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SICKLE CELL DISEASE
Sickle cell disease is the most common genetic disease among individuals of African descent and
is prevalent worldwide. According to recent market research this disease affects approximately 120,000 children and adults within the United States. Sickle cell disease affects approximately one in every 500 African-American births and one in every 1,000 to 1,400 Hispanic American births. Approximately 1,000 children are born with sickle cell disease in the United States each year. Screening programs have been established in most states to ensure that a child born with sickle cell disease receives prompt medical attention and parents receive counseling on caring for their child. Worldwide, sickle cell disease affects millions of people.
Sickle cell patients suffer from a multitude of medical complications, including among others vaso-occlusive crises, pulmonary hypertension and stroke, particularly in pediatric patients.
The most common complication of sickle cell disease is acute pain due to vaso-occlusion,
which can occur anywhere in the body. In many cases, only powerful opiate drugs can
alleviate this pain. During painful crises, tissues die from a lack of oxygen, leading to
problems in the lungs, kidney, bones, skin, heart, spleen, liver and joints. Virtually no tissue
or organ is spared from this destructive process.
Another common complication of sickle cell disease is pulmonary hypertension.
Approximately 30% of patients with sickle cell disease are believed to have pulmonary
hypertension, which can lead to compromise of the cardio-pulmonary system. Pulmonary
hypertension is believed to result from several factors, with the chronic destruction of the
abnormal red blood cells, a processs known as hemolysis, playing an important role.
Current treatment options for patients with this complication are limited.
- Stroke in Pediatric Patients
Stroke, particularly in pediatric patients, is a not uncommon complication of sickle cell
disease. Left untreated, approximately 10% of pediatric sickle cell disease patients will
suffer from a stroke. The risk of stroke can be monitored through a diagnostic technique
known as transcranial doppler, in which the blood flow through the major cerebral vessels
is measured. An elevated TCD measurement indicates that the child is at increased risk
of stroke. Such children are currently treated with chronic transfusion therapy, but because
of the complications associated with long-term transfusion therapy there is a need for
additional treatment options for these patients.
Currently, there are few therapeutic options for sickle cell patients. Acute crises are treated through transfusions and opiates. Chronic hydroxyurea therapy is available for some individuals who frequently experience crises. Hydroxyurea, a cancer chemotherapeutic, has been demonstrated to reduce hospitalizations and spare patients from some crises, and a significant number of patients are currently on hydroxyurea. However, there is a significant need for additional treatment options for patients with this disease.
The Gardos Channel
The normal red blood cell is shaped as a bi-concave disk, is well-hydrated and readily traverses
the small vessels of the capillary beds. In patients with sickle cell disease, the normal red blood
cell physiology is altered as a result of a single point mutation in the DNA sequence coding for
hemoglobin, the oxygen-carrying protein found in red blood cells. Due to the inherited defect, the
hemoglobin in red blood cells from sickle cell patients has an increased tendency to polymerize as
it delivers its oxygen to vital tissues. As polymerization occurs, the red blood cells become
dehydrated and lose their normal shape and elasticity, resulting in stiff, spiny, sickled cells. These
abnormally shaped cells are unable to move easily through small blood vessels and therefore they
interrupt blood flow and oxygen delivery to vital organs and tissues.
One of the key pathways by which dehydration of red blood cells occurs in patients with sickle cell
disease involves a particular potassium ion channel called the Gardos channel. The Gardos
channel is an ion channel, or a protein structure that, when open, allows the passage of potassium
ions across the membrane of red blood cells. Under most circumstances the Gardos channel is
closed, and therefore does not permit the flow of potassium ions. However, for reasons which are
not completely understood, in patients with sickle cell disease the Gardos channel is sometimes
inappropriately opened. When this occurs, potassium ions are able to flow out of red blood cells.
This outward flow of potassium ions from the affected red blood cells is accompanied by an
outward flow of chloride ions and water, leading to dehydration of the red blood cells. Dehydration
of the red blood cells results in further polymerization of the abnormal hemoglobin and in the
formation of dense and sickled red blood cells. Because of its integral role in the process of red
blood cell dehydration, the Gardos ion channel presents a potential therapeutic opportunity for the
treatment of sickle cell disease.
Senicapoc
Based upon this scientific rationale, Icagen has discovered and developed senicapoc, a novel
potent and selective small molecule inhibitor of the Gardos channel. In preclinical and clinical
studies, senicapoc has been shown to reduce red blood cell dehydration and the subsequent
formation of dense cells. In clinical trials, senicapoc has been shown to decrease red blood cell
hemolysis and improve anemia.
Following a successful Phase II study, Icagen had been conducting a Phase III study designed to
evaluate the ability of senicapoc to reduce the frequency of vaso-occlusive crises in adult patients
with sickle cell disease. However, following a planned meeting of the independent Data Monitoring
Committee of this trial, the DMC recommended that the trial be terminated because of the low
probability of achieving a reduction in crisis rate, the primary endpoint. In making their
recommendation, the DMC noted that data from the trial indicated the expected improvement in
anemia and reduction in hemolysis that had been demonstrated in the Phase II trial. Among the
available data, there were no statistically significant differences in safety measurements between
the senicapoc and placebo treatment groups. The Company plans to analyze final data when
available and consider future options for the development of senicapoc, including pulmonary
hypertension and reduction of the risk of stroke in pediatric patients.
More recently, an extensive body of scientific literature has evolved suggesting a potential role for
Gardos channel inhibition in other diseases, including, among others, various
immuno-inflammatory disorders. The IK channel, as the Gardos channel is also known, is expressed on a wide variety of immune and inflammatory cell types. Given the favorable safety profile of senicapoc observed thus far, Icagen intends to explore the potential utility of this novel molecule in indications outside of sickle cell disease. Preclinical studies to better define the potential role of senicapoc in these other indications are currently underway.
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