Pursuing a Cure For an 'Orphan' Ailment

Submitted by Charles Frost on Thu, 12/20/2007 - 21:38.

Pursuing a Cure For an 'Orphan' Ailment

A Doctor Struggles to Develop A Drug for Lead Poisoning; Bypassed by Patient Advocates

December 18, 2007; Page D1

For more than 20 years, Michael Shannon has used a drug called d-penicillamine to treat children with lead poisoning. The problem is that children often won't take the drug because "it tastes and smells like rotten eggs," says the pediatrician at Children's Hospital Boston.

That's why he was thrilled when a company he collaborated with, Tedor Pharma Inc., came up with a kid-friendly grape-flavored formula. He figured pharmaceutical companies would be eager to license it and launch a trial to obtain Food and Drug Administration approval, and parents would embrace it. He even expected the FDA to help out, and applied for a grant to help defray the costs of a trial.

 Instead, "no one was interested," says Jacqueline Armstrong, project leader in the hospital's intellectual-property office, which guides development of drug discoveries.
Drug companies said the costs were too high to commercialize a drug for a condition that affects relatively few children. Doctors were divided on the use of drugs to treat the moderate levels of lead poisoning Dr. Shannon targets; there was no proof that treatment could reverse cognitive damage. And Dr. Shannon says that the FDA, in its rejection of his grant request, said it wanted him to focus on higher levels of lead poisoning.
Most surprising was that no patient advocates took up the cause. Parents of lead-poisoned children were leery of using drugs to treat lead poisoning -- a process known as chelation that carries side effects of its own. In a population that is disproportionately poor, urban and minority, many patient advocates instead prefer to focus on cleaning up homes with high levels of lead paint, the chief source of lead poisoning.
"I don't believe it is possible to reverse the damage from lead poisoning, so I don't want to take the risks of giving my son a medical intervention that might cause other damage," says Zakia Shabazz, who founded a parent-advocacy group, United Parents Against Lead National, in 1996 after her son, Zaki, was diagnosed with lead poisoning.
Patient-advocacy groups are increasingly powerful. They are raising huge sums of money for research, particularly for rare diseases that might otherwise be overlooked. Impassioned patients have recently funded their own trials, hired scientists and successfully lobbied government agencies. But as Dr. Shannon discovered, some rare diseases are true orphans, unable to attract drug-company, philanthropic or even patient-advocate interest.
Dr. Shannon's efforts might have remained stalled if not for a Boston-based venture capitalist named Roger Kitterman. His suggestion for how to jump-start the project -- selling the idea to a group of investors willing to accept smaller profits in order to fill a critical need -- brought in the vital initial investment.
Focus on Lead
Dr. Shannon's push for a clinical trial came at a time that seemed promising. Massive recalls this year of millions of toys because of lead paint drew attention to the serious health hazards posed by lead, which include brain and organ damage, learning disabilities and antisocial behavior. Though lead-based paint was banned in 1978, the Centers for Disease Control and Prevention estimate that at least 24 million older housing units in the U.S. pose a potential threat because of lead paint.
But lead poisoning -- how to treat it, prevent it, even define it -- is a divisive issue. The CDC says a level of 10 micrograms or more of lead per deciliter of blood in a child's body is cause for concern. But Dr. Shannon and other pediatricians argue that blood-lead concentrations below 10 mg/dl also cause cognitive damage, and they have urged the CDC to lower the level even further.
The latter view was supported in a recent study published in the New England Journal of Medicine. In the study, researchers found that "there is no evidence of any safe threshold for lead," said Richard L. Canfield of Cornell University, one of the investigators.
At the same time, there is little evidence that treating low blood levels of lead poisoning makes a difference. The only FDA-approved drug for lead poisoned children, called Chemet, has proved effective only in preventing life-threatening complications such as seizures in children with very high blood levels of lead, over 45 mg/dl. Some doctors will still treat levels under 45, but at that point, the risks of chelating drugs -- which can cause fevers, rashes, and drops in platelets and white blood cell counts -- are seen by many as outweighing the potential benefits. At lower levels of lead poisoning, these doctors argue, it may be preferable to let levels fall naturally over time.
To address lower-level poisoning, Dr. Shannon needed something else. Enter d-penicillamine, a drug for rheumatoid arthritis and adults with a rare genetic disorder. Dr. Shannon says years of off-label use of the drug in thousands of children show that it significantly lowers patients' blood-lead levels and keeps them down even after the drug was stopped. And while d-penicillamine has potentially serious side effects at adult doses, at the low doses given to the children, he says, there were milder reported events, such as rashes and stomach upset.
Though there isn't enough research yet to show that cognitive damage from lead poisoning can be reversed, Dr. Shannon and some other doctors argue that treatment can halt or reverse other serious damage done to organs. "Lead affects every organ," he says. "The brain is the most important, but we also have to think about the kidney, liver and bone marrow. The benefits there of removing the lead are incontrovertible." So he and the hospital were eager to work with Tedor to develop a new, better-tasting formula for d-penicillamine that could be FDA approved for kids and thus gain wider use.
