized trial involving 345 participants (204 adults and 141 children) who were hospitalized for vaso-occlusive pain, rivipansel did not appreciably alter the time to discharge [35].

Antiinflammatory heparinoid (sevuparin) — Sevuparin is a short heparinoid altered to remove its anticoagulant properties while maintaining its antiinflammatory, anti-aggregation, and anti-adhesive properties. In a trial that randomly assigned 144 adults with SCD to receive sevuparin or placebo intravenously for two to seven days, there was no significant difference between groups in the median time to resolution of vaso-occlusive pain [36]. There was no significant difference in the median time to vaso-occlusive pain resolution between the sevuparin and placebo groups (100.4 hours [95% CI 85.5-116.8]) versus 86.4 hours [70.6-95.1]; hazard ratio [HR] 0.89, 95% CI 0.6-1.3]). Serious adverse events occurred in 22 percent of patients in both arms. The observation that sevuparin did not attenuate recovery to baseline for acute vaso-occlusive pain events does not mean therapy will be ineffective for pain prevention, only that sevuparin therapy is not beneficial for abating a severe vaso-occlusive pain episode requiring hospitalization. Further research in this area is needed.

Decreasing neutrophil interactions (IVIG) — Neutrophil interactions with RBCs and endothelial cells could contribute to vaso-occlusion by creating a nidus of adhesion and retarded blood flow. (See "Pathophysiology of sickle cell disease", section on 'Inflammation'.)

Decreases in neutrophil counts may be one of mechanisms by which hydroxyurea reduces vaso-occlusion. (See "Hydroxyurea use in sickle cell disease", section on 'Mechanism of action'.)

Intravenous immune globulin (IVIG) has been studied to improve outcomes of vaso-occlusive pain. In a mouse model of SCD, IVIG decreased neutrophil adhesion to the endothelium and neutrophil interactions with RBCs [37,38]. Preliminary studies in children and adolescents with SCD suggest a trend towards shorter duration of vaso-occlusive pain with IVIG, although opioid use was not dramatically affected [39].

Administration of recombinant TGF-β1 administration decreased TNFα-induced leukocyte rolling, extravasation, and adhesion in a murine SCD model [40]. On the other hand, inhibition of TGF-β increased those factors.

Decreasing neutrophil activation and adhesion — Abnormal neutrophils may contribute to thromboinflammation in SCD. Annexin A1 (AnxA1) enables resolution of inflammation through formyl peptide receptors (FPR). In a mouse model of SCD, administration of the AnxA1 mimetic peptide AnxA1Ac2-26 increased blood flow cessation time in cerebral venules and arterioles [41]. This effect was reversed in SCD mice that were neutropenic prior to peptide administration, suggesting the decreased flow-cessation time in SCD mice is neutrophil dependent.

The oral tyrosine kinase inhibitor imatinib mesylate reduces neutrophil count and may decrease adhesion to the endothelium. In a mouse model of SCD, imatinib mesylate prevented neutrophil adhesion to inflammatory activated vascular endothelial cells [42,43]. Imatinib also decreased the hypoxia/reperfusion-induced inflammatory response in the lungs and kidneys. A trial is ongoing to evaluate whether imatinib decreases the frequency of vaso-occlusive pain in adults with SCD [44].

Decreasing sickle RBC-endothelial adhesion

●Recombinant ADAMTS13 – Ultralarge von Willebrand factor (ULVWF) multimers promote sickle RBC-endothelial adhesion. The metalloprotease ADAMTS13 cleaves ULVWF multimers. In one study, the ratio of ADAMTS13 to VWF:Ag was decreased in individuals with SCD, especially during a pain episode [45]. In a murine model of SCD vaso-occlusion, administration of recombinant ADAMTS13 reduced hemolysis and inflammation in the lungs and kidneys [46]. A clinical trial is ongoing.

●Olinciguat – Olinciguat is a soluble guanylyl cyclase. In a mouse model of SCD, olinciguat improved survival and biomarkers of leukocyte-endothelial cell interactions and endothelial cell activation following treatment with tumor necrosis factor (TNF)-alpha [47]. A clinical trial is ongoing.

