Sickle cell disease (SCD) is an inherited blood disorder characterized by the presence of abnormal hemoglobin S (HbS). HbS polymerization causes red blood cells (RBCs) to deform into a crescent or sickle shape. Sickle cells are less flexible and deformable than normal RBCs.They adhere to other cells, interrupt vascular blood flow, and trigger vaso-occlusive events, causing severe pain, hypoxia, and organ damage.1,2
In SCD, RBCs interact not only with the vascular endothelium but also with other blood cells, such as neutrophils, monocytes, and platelets. The constant activation of these cells promotes an ongoing inflammatory process.2
Neutrophils play a central role in vaso-occlusive events by interacting with RBCs and with the endothelium, upregulating the expression of P- and E-selectins. Activated platelets form clots with RBCs, monocytes, and neutrophils. The development of these aggregates is thought to be P-selectin dependent.2
An understanding of the pathophysiological processes underlying the key events in SCD has uncovered potential key therapeutic targets, such as P- and E-selectins. New therapies, such as the P-selectin inhibitor crizanlizumab (commercialized as Adakveo®), have been developed.2 Many other investigational molecules designed to target various SCD events are currently under evaluation.
Rivipansel (GMI-1070) is a pan-selectin inhibitor with activity mainly against E-selectin. A phase 2 clinical study (NCT01119833) demonstrated the efficacy of rivipansel in decreasing multiple measures of vaso-occlusion in comparison with standard treatment. A phase 3 clinical trial (NCT02187003) was then undertaken to report on the efficacy and safety of rivipansel in the treatment of vaso-occlusion in hospitalized patients with SCD. However, rivipansel failed to meet the study efficacy points; the drug failed to reduce the frequency of “vaso-occlusive sickle crisis.”2
CSL899 is a form of plasma-derived hemopexin, a naturally occurring protein whose expression is downregulated in patients with SCD. Decreased levels of hemopexin can be linked to an increase in vaso-occlusive crises.3 The US Food and Drug Administration and the European Commission have both granted orphan drug status to CSL899,3 and an open-label phase 1 clinical trial designed to study the safety, tolerability, and pharmacokinetics of CSL899 is currently enrolling patients (NCT04285827).
Panobinostat (LBH589) and Vorinostat
Panobinostat (LBH589) is a pan-histone deacetylase (HDAC) inhibitor that increases DNA transcription and protein accumulation, reduces cell proliferation, and leads to cell death.4 Inhibition of the HDAC1 or HDAC2 gene was shown to increase gamma globin expression and hemoglobin F (HbF) levels and therefore is a promising approach to treating SCD.5,6 The safety and efficacy of panobinostat are currently under investigation in a phase 1 clinical trial (NCT01245179).
Vorinostat (known as suberoylanilide hydroxamic acid, or SAHA) is also an inhibitor of HDAC that reduces the production of alpha-globin and increases the expression of gamma-globin.6 It is currently approved for the treatment of advanced cutaneous T-cell lymphoma and is under study for use in SCD. A phase 2 clinical trial to determine the efficacy, safety, and tolerability of vorinostat in the treatment of SCD was recently terminated early because of poor recruitment (NCT01000155).
