Current treatment options are few for sickle-cell disease, a genetic blood disorder that affects millions of children and adults worldwide, including about 70,000 Americans, primarily people of African descent (about 8 percent of African-Americans are carriers). The only approved sickle-cell treatment, developed at CHB 20 years ago, is hydroxyurea. Companies have been slow to invest in additional sickle-cell treatments because the potential market is relatively small. The FDA granted ICA-17043 Orphan Drug Designation in 2000 and Fast Track Status in 2002.
ICA-17043 is related to clotrimazole, an antifungal drug approved in 1975 and long used to treat vaginal yeast infections, jock itch, and athlete's foot. A team led by Dr. Carlo Brugnara, director of the Hematology Laboratory at CHB, discovered in the early 1990s that clotrimazole also reduces sickling of red blood cells.
In sickle cell disease, the body produces an abnormal form of hemoglobin, the compound in red blood cells that carries oxygen. The hemoglobin clumps up and polymerizes – forms long rod shapes. This polymerization bends the red cells into sickle-shaped structures, and also causes the cell to lose water. This dehydration, in turn, hardens the cells and promotes sickling by hastening polymerization.
"When you dehydrate, you increase by orders of magnitude the tendency to sickle," says Dr. Brugnara. "It's a vicious cycle that gets worse and worse."
The rigid, sickled cells are unable to pass through small blood capillaries and so cannot deliver oxygen efficiently to tissues. Consequently, patients suffer from acute painful crises and numerous health problems, such as acute chest syndrome and organ damage, resulting in a shortened lifespan.
Dr. Brugnara and colleagues (Dr. Orah Platt, chief of Laboratory Medicine and Dr. Nader Rifai, director of the Chemistry Lab at CHB; and Dr. Seth Alper at BIDMC) have shown that clotrimazole prevents red-cell dehydration by blocking an ion channel, known as the Gardos channel, through which potassium and water exit the cell. Blockade of this channel keeps the cells hydrated, resulting in much less sickling.
The CHB researchers also discovered that clotrimazole has metabolites (breakdown products) that can reduce sickling without the liver toxicity and other side effects of the mother drug. These metabolites were used as the backbone for developing a new drug. A private biotechnology company helped Dr. Brugnara and Dr. Jose Halperin (of Harvard Medical School) generate and test nearly 500 novel compounds based on the structure of clotrimazole, omitting the portion of the molecule that causes toxicity. One of these compounds was ten times more active than clotrimazole in blocking the Gardos channel. The biotech company ceased activity on the project, however, so the technology languished for several years.
CHB's Intellectual Property Office rescued the technology and relicensed it to Icagen, Inc., a privately-held company in Research Triangle Park, N.C. Icagen, which focuses on ion channels as drug targets, did further chemical work to optimize the drug and sponsored Phase I and Phase II studies. The studies found the drug to be safe in humans and to improve the hydration and structural integrity of red blood cells.
Under the terms of their partnership, McNeil Consumer & Specialty Pharmaceuticals and Icagen, Inc., will jointly develop and commercialize ICA-17043 in the United States and will share equally in future development and commercialization costs and benefits. McNeil will receive the rights to develop and commercialize the product in most international markets. Icagen, Inc. will receive royalties from product sales in those countries, a portion of which will be paid to CHB and BIDMC. The companies will collaborate on the development and commercialization of ICA-17043 in Canada.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults for over 100 years. More than 500 scientists, including eight members of the National Academy of Sciences, nine members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today is a 300-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital visit: www.childrenshospital.org.
Beth Israel Deaconess Medical Center is a major patient care, teaching and research affiliate of Harvard Medical School, and ranks third in National Institutes of Health funding among independent hospitals nationwide. BIDMC is clinically affiliated with the Joslin Diabetes Center and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visit www.bidmc.harvard.edu.