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Disease-modifying therapies for SCD
silencing at the γ-promoter DRED complex, which also contains the demethylase DNMT1. LSD1 inhibition in SCD mice increases HbF, reduces reticulocytosis, and decreases organ damage.39 A phase I open-label study (NCT03132324) evaluating the safety, pharmacokinetics, and biological activity of the LSD1 inhibitor INCB059872 in patients with SCD was terminated early due to a ‘busi- ness decision’ and the drug is being examined as a treat- ment for leukemia. Known for its glucose-lowering mech- anism in patients with type 2 diabetes, metformin was recently shown to induce HbF in a FOXO3-dependent manner that was additive to hydroxyurea in vitro.40 Metformin is being investigated in a phase I, dose-escala- tion pilot study in SCD patients with or without the addi- tion of hydroxyurea (NCT02981329).
Targeting HbS polymerization through sickle red blood cell hydration
Sickle RBC are naturally imperfect osmometers,41 and their biomechanical properties are dependent on RBC- intrinsic properties (e.g., membrane and cytosolic con- tents) and RBC-extrinsic factors (e.g., environmental osmolality, surface area to volume ratio, oxygen tension).8 As such, SCD pathology results directly from the conse- quences of red cell dehydration, which increases HbS con- centration within the sickle RBC, leading to polymeriza- tion under deoxygenated conditions and resultant increased cellular density and stiffness, which reduces sickle RBC deformability and increases adhesion leading to a disruption in microvascular blood flow.5,8,42,43 Theoretically, sickle RBC dehydration is ‘targetable’ and could lead to clinical improvement, but studies of agents directed at cation transport and RBC hydration mecha- nisms have, to date, been disappointing. While early stud- ies suggested dipyridamole may inhibit sickling-induced cation transport and inhibit sickle RBC dehydration,44 a phase II study (NCT00276146) investigating its use was closed because of poor enrollment. A phase III, random- ized, double-blind study of senicapoc (NCT00102791), a small-molecule inhibitor of Ca2+-activated K+ efflux (Gardos channel), reduced sickle RBC dehydration and hemolysis,45 which may be pathophysiologically impor- tant. However, the study was terminated early because of lack of improvement in vaso-occlusive event rates in adults with SCD treated with this drug in comparison to those given placebo. Early observations also found magne- sium supplementation improved sickle RBC hydration in patients with SCD through inhibition of K-Cl co-transport and reduction of dense sickle RBC.46 However, in the Magnesium for Children in Crisis (MAGiC) study (NCT01197417), which included young adults up to 21 years of age, when compared to the effects of placebo, intravenous magnesium did not reduce duration of stay or opioid use in patients hospitalized for vaso-occlusive events.47
Other anti-sickling agents
Allosteric modification of HbS from the low-oxygen affinity tense (T) state to the high-oxygen affinity relaxed (R) state reduces the risk of HbS polymer formation.29 Several novel agents manipulate this biochemical phe- nomenon and show promise in interrupting the molecular pathogenesis of SCD. Voxelotor (GBT440) is a small mol- ecule that binds to the a-globin chain in HbS, increasing oxygen affinity to favor the R state. Early phase trials
demonstrated that GBT440 is well-tolerated in adults with SCD and reduces morphological changes in sickle RBC.48,49 The Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization (HOPE) study (NCT03036813) is a phase III randomized, double-blind, placebo-controlled, multicenter study evaluating the efficacy and safety of GBT440 in adolescents and adults with SCD. Early results suggest treatment with GBT440 increases hemoglobin levels in patients with SCD who have decreased markers of hemolysis when compared to patients given placebo.50 Importantly, initial evaluations did not suggest physiolog- ical oxygen deprivation with GBT440 (i.e. erythropoietin levels do not change); studies of oxygen delivery to the brain and during exercise in patients taking GBT440 are reportedly in process (unpublished, ASH 2018). AES-103 is a naturally occurring small molecule (a 5-hydroxymethyl furfural) that also binds to the a-globin subunit in HbS, increasing oxygen affinity and favoring the R state. AES- 103 has completed a phase I trial (NCT01597401) and was shown to be well-tolerated in a double-blind, placebo- controlled dose-escalation trial in adults with SCD.51
PEGylated bovine carboxyhemoglobin (PEG-bHb-CO; SANGUINATETM) is a combined oxygen transfer and car- bon monoxide-releasing molecule that is given intra- venously with the rationale of reducing hypoxemia- induced sickle RBC pathology. It was found to be safe and well-tolerated in a phase I trial among adults with SCD.52,53 A prospective, randomized single-dose, placebo-con- trolled phase II study (NCT02411708) was recently com- pleted and interim results showed that PEG-bHb-CO administration was associated with reduced pain scores and anti-sickling properties during vaso-occlusive episodes when compared to placebo administration.54 SCD-101 is marketed as a ‘botanical drug’ with anti-sick- ling activity through an unknown mechanism and was shown in an interim analysis of a recent phase I study (NCT02380079) to be well-tolerated, and may reduce chronic pain and fatigue, improve leg ulcers, and improve sickle RBC morphology in the peripheral blood.55
The kinetics of some of the allosteric-acting agents are much faster (hours to days) than are the predominant effects of HbF inducers, which may take weeks to months to fully alter erythroid precursors. This difference could suggest complementary ways for using these agents.
Targeting intracellular sickle red blood cell oxidative changes (antioxidant therapy)
RBC are oxygen carriers, which places them in constant danger from the cumulative impact of reactive oxygen species and free radicals formed by oxygen and hemoglo- bin metabolism inside the RBC.56 Sickle RBC, due to their unique intracellular milieu with high concentrations of HbS forming and re-forming polymers, are at increased risk of oxidative damage. L-glutamine is an amino acid and a precursor used in the synthesis of glutathione and reduced nicotinamide adenine nucleotide diphosphate, which can protect the sickle RBC from oxidative dam- age.57 A recent multicenter, randomized, placebo-con- trolled, double-blind, phase III trial (NCT01179217) found that oral administration of pharmaceutical-grade L-gluta- mine (EndariTM) reduced the number of vaso-occlusive events and episodes of acute chest syndrome, and hospital admissions compared to those in placebo-treated children and adults with SCD.58 In 2017, EndariTM received orphan drug status and is FDA-approved to reduce acute compli-
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