Treatments emerge for a rare and life-threatening disease
Novel drugs relieve attacks of swelling in hereditary angioedema
August 14, 2007
An investigational drug called ecallantide (also known as DX-88 [Dyax Corp., Cambridge, MA]) significantly relieves attacks of a rare, life-threatening disease called hereditary angioedema, report researchers from Children's Hospital Boston and 25 other study sites. The placebo-controlled trial was published in the August issue of the Journal of Allergy and Clinical Immunology.
A second investigational drug, called C1 inhibitor, is showing promise in other multicenter trials. Both drugs, if approved by the FDA, would be the first emergency treatments available to patients with this difficult disease.
Hereditary angioedema (HAE) is marked by attacks of swelling lasting hours to days, most often in the arms and legs. Many patients also have swelling of the bowel wall, causing severe abdominal pain; disfiguring facial swelling; genital swelling; and, of greatest concern, swelling of the larynx that can cause difficulty breathing. These laryngeal episodes are unpredictable and can be fatal.
Chronic treatment with androgens can prevent HAE attacks, but these hormones cannot be given to children and have virilizing side effects in women. Once an attack begins, no acute treatment is currently available other than supportive care, such as pain medications for severe abdominal swelling or intubation to prevent patients from asphyxiating in episodes of laryngeal swelling.
"Researchers have spent many years trying to get emergency treatments for HAE into the market," says Lynda Schneider, MD, in the Division of Immunology at Children's Hospital Boston, lead author of the ecallantide report. "The pathways involved in HAE have only recently been understood." Much of this understanding stems from years of work by the late Fred Rosen, MD, former chief of the Division of Immunology at Children's.
Ecallantide blocks generation of kallikrein and its byproduct bradykinin, which is thought to be responsible for the swelling that marks HAE attacks.
The trial, involving 26 different institutions, randomized 48 patients aged 10 and older with HAE to receive a single intravenous dose of ecallantide (40 patients) or placebo (8 patients) while an attack was in progress. Seventy-three percent of patients given ecallantide reported significant relief of symptoms within four hours, versus just 25 percent of the placebo group. All four doses tested were well tolerated, though some patients had allergy symptoms.
The C1 inhibitor study sponsored by ZLB Behring, King of Prussia, PA and called I.M.P.A.C.T., is currently enrolling patients at Children's Hospital Boston and other study centers. Naturally found in the blood, C1 inhibitor is part of the complement system, a complex set of proteins involved in immune and inflammatory reactions. Patients with HAE have a mutation in the C1 inhibitor gene, so lack functional C1 inhibitor protein.
People usually begin suffering HAE attacks in their teens and twenties; often, the disease first strikes during college. Although HAE may run in families, other patients have so-called sporadic cases that are often missed or misdiagnosed for years. The abdominal swelling many patients experience sometimes leads to unnecessary exploratory surgery; in one study, at least five HAE patients who suffered abdominal episodes had undergone such surgery before being diagnosed with HAE, and two had appendectomies.
There are known triggers for HAE, such as injury (including surgery), infections and menstrual periods, but episodes sometimes seem to happen out of the blue. "Patients may have many episodes or only a few episodes a year," says Schneider, who has treated about 30 people with HAE over the past 10 years. "Out of nowhere, patients can have a life-threatening laryngeal episode. It's a very difficult disease."
Both ecallantide and C1 inhibitor have been designated as orphan drugs. The ecallantide study was supported by Dyax Corp. and at Children's Hospital Boston by a General Clinical Research Center grant from the National Institutes of Health.
For information about enrolling a child in an HAE trial at Children's Hospital Boston, contact 617-355-6127.
For more information on HAE and clinical trials for HAE, visit www.haea.org.
Founded in 1869 as a 20-bed hospital for children, Children's Hospital Boston today is the nation's leading pediatric medical center, the largest provider of health care to Massachusetts children, and the primary pediatric teaching hospital of Harvard Medical School. In addition to 347 pediatric and adolescent inpatient beds and comprehensive outpatient programs, Children's houses the world's largest research enterprise based at a pediatric medical center, where its discoveries benefit both children and adults. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. For more information about the hospital visit:www.childrenshospital.org/newsroom.
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Lynda Schneider, MD