Decreasing inflammasome activation (canakinumab) — Inflammasomes are cytosolic multiprotein oligomers of the innate immune system that promote inflammation. Activation of inflammasomes leads to an inflammatory cascade that includes cleavage of pro-interleukin-1 beta (pro-IL-1b) into its active form, IL-1b, thereby inducing other inflammatory responses.

Canakinumab is a monoclonal antibody that inhibits IL-1b. In a randomized trial involving 49 individuals with SCD ages 8 to 20 years who had two or more vaso-occlusive events in the previous year, treatment with canakinumab for 24 weeks led to a modest decrease in the number of hospitalizations (mean, 0.9 versus 1.1 per patient), a shorter average duration of hospitalization (mean 6 versus 16; maximum 37 versus 127), and fewer days of opioid use (27 versus 48 days) [48]. Clinically meaningful pain reductions recorded by electronic diary were not statistically different in the canakinumab group compared with the placebo group. Markers of inflammation including high-sensitivity C-reactive protein, total leukocyte count, and neutrophils showed greater reductions in the canakinumab group. Therapy was well tolerated without an increase in infectious complications.

Decreasing platelet binding — Platelet activation is increased at baseline in SCD, and it is further increased during vaso-occlusive events, leading to the hypothesis that blocking platelet function might decrease vaso-occlusion. However, two randomized trials failed to show a benefit. A 2022 trial comparing the platelet adenosine diphosphate (ADP) P2Y₁₂ inhibitor ticagrelor versus placebo in children with SCD did not show a statistically significant reduction in pain episodes or other endpoints (annualized rate of vaso-occlusive pain episodes, 2.74 with ticagrelor and 2.60 with placebo; rate ratio 1.06, 95% CI 0.75-1.50) [49]. The 2016 DOVE trial evaluating the ADP P2Y₁₂ inhibitor prasugrel also did not show a meaningful reduction in vaso-occlusive episodes [50].

DECREASING OXIDATIVE STRESS (CATHEPSIN B INHIBITOR, ARGININE) — Oxidative stress might contribute to vaso-occlusion by affecting the vasculature (vascular tone or adhesivity). (See "Pathophysiology of sickle cell disease", section on 'Vasoconstriction' and "Pathophysiology of sickle cell disease", section on 'Hypercoagulable state'.)

Oral L-glutamine is an FDA-approved agent for SCD that likely reduces oxidative stress by increasing the relative amount of reduced nicotinamide adenine dinucleotides in sickle RBCs [51]. L-glutamine decreases the frequency of hospitalizations for vaso-occlusive pain, even in individuals taking hydroxyurea. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease".)

Other agents that might reduce oxidative stress are under investigation:

●Inhibitor of cathepsin B – Investigators have reported abnormal retention of mitochondria in the RBCs of some individuals with SCD and in a mouse model [52,53]. Autophagy dysregulation may be responsible for the abnormal mitochondrial retention. Cathepsin B, a negative regulator of autophagy, was found to be overexpressed in the reticulocytes of patients with SCD and in the mouse model, and unpublished reports suggest that the cathepsin B inhibitor E64d might be a therapeutic target.

●L-arginine – L-arginine is an amino acid that is the obligate substrate for nitric oxide production; levels of arginine and nitric oxide are depleted by hemolysis in SCD [54,55]. Low bioavailability of arginine is associated with adverse clinical outcomes in SCD, including increased risk of pulmonary hypertension, pain severity, and early mortality [56-60]. Studies have demonstrated that arginine increases nitric oxide levels and lowers oxidative stress in children with SCD [61-63].

Arginine is also an endogenous analgesic with opioid-sparing effects [64-67]. In randomized trials in children with SCD-associated vaso-occlusive pain, arginine decreased pain scores relative to placebo and improved cardiopulmonary parameters including tricuspid regurgitant jet velocity and systolic blood pressure [64-70]. Further demonstrations of marked analgesia were reported in non-SCD patients with various forms of pain approximately 30 to 40 minutes after treatment with intravenous arginine, with a dose-dependent effect that lasted 6 to 24 hours and was blocked by intravenous naloxone [66,67].

