Rare Disease Treatments: Orphans' Saving Lives : Part 2

by Food and Drug Administration (FDA)

(Page 2 of 3)

Ucephan

That was the case with Ucephan, made by Saul Brusilow, M.D., at Johns Hopkins University until it was picked up by Kendall-McGraw. Ucephan is used to treat three forms of urea-cycle disorder that, combined, affect perhaps 30,000 people.

Each day Americans eat about 100 grams of protein, which contains nitrogen that the body cannot incorporate. People with normal urea systems excrete nitrogen in the urine in the form of urea, the end product of a complex biological process. But someone with urea-cycle disorder, a genetic defect, accumulates nitrogen in the blood as ammonia, causing lethargy, stupor, vomiting, brain swelling, seizures, and, ultimately, death.

Brusilow said he was talking with some colleagues about the disorder when someone suggested he try Ucephan, a drug made of sodium benzoate (a preservative in food and soft drinks) and another chemical, sodium phenyl acetate. The body converts both components to a nitrogen-containing compound and then excretes it.

"Ucephan sponges up the nitrogen that the defective urea enzyme can't handle," Brusilow said. "The problem is that sodium phenyl acetate, which is more effective, smells very bad. When I was the only source of sodium phenyl acetate in the world, making it in my lab, I was stinking up the building." The sodium benzoate made the drug more palatable by reducing the smell.

Because Ucephan's patent had run out, without the seven years of marketing exclusivity offered by the Orphan Drug Act, it would have been unlikely that a manufacturer would have put millions of dollars into sponsoring Ucephan for urea-cycle disorder, because once FDA approval was granted any manufacturer could have submitted an application to FDA to market a generic copy of the drug. But market exclusivity permitted an opportunity to recover the development costs.

Brusilow said handing production over to Kendall-McGraw has allowed him to concentrate on second- and third-generation forms of the drug. He has obtained investigational new drug status for a new compound that replaces the phenyl acetate with sodium phenyl butyrate, which costs more but is odorless.

Serendipity

Occasionally there have been serendipitous outcomes of orphan drug development resulting in more possible uses for a drug than originally expected. Penicillamine, for instance, was used to treat about 2,000 people for Wilson's disease, and, although it was not a money-maker, the manufacturer continued to make it available as a public service. Then a university in England discovered it was also effective as an arthritis therapy.

"If that manufacturer had stopped making that drug, we would not have one of the key treatments for severe rheumatoid arthritis today," Meyers said. "That's really the lesson of orphan drug development."

The same thing appears to be happening with Cytomegalovirus Immune Globulin Intravenous, or CMV-IGIV, a biologic for treating kidney transplant patients. The CMV-IGIV contains high concentrations of the cytomegalovirus antibodies, which ward off the severe effects of the infection. Most adults in the United States have been exposed to cytomegalovirus, and it is usually harmless to normal, healthy adults. In those whose immune response has been compromised, however, the virus can destroy the lungs, liver, eyes, and other critical organs. In kidney and other organ transplants, the immune system is purposely suppressed to prevent organ rejection.

On April 17, 1990, FDA granted Massachusetts Public Health Biologic Laboratories a license for CMV-IGIV, and the Red Cross began distributing it.

"Demand has been growing faster than expected and, unfortunately, production hasn't been able to keep up yet," said Lauren M. Foohey of the Red Cross product management unit.

Although CMV-IGIV is licensed only for kidney transplants now, Foohey said the Red Cross has been getting a lot of calls from physicians who are interested in its application in heart, liver, and other organ transplants, and there is some indication CMV-IGIV might be used for people with AIDS, whose immune systems are suppressed by the disease.

PEG-ADA

One of the premier examples of how well the Orphan Drug Act can work came this year with the approval of PEG-ADA.

"This was a breakthrough," FDA's Haffner said of PEGnology, the enzyme replacement process developed by Enzon. "If it works the way it's thought it will, this technology will change the way we can provide drugs to patients."

The drug's roots date back to the 1970s, when Abraham Abuchowski was a graduate student at Rutgers University and wanted to do his thesis on the enhancement of enzyme therapy.

About the Author

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