The future looks bright for yet another potential therapeutic agent for preventing acute vaso-occlusive pain episodes in sickle cell disease (SCD). In the past 12 months, Dr. Kenneth Ataga and colleagues published a phase II trial demonstrating the safety and potential efficacy of crizanlizumab, an antibody against the adhesion molecule P-selectin, administered intravenously.1 Now we have a second agent that has similar promise — an oral agent and a selective AKT inhibitor that was demonstrated in preclinical studies to prevent acute vaso-occlusive events.
AKT isoforms have a critical role in cell biology; their activity includes, but is not limited to, cell-to-cell interaction, cell growth, cell migration, and cell apoptosis. Given the distinct properties of AKT, inhibitors have been developed for cancer therapy, one of which is ARQ 092 — an orally available and highly-selective AKT inhibitor. Based in part on evidence that ARQ 092 blocks αMb2 integrin function in neutrophils, the agent was shown to reduce P-selectin exposure and glycoprotein Ib/IX/V–mediated agglutination in platelets. Dr. Kyungho Kim and colleagues designed a series of well-planned experiments to assess the potential for ARQ 092 to attenuate vaso-occlusive events in SCD. Six key findings are demonstrated from the series of experiments: 1) ARQ 092 inhibits activation of neutrophils and platelets isolated from individuals with SCD; 2) ARQ 092 attenuates heterotypic aggregation of neutrophils and platelets from individuals with SCD under stirring conditions; 3) ARQ 092 specifically inhibits AKT phosphorylation in neutrophils and platelets and reduces cell activation in SCD mice ex vivo; 4) oral administration of hydroxyurea and ARQ 092 reduces cell-to-cell interactions in SCD mice challenged with tumor necrosis factor-α; 5) ARQ 092 decreased neutrophil transmigration into the alveoli of TNF-α-challenged SCD mice; and 6) hydroxyurea alone or in combination prolongs the life of transgenic SCD mice when compared with ARQ 092 alone, after being challenged with tumor necrosis factor-α.
In Brief
The experiments using ARQ 092 are promising for several reasons. First, as proof of principle, these results support therapy such as ARQ 092 and crizanlizumab (anti-P selecting antibody) directed at decreasing cell adhesion, decreasing activation of platelets and white blood cells, or both in the intervascular space, which may in turn decrease the incidence rate of acute vaso-occlusive events. Second, results from experiments and clinical studies focusing on decreasing cell-to-cell adhesion in the intravascular space provides evidence that a different mechanism other than increasing hemoglobin F levels may attenuate the incidence of vaso-occlusive events. Finally, as is the case in other chronic diseases, combination therapy focused on exploiting different mechanisms of disease, may be more beneficial in preventing progression of the disease than single-modal therapy, such as hydroxyurea or other agents designed to decrease the events. The future looks bright for complementary therapeutic strategies to attenuate vaso-occlusive events in children and adults with SCD. The SCD community looks forward to the next stage of moving the ARQ therapy from a preclinical stage to phase I and II trials.
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Competing Interests
Dr. DeBaun indicated no relevant conflicts of interest.
