Sickle cell anemia is caused by a mutation in the hemoglobin gene and is characterized by red blood cell dehydration due to loss of potassium, chloride, and water. Volume decrease causes red blood cells to attain an abnormal rigid sickled shape which functionally causes increases in hemoglobin concentration and leads to an increased rate of hemoglobin polymerization under hypoxic conditions, causing irreversibly sickled, dense and dehydrated red blood cells that are more susceptible to becoming trapped in the capillaries and could lead to microvascular obstructions and chronic organ damage.
Senicapoc (ICA-17043; bis(4-fluorophenyl)phenyl acetamide) was initially developed for the treatment of sickle cell anemia by scientists at Icagen Inc. Senicapoc was designed to target the potassium channel Kcnn4 as one of the main routes of potassium loss is through the Gardos channel, later known as Kcnn4. Senicapoc shows a great potency and an outstanding selectivity for Kcnn4 over other potassium channels while displaying a promising pharmacokinetic and safety profile, selectively inhibiting potassium efflux from red blood cells of both human patients and mouse models of sickle cell anemia. Senicapoc is orally bioavailable in humans with superior metabolic stability (half-life of 12.8 days, 1 hour in mouse and 4 hours in rats) compared to previous Kcnn4 inhibitors, namely clotrimazole and TRAM-34, which have shorter half-life, are not orally available, and are sensitive to acid.
Senicapoc was first tested in the mouse models of sickle cell anemia and showed improved disease outcome; mice experienced marked and constant inhibition of the Gardos channel activity, an increase in red blood cell potassium content and decrease in hemoglobin concentration. More importantly, Senicapoc was well-tolerated with no sign of toxicity or body
weight change.
Senicapoc was later given to human participants in clinical trials. The 12-week Phase II trial was very promising. Hemoglobin concentration increased with concomitant decrease in hemolysis, suggestive of increased survival of sickled red blood cells and amelioration of the anemic state. The safety and efficacy of Senicapoc were evaluated in parallel and indicated a good overall safety profile and good tolerance in both patients and healthy volunteers. The most frequent adverse events reported were diarrhea and nausea which occurred sporadically and appeared dose-dependent, described as mild to moderate in intensity, but no difference was detected in overall frequency of painful crises with Senicapoc treatment.
Despite the success of the Phase II trial for sickle cell anemia, the 52-week Phase III trial had to terminate early due to no significant improvement in the rate of sickle cell painful crises, although hematological parameters appeared to reinforce the improved clinical outcomes observed in Phase II trial. Participants in the Senicapoc and in the placebo groups experienced similar adverse events, but the crises rate was significantly higher in the Senicapoc group than in the placebo group, with nausea and urinary tract infections being the most frequent. In spite of the strong hematologic and pharmacodynamic data that demonstrate Senicapoc led to positive outcomes, the clinical trial had to be terminated due to the adverse events. Recently, following the accelerated approval of another drug, voxelotor, for treating sickle cell anemia, the investigators of the Senicapoc trial revisited results of the Phase III trial and reanalyzed their data in the same way the analysis was
done for the voxelotor trial. Comparison between the Senicapoc and the voxelotor trials revealed that a lower dose of Senicapoc achieved a more pronounced improvement in hemolysis compared to voxelotor, with no differences in the crises rate. Hence, the investigators belive that if the Senicapoc trial were to be reassesed with the current criteria which emphasize hemoglobin increase, Senicapoc could be approved.
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