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M.C. Carden and J. Little et al.
cations of SCD in patients 5 years or older. However, there remain concerns among many providers regarding the limitations of the study leading to approval for EndariTM, along with its potentially prohibitive cost, limit- ed insurance coverage, and twice-daily powder form, which may reduce adherence.57,59 Another antioxidant agent, N-acetylcysteine, maintains and replenishes glu- tathione, which is an intracellular antioxidant and scav- enger of reactive oxygen species. In a phase II trial, N- acetylcysteine reduced vaso-occlusive episodes and dense sickle RBC formation.60 However, a placebo-controlled, phase III trial (NCT01849016) found N-acetylcysteine had no clinical benefit in reducing pain when given orally, albeit adherence was poor.61 Of note, N-acetylcysteine can also reduce the formation of von Willebrand factor multimers and of von Willebrand factor-dependent platelet aggregation.62 von Willebrand factor reactivity is high during vaso-occlusive episodes, and may sustain microvascular vaso-occlusion.63 A phase I/II trial of N- acetylcysteine administered intravenously during vaso- occlusive episodes (NCT01800526) is recruiting adult patients to determine whether this antioxidant can affect von Willebrand factor levels or function and curb pain associated with vaso-occlusion.
Red blood cell extrinsic targets
The disease-modifying approaches to SCD that target factors extrinsic to the sickle red blood cells, namely abnormal cellular adhesion and vascular dysfunction, platelet activation and hypercoagulability, and leukocytes, cytokines and other inflammatory mediators are outlined in Online Supplementary Table S2A-C, respectively, and dis- cussed below.
Targeting abnormal cellular adhesion and vascular dysfunction
Abnormal cellular adhesion
Pioneering work in the 1980s showed that intracellular hemoglobin polymerization in SCD resulted in abnormal RBC adhesion to the endothelium.64 This observation was soon expanded and enhanced by thoughtful investiga- tions, and it is now recognized that many cell types, endothelial and hematopoietic, show abnormal activation and adhesion in SCD. Further, precise experimental iden- tification of adhesive partners, such as integrins,65,66 blood group antigens,67 selectins,68-70 and white cell proteins71 have increased the repertoire of potential therapeutic tar- gets (Online Supplementary Table S2A).
BCAM/Lu, expressed on sickle RBC, mediates adhesion to the sub-endothelial protein laminin, and this is aug- mented by β−adrenergic signaling.72 The effect of β−block- ade by propranolol on RBC adhesion and clinical out- comes was tested in people with SCD, with suggestive but inconclusive results (NCT01077921).73
Abnormal cellular adhesion to the endothelium has been shown to be mediated by P- and E-selectins, and early work showed some benefit from an oral agent that blocked P-selectin.74 More recently, the most actively test- ed agents are crizanlizumab,75 which is an anti-P-selectin monoclonal antibody given prophylactically monthly, and rivipansel, which is an intravenous glycomimetic pan- selectin antagonist given acutely during vaso-occlusive
episodes. In a randomized phase II study, crizanlizumab was tested internationally in 198 people with SCD. Compared with placebo, higher dose crizanlizumab resulted in a 45% reduction in annual crises, from 2.98/year to 1.63/year (P=0.01). In addition, the median time to a first crisis was longer in people with SCD who were on high-dose crizanlizumab than in those on place- bo (4.07 vs. 1.38 months, respectively; P=0.001). Serious adverse events did not differ between patients treated with the active drug or placebo. However, normal surveil- lance for infection and platelet function rely on intact function of P-selectin, and this aspect will need to be mon- itored during more widespread use of this preventive ther- apy. In a phase II study, 76 people with SCD were treated with intravenous rivapansel or placebo during vaso-occlu- sive episodes. There were trends toward reductions in mean and median times to resolution of vaso-occlusive episodes in treated patients [41 h and 63 h, respectively (28% and 48% reductions in the mean and median time to resolution, respectively); P=0.19 for both]. These reduc- tions were more substantial than those in the placebo- treated group. A secondary endpoint, cumulative intra- venous opioid use, was reduced by 83% with GMI-1070 versus placebo (P=0.010). These results suggest that this agent has some efficacy during vaso-occlusive episodes.76 Both crizanlizumab (NCT03814746) and rivipansel (NCT02433158) are now undergoing phase III studies.
Intravenous immunoglobulins decrease cellular adhe- sion in SCD in vitro, likely due to effects on RBC-white blood cell adhesion mediated through the integrin Mac- 1.77 This observation formed the rationale for a phase I trial of the use of intravenous immunoglobulins in pedi- atric and adult patients with SCD,78 while a phase II study is currently ongoing only in children (NCT01757418).
Vascular dysfunction
People with homozygous SCD experience a lifelong risk of multi-organ vasculopathy, due to the cumulative effects of hemolysis, nitric oxide depletion, inflammation and abnormal cellular adhesion.79 Therapeutic strategies including repletion of nitric oxide via inhalation have not been successful in randomized controlled studies during acute pain episodes or acute chest syndrome,80,81 but when given topically it has shown some quantitative and quali- tative success in healing leg ulcers.82,83 A prospective phase II study to test topical nitric oxide as a treatment for leg ulcers is ongoing (NCT02863068).
Dietary supplementation to improve nitric oxide avail- ability, including arginine and its precursor citrulline, has also been tried. Citrulline was studied in a small number of people with SCD, and appeared to have some benefit,84 but is not actively under study currently. Arginine has had a more robust clinical history. Thirty-eight children and young adults up to 19 years old with SCD received argi- nine or placebo intravenously for 5 days during a hospital admission for vaso-occlusive crisis. A significant reduction in opioid use was reported (1.9 ± 2.0 mg/kg vs. 4.1 ± 4.1 mg/kg, respectively; P=0.02) and lower pain scores at dis- charge (1.9 ± 2.4 vs. 3.9 ± 2.9, respectively; P=0.01).85 A larger phase II study is near completion at Emory in Atlanta (NCT02536170).
Targets within the nitric oxide signaling pathway have also been identified and are being tested in clinical trials. Soluble guanylate cyclase catalyzes the production of cyclic GMP, which promotes vascular health.86 One agent,
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