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M.C. Carden and J. Little et al.
agonist, is a coronary vasodilator and approved by the FDA for myocardial perfusion imaging. A phase I study (NCT01085201) demonstrated that regadenoson can be safely administered to patients during vaso-occlusive episodes and reduces iNKT cell activation.112 A random- ized phase II, placebo-controlled trial (NCT01788631) among patients with vaso-occlusive episodes demonstrat- ed low-dose infusion of regadenoson did not significantly reduce iNKT cell activation, duration of hospital stay, mean total opioid use, or pain scores when compared to placebo.113 NKTT120, a humanized anti-iNKT cell mono- clonal antibody, recently completed a phase I study (NCT01783691) and was found to be safe and produced rapid, sustained iNKT cell depletion in adults with SCD.114
Other novel anti-inflammatory agents are also being investigated in trials among patients with SCD. ACZ885 (canakinumab) is a monoclonal antibody that targets inter- leukin-1β, a cytokine upregulated due to hemolysis- induced free heme and inflammasome activation.115 A phase II trial (NCT02961218) is recruiting adolescent and young adult patients to determine whether canakinumab can reduce daily pain scores. Leukotrienes are biologically active inflammatory mediators produced by leukocytes which are associated with SCD-related morbidity, includ- ing asthma.116 Zileuton inhibits 5-lipoxygenase, a leukotriene synthesis enzyme, and was safe and tolerable in a phase I trial (NCT01136941).117 Montelukast, a cys- teinyl leukotriene receptor antagonist, is FDA-approved for the treatment of asthma. The aim of a recently com-
Figure 3. Risk-benefit assessments for emerging non-genetic therapies in sickle cell disease. The figure is a visual represen- tation of risk-benefit analyses relative to the proximity of the novel therapy to red blood cell intrinsic targets, such as HbF or polymer formation, which are likely to have the great- est impact on disease modification (green shading). Risk tolerance (red shading) may be greater for treatments that modify dis- ease. Downstream targets may offer signifi- cant palliation and may lengthen life, but are primarily management tools and may not warrant as great a risk. We propose a shifting level of risk tolerance (black arrow) based on the projected impact of a therapy.
pleted phase II study (NCT01960413) among adolescents and adults with SCD was to determine whether mon- telukast versus placebo added to hydroxyurea could improve markers of tissue injury associated with vaso- occlusion. Results are pending. Omega-3 fatty acids may improve SCD-related pathology through reduction in vaso-occlusion-induced systemic and local inflamma- tion.118 A phase I/II study (NCT02947100) was terminated early due to manufacturing problems. A phase III study (NCT02525107) is recruiting patients to determine whether prophylactic administration of omega-3 fatty acids can reduce the number and severity of vaso-occlu- sive episodes.
Lastly, intriguing research suggests that the microbiome may play a significant role in the pathology of SCD through mechanisms involving translocation of gut flora and inflammation which can affect sickle RBC and leuko- cytes.108,119 In a single-arm, phase II study (NCT03719729) investigators are recruiting patients with SCD to deter- mine whether gut decontamination with rifaximin, a broad-spectrum antibiotic that inhibits bacterial RNA polymerase, is well-tolerated and can reduce admissions due to vaso-occlusive episodes.
Discussion
While stem cell and gene therapies are becoming more commonplace, they are not yet widely available to most
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haematologica | 2019; 104(9)