Thursday, June 15, 2006

Treatment for Rare Disease Approved
By Julie McKeel

Infants born with a severe form of a rare metabolic condition called Pompe usually die by their first birthdays, but a new treatment, called Myozyme, promises to change the lives of thousands of patients and their families.

Dr. Priya Kishnani

The new drug delivers to muscles a laboratory synthesized form of the enzyme Pompe patients lack, helping the body process sugars normally. It has greatly extended the lives of babies in clinical trials.

"It's critical that babies are identified and treated as early as possible," said the DCRI's Dr. Priya Kishnani, an associate professor of pediatrics in the division of medical genetics at Duke University and principal investigator in the studies.

Kishnani's mentor, Dr. Yuan-Tsong Chen, a pediatric geneticist at Duke, developed the enzyme-replacement therapy nearly 10 years ago. The first of three babies who received the enzyme therapy in 1999 is still alive.

According to Kishnani, the patient is now attending elementary school, talking, walking, and enjoying school like any of the other children around him.

Grim prognosis

Pompe is a swift killer when symptoms emerge shortly after birth. By 5 months of age, many babies suffer heart failure. Eventually, the heart swells in their chests and their tongues become enlarged. Few live beyond their first birthdays.

The disease moves more slowly when it strikes later in life But its effects are equally grim. Adults mature normally, only to have the disease rob them of strength and independence. The first signs are muscle weakness and breathing trouble. As the disease advances, patients end up in a wheelchair and on a respirator. Much like patients with ALS (Lou Gehrig's disease), many end up confined to their beds, their minds intact, unable to do much more than make slight hand movements.

People born with the disease either cannot make or make enough of an enzyme that is needed to convert stored sugars in muscles into glucose, the body's main source of energy. As a result, sugars called glycogen build up in muscles, crowding out muscle fibers that give the body strength.

Drug companies haven't exactly lined up to develop a treatment.

Rare diseases and 'orphan' drugs

Pompe (pronounced pom-PAY) disease was first described by Dutch pathologist Johannes Pompe in the 1930s. Thirty years later, scientists established the link between Pompe disease and an inherited deficiency of the enzyme acid alpha-glucodaise, also known as acid maltase.

Pompe affects about 10,000 people worldwide. Around 35 people are born in the U.S. every year with the fatal infantile form. The low numbers made this disease unable to attract wide attention from drug makers and research scientists.

Until Congress passed the Orphan Drug Act in 1982, few treatments for rare diseases made it to market. This Act provides incentives for commercial development of treatments. It allows for extended exclusive marketing rights to give drug and device makers the chance to recoup some of their research and development expenses.

A drug qualifies as an orphan if the disease it treats affects fewer than 200,000 people in the U.S. There are about 6,000 such diseases recognized today, affecting an estimated 25 million Americans. Some are obscure, like Pompe disease. Better-known ones are Tourette's syndrome and ALS.

[The Office of Orphan Products Development, which administers the act, awards about $14 million a year in grants to support clinical trials of orphan drugs. Duke University Medical Center and UNC Hospitals have been frequent recipients. Recently, Duke and UNC were selected as research sites in the new Rare Diseases Clinical Research Network.]

A new hope

The manufacturer, Genzyme, specializes in treatments for rare diseases. The company estimates it has invested $500 million in Myozyme over the past eight years. Some of that paid for the pivotal clinical trial, in which Kishnani was the lead investigator, that produced the results needed to win FDA approval.

Myozyme is delivered during a four hour infusion every two weeks. If it is priced like other enzyme replacement therapies, it could cost $200,000 a year.

The treatment is not without side effects. The FDA instructed Genzyme to include a so-called black box warning on the product label, the toughest required, advising of the risk of life-threatening allergic reactions. The label listed pneumonia and fever and warned that severe allergic shock and heart and lung failure also could occur. One of the 250 patients treated experimentally had a severe allergic reaction, and another suffered heart and lung failure.

The FDA granted broad approval for the drug in treating both the infantile form of the disease, which was the group of patients studied for FDA approval, and a form that affects older children and adults, often referred to as late-onset Pompe disease, even though the use of Myozyme in older patients "has not been adequately studied to assure safety and efficacy." Genzyme is conducting a trial of 90 patients with the late onset form of the disease.