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In rare disorder, novel agent stops swelling before it starts

February 22, 2017

An early-stage clinical trial has found that, compared to a placebo, a novel medication significantly reduces potentially life-threatening episodes of swelling of the airway as well as the hands, feet, and abdomen of patients affected by a rare genetic disorder. The findings were published in the New England Journal of Medicine.

Although the small study was designed to test safety of the drug, the findings were so obviously promising that an expedited phase III clinical study has just started enrolling patients at the Icahn School of Medicine at Mount Sinai and other locations. The study's co-lead author, Paula Busse, MD, is an allergist-immunologist at Mount Sinai and an associate professor at the Icahn School of Medicine.

The disorder, hereditary angioedema (HAE), causes recurrent and unpredictable attacks of swelling throughout the body. What triggers these attacks is not known.

The multicenter, double-blind, placebo-controlled phase 1b study of 37 patients with type 1 or 2 HAE found that all participants that used a 300-mg dose of the drug, lanadelumab, were attack-free, as were 82 percent who took 400 mg. Only 27 percent of participants who used a placebo were incident-free.

"Lanadelumab appears to stop attacks of HAE before they start, and this prophylactic approach may represent an exciting new advance for patients," says Dr. Busse, who treats dozens of patients with the disorder.

"Given the uncertainty of when an attack may happen, some HAE patients don't want to travel," she says. "The disease can produce such swelling for three to five days that a face is disfigured, hands can't be used, it is difficult to walk, and the abdomen can become very painful. Having a drug that can provide an ongoing buffer against HAE will be wonderful."

Current therapies for preventing HAE attacks work, but there are some drawbacks, Dr. Busse adds. A drug known as a C-1 inhibitor needs to be given intravenously every three or four days, and another approach, the use of pills called androgens (a modified testosterone), can produce unwanted hair growth in women, affect mood, cause weight gain, affect lipid levels and liver function, and inhibit growth in children.

Lanadelumab, on the other hand, is a monoclonal antibody that is injected every two weeks and was found to be well tolerated by patients in this trial.

HAE is an autosomal, dominantly inherited blood disorder caused by a deficiency or dysfunction of a regulatory gene known as the C1 inhibitor. The C1 inhibitor protein normally suppresses the production of another protein called bradykinin, which is the cause of swelling. Without a C1 inhibitor that functions properly, a person produces more bradykinin and consumes less of it. Bradykinin causes the swelling (angioedema) by making vessels dilate and leak fluid.

The study included extensive blood analysis, which closely tracked how the drug successfully suppressed production of bradykinin.

"If the phase III clinical study confirms the benefit we have seen, lanadelumab will make life much easier for HAE patients," says Dr. Busse. "Many patients who don't like and therefore don't use current treatments will likely opt for this new therapy, which will hopefully reduce morbidity and mortality, and improve the quality of life of patients with HAE."
Dr. Busse worked with researchers from a number of universities nationally, and with a research team from Dyax, the developer of Lanadelumab and supporter of the trial.

Dr. Busse received consulting fees from CSL Behring, Shire, and Dyax.

About the Mount Sinai Health System

The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services--from community-based facilities to tertiary and quaternary care.

The System includes approximately 7,100 primary and specialty care physicians; 12 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked among the highest in the nation in National Institutes of Health funding per investigator. The Mount Sinai Hospital is in the "Honor Roll" of best hospitals in America, ranked No. 15 nationally in the 2016-2017 "Best Hospitals" issue of U.S. News & World Report. The Mount Sinai Hospital is also ranked as one of the nation's top 20 hospitals in Geriatrics, Gastroenterology/GI Surgery, Cardiology/Heart Surgery, Diabetes/Endocrinology, Nephrology, Neurology/Neurosurgery, and Ear, Nose & Throat, and is in the top 50 in four other specialties. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 10 nationally for Ophthalmology, while Mount Sinai Beth Israel, Mount Sinai St. Luke's, and Mount Sinai West are ranked regionally. Mount Sinai's Kravis Children's Hospital is ranked in seven out of ten pediatric specialties by U.S. News & World Report in "Best Children's Hospitals."

For more information, visit, or find Mount Sinai on Facebook, Twitter and YouTube.

The Mount Sinai Hospital / Mount Sinai School of Medicine

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