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August 17, 2004
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For Further Information:
Mary-Ellen Shay
617-355-6420
mary.shay@childrens.harvard.edu
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Novel drug to enter Phase III clinical trials
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A novel once-a-day treatment for sickle-cell disease, based on technology developed at Children's Hospital Boston (CHB) and Beth Israel Deaconess Medical Center (BIDMC), has taken an important step toward the clinic. McNeil Consumer & Specialty Pharmaceuticals and Icagen, Inc., a private biotechnology company, have agreed to jointly develop and commercialize the drug, known as ICA-17043. The agreement follows successful Phase II clinical trials in 90 adults with sickle-cell disease. The companies will collaborate on multicenter Phase III trials, the final step before seeking marketing approval from the U.S. Food and Drug Administration.
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. The FDA granted ICA-17043 Orphan Drug Designation in 2000 and Fast Track Status in 2002.
ICA-17043 is related to clotrimazole, a drug approved in 1975 and long used to treat topical fungal infections. 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.
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In sickle cell disease, the body produces an abnormal form of hemoglobin, the molecule 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 Brugnara. ''It's a vicious cycle that gets worse and worse.''
The rigid, sickled cells are unable to pass through small blood vessels 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.
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.
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The CHB researchers, joined by Dr. Jose Halperin of Harvard Medical School, also discovered that clotrimazole has metabolites (breakdown products) that can reduce sickling without the liver toxicity and other side effects of the mother drug. Through its intellectual property office, CHB partnered with Icagen, Inc., a privately-held company in Research Triangle Park, N.C. that focuses on ion channels as drug targets and had independently discovered compounds related to clotrimazole, including ICA-17043, that were potent blockers of the Gardos channel. Icagen completed preclinical studies and sponsored Phase I and Phase II studies of ICA-17043. The studies found the drug to be safe in humans, to improve the structural integrity of red blood cells, and to decrease anemia.
Under the terms of their partnership, McNeil Consumer & Specialty Pharmaceuticals and Icagen, Inc., will jointly develop and commercialize ICA-17043 in the U.S. 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 sales in those countries, a portion of which will be paid to CHB and BIDMC.
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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 CHB's research community. Founded in 1869 as a 20-bed hospital, CHB today is a 300-bed comprehensive center for pediatric and adolescent health care, and 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.
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