IMR-687 is a phosphodiesterase 9 inhibitor that increases HbF production by promoting intracellular cyclic guanosine monophosphate (cGMP) levels through the selective inhibition of cGMP hydrolysis.7 IMR-687 was specifically designed to target SCD, and its efficacy, safety, and tolerability were assessed in a phase 2 clinical trial (NCT03401112). In this study, IMR-687 reduced the number of vaso-occlusive crises in patients with SCD. An extension study to evaluate its long-term safety and tolerability (NCT04053803) is currently enrolling by invitation.2
Mitapivat and FT-4202
Mitavipat (AG-348) and FT-4202 are pyruvate kinase (PK) activators that decrease 2,3-diphosphoglycerate (2,3-DPG) levels. PK is an enzyme involved in the final step of glycolysis. PK activation increases hemoglobin oxygenation via 2,3-DPG inhibition and so inhibits sickling. In addition, a beneficial effect on RBC membrane integrity is associated with an increase in adenosine triphosphate (ATP) levels.8 Mitapivat was reported to be well tolerated and safe in a phase 1 trial (NCT04000165). A phase 1/phase 2 extension study will assess the long-term tolerability and safety of mitapivat in patients with SCD (NCT04610866). The safety, pharmacokinetics, and pharmacodynamics of FT-4202 are being investigated in a phase 1 clinical trial (NCT03815695). A phase 2/phase 3 clinical trial (HIBISCUS) is currently recruiting patients to assess the efficacy and safety of FT-4202 in adults and adolescents with SCD.8
Patients with SCD typically have high levels of pro-inflammatory cytokines, neutrophils, and other molecules capable of inducing inflammation, so that exploring anti-inflammatory strategies is an interesting therapeutic approach.8 Regadenoson is an adenosine 2A receptor agonist that acts as an anti-inflammatory agent and is used for myocardial perfusion imaging.9 The expected mode of action of adenosine 2A receptor agonists in patients with SCD is to decrease the activation of invariant natural killer T (iNKT) cells, thus reducing the number of vaso-occlusive crises. A phase I study reported the safe administration of regadenoson to patients with SCD and vaso-occlusive crises (NCT01085201); however, in a phase 2 trial, the drug failed to achieve a statistically significant reduction in iNKT cells in comparison with no treatment (NCT01788631).10
1. Sickle cell disease. National Organization for Rare Disorders (NORD). Accessed November 28, 2021.
2. Salinas Cisneros G, Thein SL. Recent advances in the treatment of sickle cell disease. Front Physiol. 2020;11:435. doi:10.3389/fphys.2020.00435
3. Orphan drug designation granted for CSL Behring’s investigational plasma-derived hemopexin therapy for sickle cell disease. News release. CSL Behring; November 2, 2020.
4. Van Veggel M, Westerman E, Hamberg P. Clinical pharmacokinetics and pharmacodynamics of panobinostat. Clin Pharmacokinet. 2018;57(1):21-29. doi:10.1007/s40262-017-0565-x
5. Esrick EB, McConkey M, Lin K, Frisbee A, Ebert BL. Inactivation of HDAC1 or HDAC2 induces gamma globin expression without altering cell cycle or proliferation. Am J Hematol. 2015;90(7):624-628. doi:10.1002/ajh.24019
6. Mettananda S, Yasara N, Fisher CA, Taylor S, Gibbons R, Higgs D. Synergistic silencing of α-globin and induction of γ-globin by histone deacetylase inhibitor, vorinostat as a potential therapy for β-thalassaemia. Sci Rep. 2019;9(1):11649. doi:10.1038/s41598-019-48204-2
7. McArthur JG, Svenstrup N, Chen C, et al. A novel, highly potent and selective phosphodiesterase-9 inhibitor for the treatment of sickle cell disease. Haematologica. 2020;105(3):623-631. doi:10.3324/haematol.2018.213462
8. Salinas Cisneros G, Thein SL. Research in sickle cell disease: from bedside to bench to bedside. Hemasphere. 2021;5(6):e584. doi:10.1097/HS9.0000000000000584
9. Carden MA, Little J. Emerging disease-modifying therapies for sickle cell disease. Haematologica. 2019;104(9):1710-1719. doi:10.3324/haematol.2018.207357.
10. Field JJ, Majerus E, Gordeuk VR, et al. Randomized phase 2 trial of regadenoson for treatment of acute vaso-occlusive crises in sickle cell disease. Blood Adv. 2017;1(20):1645-1649. doi:10.1182/bloodadvances.2017009613
Reviewed by Debjyoti Talukdar, MD, on 11/28/2021.