Baby Z Cured of Rare Disease in 3 Days

Orphan drug treatment used only on mice to get hearing before FDA.

November 8, 2009, 11:12 PM

Nov. 9, 2009— -- Baby Z had a one in a million chance of developing a rare metabolic disorder called molybdenum cofactor deficiency and zero chance of avoiding the inevitable death sentence that comes with it.

The Australian girl had a seemingly normal birth in May 2008 but, within hours, she began having multiple seizures -- as many as 10 an hour -- as sulfite build-up began to poison her brain.

But her parents refused to let her die and successfully lobbied Southern Health's Monash Children's Hospital in Melbourne to try an experimental treatment that had only been used on mice.

"There was courage or there was death," the mother, who requested anonymity, told Australia's TV 9 in a telephone link-up. "If she wasn't treated, she would die a very painful death."

With the clock ticking, doctors who treated Baby Z gained approval from the hospital's ethics board and a family court to use the experimental treatment.

The drug -- cPMP, a precurser molecule made from E. coli bacteria -- was airlifted on ice from the lab of German professor Guenter Schwarz and, within three days, it worked.

Now, doctors consider 18-month-old Baby Z cured and a second child, Baby P of Germany, is successfully undergoing the same therapy.

Schwarz and others who pioneered her startling recovery will appear before the Food and Drug Administration Tuesday looking for a fast-track application for an orphan drug approval in the United States.

But their medical journey raises ethical questions about using untested therapies on children who can't speak for themselves.

"This is not voodoo or snake oil," said Mark Sands, professor of internal medicine and genetics at Washington University School of Medicine in St. Louis, who knows one of the German co-researchers, Jochen Reiss.

"This approach is based on very good science," he said.

About 25 million Americans suffer from orphan diseases, those that affect fewer than 200,000 nationwide.

"A lot of things are very debilitating for a small number of people," said Dr. Timothy Cote, director of orphan drug product development at the FDA. "They are individually infrequent, but collectively common."

Created in 1983, the program has given incentives and pioneered therapies for conditions ranging from venom bites to plutonium poisoning.

Worldwide, there are only about 50 cases of molybdenum cofactor, or sulfite oxidase deficiency, mostly in Europe and in the United States, according to the National Institutes of Health.

Baby Z Cure Pioneered in Australia

Molybdenum, like other organic metals, is essential for the human body. Its cofactor is a small, complicated molecule that acts as a carrier to help the metal interact with proteins and enzymes so they can function properly.

When the cofactor is missing, toxic sulfite builds and begins to cause degeneration of neurons on the brain and eventually death.

"This was the first time I ever saw this," said Dr. Alex Veldman, the Monash pediatrician and neonatologist who headed up Baby Z's treatment. "It's very funny, now I am regarded a world specialist but I can tell you that before last May, I couldn't even spell it."

Baby Z had a healthy birth on May 1, 2008, at a local children's hospital and, at first, doctors didn't realize she lacked the cofactor.

"As long as the baby is in utero, the mom is detoxifying," Veldman told "When she was born and the cord is clamped, the detox mechanism is interrupted and the sulfite builds up."

About 60 hours after Baby Z's birth, nurses noticed she was jittery and didn't attach well to her mother's breast.

When the baby went into seizures, doctors knew something was wrong and rushed her to Monash's neonatal center, where blood tests revealed she was intoxicated with sulfite.

Veldman delivered the news that Baby Z had a fatal, untreatable disease but the parents refused to give up.

"Always, there's a hope that you are wrong," he said.

Baby Z's family enlisted the help of a friend who was a biochemist at Monash University, one of the most research-intensive institutions in Australia, and the search for a cure began.

On May 26, they found a 2005 research paper by Schwarz, a former plant biologist who is now a researcher-professor at the University of Cologne in Germany.

Molybdenum cofactor is found widely throughout nature, and Schwarz was able to discover the precurser molecule in E. coli bacteria, or "gut flora," that was chemically identical to that in humans.

Using mice as human models, he injected the animals with the cofactor and, instead of dying of the disorder in eight days, they lived 100 days.

Schwarz kept a large stock, thinking there might one day be a human application. That day came when Veldman called about Baby Z, whose sulfite levels were growing daily.

"We were all very skeptical of the animal model because it had never been tried in humans," he said. "But the baby would have certainly died."

Excited that his drug might save a child, Schwarz packed his glass tubes in dry ice and sent it on a plane to Australia.

Doctors had no idea of the proper dosages or side effects. "We had a million questions," Veldman said, but he didn't want to let the chance to cure Baby Z slip away.

Still, they knew they needed legal back up for what seemed a "free-style act."

The bioethics panel scrutinized the treatment for three hours and agreed to support it. And the hospital's legal department also weighed in and agreed.

"They told me, 'Alex, if this works, great,'" he said. "'If it doesn't, crucify me at the door.'''

The medical team went one step further and got the legal back up they needed from Australia's family court at 3:30 p.m. on June 6, and at 5 p.m., they began treatment.

The team proceeded cautiously, injecting 10 percent of the dosage they had calculated and waiting 30 minutes between dosages.

"The first half hour the baby was good, sleeping and looking better," Veldman said.

Within two days, sulfite levels dropped from 300 to 80. On the fourth day, when Schwarz arrived to see his experiment in action, Baby Z was nearly normal.

"She was comatose before on feeding tubes, and now she was looking around and drinking a bottle," he said.

The seizures that had been reoccurring 10 times an hour decreased to two or three a day.

Today, at 18 months old, Baby Z is active and social, communicating with her parents, although she has some brain damage from the six weeks of sulfite poisoning.

"It's difficult to tell what her prognosis is in terms of development but she's making progress," he said.

Doctors had hoped to keep the news quiet until they could publish in a medical journal but journalists reading through court documents made it public.

Baby Z Raises Ethical Questions

Despite the fanfare, some people say the exciting news raises questions about how medical experimentation should be used on children, even those who are dying.

"There are 2 billion issues here," said Art Caplan, director of the Center for Bioethics at the University of Pennsylvania in Philadelhia. "First, the subject can't consent. Your parents are desperate to do anything with their emotions and guilt, so it's hard to say they can consent.

"Doctors also have the desire to help and fear, even it it's crazy and nutty, not to do anything," he said.

"You need to have someone take a hard look at the science who doesn't have an interest, an objective view."

Caplan said the biggest hurdle for those promoting the orphan drug won't be the FDA, but the pharmaceutical industry.

"When the science is there, there is a reasonable shot that the authorities will approve and go ahead," he said. "The problems are companies are terrified of having a death with a drug."

But Veldman, who has watched Baby Z's recovery without any ill effects, is hopeful that the drug could shed light on treatment of other diseases where replacing a cofactor might have potential.

Baby Z and her "carbon copy" Baby P will need a lifetime supply of cPMP, so production of the drug has been stepped up in Germany and Austria and toxicology studies and a global trial are to follow.

"It was the most challenging and most traumatic time of our lives," Baby Z's mother said. "We are looking at her now and she is just an absolute miracle. She has defied everybody."

Veldman said he is still reeling over the one in a million chance that Baby Z was saved and that he played a part.

"I have been in research for 20 years," he said. "I don't think this happens often, maybe once in a career, if at all. It was the right family with the right scientific back-up and the right science in Germany."

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