Carlo Brugnara, MD
Over a decade of work by Children's Hospital Boston researchers
and a heroic rescue operation by the Intellectual Property Office
have brought a new drug for sickle-cell
disease one step closer to the bedside. That drug is ICA-17043,
the "ICA" standing for Icagen,
Inc., the biotech company that licensed the technology from
Once it's clinically available, the drug will be a boon to patients
with sickle-cell disease, which is a genetic disorder in which red
blood cells become distorted and cannot deliver oxygen to tissues.
Currently, patients only have access to one approved drug, hydroxyurea,
developed 20 years ago at CHB. Drug companies have been slow to
invest in sickle-cell treatments because a relatively small number
of people are affected.
ICA-17043 is derived, oddly enough, from clotrimazole—an
antifungal drug used to treat vaginal yeast infections, jock itch
and athlete's foot. The CHB team, led by Carlo
Brugnara, MD, director of the Hematology Laboratory,
discovered in the early 1990s that clotrimazole reduces sickling
of red blood cells—distortion of the cells into sickle shapes—by
preventing them from losing water. "When you dehydrate,"
Brugnara explains, "you increase by orders of magnitude the
tendency to sickle." He and collaborators——including
Platt, MD, chief of Laboratory Medicine, Nader
Rifai, PhD, director of the Chemistry Lab, and Seth
Alper, MD, PhD, at Beth Israel Deaconess Medical Center——found
that clotrimazole blocks a channel that allows water to exit the
Further study found that breakdown products (metabolites) of clotrimazole
can reduce sickling without the mother drug's toxicity. Normal subjects,
including some of the investigators themselves, swallowed clotrimazole
tablets and gave blood samples repeatedly over a 24-hour period.
"The study showed that clotrimazole metabolites could be used as
the backbone for developing a new drug," says Brugnara.
With this knowledge, a private biotechnology company helped the
researchers tweak the clotrimazole molecule, creating and testing
nearly 500 novel compounds. One, which later became ICA-17043, was
10 times more active than clotrimazole in blocking the cellular
channel that causes dehydration, and was nontoxic.
But the biotech company ceased activity on the project, leaving
the technology in development limbo. "We were left with a huge mess,"
says Donald Lombardi, chief Intellectual Property
officer. The firm had hired a subcontractor and created a subsidiary
company, and all three companies had an ownership interest in the
technology, as did CHB, Beth Israel Deaconess Medical Center, Harvard
Medical School, and a Canadian firm.
"For each patent, we had to figure out how to get these interests
back, so we could license them to someone else," Lombardi says.
"It took a heroic effort by a number of people. Because the
technology was solid, and because the indication—sickle-cell
disease—is so important, we put all we had into it."
Over a period of about two years, CHB reassembled all the rights
and transferred them to Icagen, Inc.
Phase III studies with clotrimazole are expected to begin in 2005
and will involve 200 to 300 adult patients around the country. Once
the drug is approved in adults, pediatric trials will begin with
patients being recruited from CHB and other centers.