In the months following the setbacks for the new version, Children's Hospital brought in business advisers to find a way to get the reformulated drug into trial. Soon after, Mr. Kitterman, the Boston-based venture capitalist, pitched his idea: Eschew philanthropists and patient advocacy groups and focus on finding investors who want to help the kids and are willing to accept a more modest profit than they might typically expect. If costs stayed under $2 million, Mr. Kitterman calculated, the early investors could eventually make at least two to three times what they put in.
Seed Money
With the hospital's OK, Mr. Kitterman formed Bezoloven -- the Bulgarian word for "lead-free" -- a company with no office, no employees and very little overhead. By fall 2006, he had raised $100,000 from a group of investors called Boston Harbor Angels. While small, that initial funding enabled Dr. Shannon to begin planning a full clinical trial.
The idea was to enroll 50 children over the course of three years, randomized into a group that would receive the drug and a group that would receive a placebo, and see if it was effective in lowering lead levels.
If Bezoloven proves successful, the model could be used to support research in other rare diseases, says Donald P. Lombardi, CEO of the Institute for Pediatric Innovation in Cambridge, Mass., which launched a consortium of pediatric hospitals to identify and develop promising pediatric therapies. He says he knows of at least a dozen compounds that, like d-penicillamine, could be reformulated for FDA approval for pediatric use with investments of $2 million to $8 million. "This is the proof of a very important principle," Mr. Lombardi says.
For now, the debate over when to use drugs to treat lead poisoning remains unresolved. Treatment with chelating drugs is widely understood to be necessary in cases where high levels of lead threaten the child's life. But in a seminal 2002 study of 741 toddlers with moderate lead poisoning (under 45 mg/dl), Chemet didn't significantly reduce lead levels. And after following the children through ages 5 to 7, the study also found no difference in IQ between children who had used Chemet, and those whose lead levels fell naturally over time. Chelation, the study in the journal Pediatrics concluded, "is of no proven benefit" to children with moderate lead poisoning.
Walter Rogan, a medical epidemiologist at the National Institutes of Health and an investigator on that study, says he doesn't believe d-penicillamine will prove to be any more effective at lowering blood levels or improving cognition. "There is no evidence that you can reverse the damage," Dr. Rogan says. "It appears to be permanent."
The patient-advocacy community is similarly skeptical. In Richmond, Va., Ms. Shabazz of United Parents Against Lead National says that lead levels in her son, who is now 13, have fallen to below 3 mg/dl, but he still struggles in school with short-term memory problems.
Ms. Shabazz's group works mainly with lower-income families "struggling to make a living," she says. "Lead poisoning is invisible, so it's not at the top of the list of their priorities because the child is not broken or bleeding." Her group helps families remove lead hazards in their homes. The group is setting up a lead safe house registry for two cities in Virginia that allows residents to see which houses have passed muster.
Dr. Shannon, though, says he has anecdotal evidence to suggest that cognitive problems can improve. In his office at Children's Hospital Boston recently, Dr. Shannon points to the table where he sits with parents after a child has completed the d-penicillamine regimen. "They ask me the $1 million question: 'Has my child been irreversibly harmed?' " he says. Most children are 2 to 2½ years old when treatment ends, too soon to tell, he says. Only after the children start school do attention-deficit disorder, speech delays, antisocial behavior, learning disabilities and other damage associated with lead poisoning emerge.
Among parents who have used d-penicillamine, no one questions the need for a palatable recipe. Connie Orcutt of Brookline, Mass., says that getting her 7-year-old daughter to take the medicine was a constant battle. The little girl, who was adopted from China, had a lead level of 58 mg/dl when she arrived here. After hospitalization lowered her levels, Dr. Shannon prescribed d-penicillamine to try to get the lead down even further. "It is really noxious smelling and it doesn't taste much better," says Dr. Orcutt, a veterinarian.
She tried to mix it in food -- jam, chocolate sauce, pudding -- to mask the smell. Every few days, her daughter would reject the latest concoction. "She had to take it every morning and every night. She was always upset," says Dr. Orcutt. She notes that while her daughter did experience some rashes and diarrhea, it was never clear if it was connected to the drug, and her daughter's lead levels did improve.
Low and Moderate Cases
Dr. Shannon's trial of the kid-friendly version will enroll only children whose blood lead levels are between 15 and 25 mg/dl. If the experiment is successful, a follow-up study could be conducted to see if the drug is effective at treating even lower levels. Dr. Shannon estimates that up to 80% of lead-poisoning cases fall in these low and moderate ranges. "If we show that this drug works," he says, "it will address the majority of childhood lead-poisoning cases in the country."
As progress on the trial moved forward, Mr. Kitterman, the financier, went back to the Boston Harbor Angels in September to give them an update. He reported that Dr. Shannon had applied again for an FDA grant. This time, the application explained why he chose to study children with lower levels of lead. And the $100,000 in seed money allowed him to lower his budget. Dr. Shannon got his grant: $573,893 over three years to defray the costs of the trial, which is set to begin in the spring. (An FDA spokeswoman says the agency can't comment on specific cases.)
Mr. Kitterman added that he had also been in touch with a Paris-based pharmaceutical company that was interested in selling the reformulated drug in Russia and China, where lead poisoning is an even larger problem than it is in the U.S. "The lead-poisoning problem," Mr. Kitterman concluded, "is not going away."

Write to Amy Dockser Marcus at amy [dot] marcus [at] wsj [dot] com

From: http://online.wsj.com/services/article/SB119794234749235667-search.html?KEYWORDS=orphan&COLLECTION=wsjie/6month

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