DECREASING HEMOLYSIS (HEMOPEXIN) — Hemolyzed sickle RBCs release heme, which induces expression of pro-inflammatory adhesion molecules and cytokines by endothelium and blood cells, promoting vaso-occlusion.

Hemopexin scavenges heme in plasma. In a murine model of SCD, injection of free hemoglobin induced vaso-occlusion [71]. Hemopexin administration prevented or decreased hemoglobin-induced and hypoxia/reoxygenation-induced vaso-occlusion in a dose-dependent manner. Hemopexin was given safely to rats and nonhuman primates. A clinical trial is ongoing.

DECREASING PAIN (TOPICAL CAPSAICIN, ARGININE) — TRPV1 (transient receptor potential cation channel, subfamily V, member 1, also a vanilloid and capsaicin receptor) is a nociceptive ion channel found to be upregulated in a mouse model of SCD; it may have a role in the transition from acute vaso-occlusive pain to peripheral sensitization and eventually central sensitization [72]. In a study involving 10 patients with SCD treated with 8 percent topical capsaicin, pain scores improved significantly without severe adverse events [73].

L-arginine also has natural analgesic effects. (See 'Decreasing oxidative stress (cathepsin B inhibitor, arginine)' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sickle cell disease and thalassemias".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Sickle cell disease (The Basics)" and "Patient education: Sickle cell trait (The Basics)" and "Patient education: When your child has sickle cell disease (The Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY AND RECOMMENDATIONS

●Existing therapies – Hydroxyurea, chronic transfusions, and new drugs approved by the US Food and Drug Administration (FDA) in 2017 to 2019 are effective at reducing vaso-occlusive pain and other complications of sickle cell disease (SCD). Indications are discussed in separate topic reviews. (See 'Timeline of drug development in SCD' above and "Hydroxyurea use in sickle cell disease" and "Disease-modifying therapies to prevent pain and other complications of sickle cell disease" and "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques".)

●Need for new therapies – Existing therapies require lifelong administration, do not eliminate vaso-occlusive complications, and may be challenging for some individuals to take. Transfusions carry several risks and burdens and often cannot be continued indefinitely. (See 'Limitations of available therapies' above.)

●When to consider – Pharmacologic therapies may be explored as part of a well-conducted clinical trial if vaso-occlusive complications persist despite adequately administered hydroxyurea or other disease-modifying therapies or if these therapies cannot be used. (See 'When to consider investigational therapies' above.)

●Pharmacologic approaches – Many new agents are being investigated. Combining approaches with different mechanisms might produce additive or synergistic effects. The following are broad categories based on mechanism of action:

•Increasing fetal hemoglobin – (See 'Increasing Hb F' above.)

•Reducing sickle hemoglobin polymerization – (See 'Reducing Hb S polymerization' above.)

•Blocking sickle RBC or neutrophil interactions with the vasculature – (See 'Decreasing cell adhesion' above.)

•Decreasing inflammation or oxidative stress – (See 'Decreasing inflammation' above and 'Decreasing oxidative stress (cathepsin B inhibitor, arginine)' above.)

•Reducing hemolysis – (See 'Decreasing hemolysis (hemopexin)' above.)

●Curative approaches – Curative approaches include allogeneic hematopoietic stem cell transplantation using a matched sibling donor, haploidentical related donor, or matched unrelated donor; o autologous transplantation using autologous stem cells modified by gene therapy or gene editing. These approaches, including indications and risk-benefit calculations, are discussed separately. (See "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy".)

ACKNOWLEDGMENTS

UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic review and was a founding Editor-in-Chief for UpToDate in Hematology.

The editorial staff at UpToDate would also like to acknowledge Griffin P Rodgers, MD, who contributed to earlier versions of this topic review.