Experimental Treatment Urged For Children With Rare Disorder, April 18, 2000
River Oaks, Texas (Fort Worth Star-Telegram) - Madison Holland of River Oaks knew that God had made her - and her brother and sister - special long before a little boy named Simon Birch said the same thing in a 1998 movie bearing his name. Birch, a character with severely arrested growth, firmly believed that he played a very important part in God's plan.
So does Maddie. Maddie, 8, and her siblings, Spencer and Laynie, who are 10 and 6, respectively, share the same rare disorder as 12-year-old Ian Michael Smith of Chicago, who played Birch in the movie.
Mucopolysaccharidosis, or MPS, is a hereditary defect in metabolism caused by an inability to break down certain sugars. The disease leads to defects in bones, cartilage and connective tissue. Children with MPS are unusually short and experience clouding of the eyes and deterioration of the liver, spleen, heart and brain. Often they develop mental retardation, and many die by age 10.
A few years ago, there seemed to be little hope for the Hollands and other children with this disease. But a 1997 clinical study conducted by the University of California Medical Center at Los Angeles and involving 10 children shows that enzyme replacement therapy may extend the children's lives and reverse their symptoms.
Two weeks ago, Steve Holland, the children's father, traveled to Washington, DC, with Smith's father and Lt. Mark Dant of the Carrollton Police Department. Dant's 12-year-old son, Ryan, also has MPS. Their mission: to urge the Food and Drug Administration to approve the experimental enzyme treatment.
The treatment has been very good for Spencer Holland and Ryan Dant, who were a part of the clinical study and continue to receive the weekly intravenous infusions.
But for other children whom God made special, including Spencer's sisters, the experimental treatment is not available. While the FDA waits for more information, hope stands for the Hollands at an achingly uncertain distance.
When he was enrolled in a clinical study two years ago, Spencer Holland had difficulty breathing and very little stamina. The then-second-grader could not walk more than half a block - much less run. His spleen and liver were grossly enlarged. His facial features had begun to coarsen.
But while the IV treatment that he continues to receive each Friday afternoon buys Spencer precious time and the stamina he needs to swim and play basketball again, time is running out for more than 2,000 children who suffer from MPS in the United States.
"When Spencer started, it was to be a 6-month trial. We never considered he might be on the enzyme two years while our little girls continued to get worse," says his mother, Amy Holland. "Every time the FDA says they need more information, it just kills me. We have seen the benefits. The enzyme has stopped Spencer's disease in its tracks."
Nine of the 10 children in the California study have experienced similar improvements. The enzyme has been less effective for one little girl who has Hurler's syndrome, the most severe form of the disorder.
The FDA has asked for a double-blind study to confirm that the enzyme is responsible for the improvements. Maddie and Laynie Holland are on the list of those waiting to find out whether they will be included in the confirmation study. Forty-two people will be included, but there is no assurance that they will be given the real drug (half will get a placebo) if they are accepted.
For Amy Holland, the waiting is excruciating. "This time, I know what the benefits are," she says. "Every minute while we are waiting is just heart-wrenching. ...We've put both our little girls' names on that list. After the trial, every child in the study will get the enzyme."
Since the end of the 6-month study, which began in November 1997, Spencer has continued to receive the enzyme replacement through the pharmaceutical company that makes it. The infusions, which take about 3 1/2 hours once a week, are given at the University of Texas Southwestern Medical School in Dallas.
Holland says she has called researchers and asked if there was any way they could take Spencer off the enzyme and substitute Maddie, at least temporarily.
"Of course, they couldn't do that," she says. "But this year has been very difficult for Maddie. We applied for all three of our children to participate in that trial. They took Spencer because he is the oldest."
But MPS is crippling Maddie, whose joints have become very stiff. She has a brain shunt to relieve vision disturbances and severe headaches and may need a second shunt to prevent damage from hydrocephalus.
Laynie has had heart valve surgery and is starting to get the severe headaches that signal she will probably need a brain shunt soon.
Spencer also has a brain shunt. All 3 Holland children have had carpal tunnel surgery on both wrists.
The Holland children and Ryan Dant all have MPS-1, also known as Hurler- Scheie's syndrome. Smith has MPS-4, or Morquio's syndrome. The science is available to treat four of the seven forms of MPS, including Morquio's, but researchers are waiting to complete the MPS-1 studies before expanding to deal with other forms of the disease.
Meantime, the treatment is available only to the 10 children in the original study.
Steve Holland is among the people trying to change that. "We want the FDA to realize that without enzyme therapy, kids are regressing every day, and the longer they wait, the more damage there is - some of it irreparable, and we question the idea of doing a double-blind study where half the kids are not getting the only treatment that works for this," Holland says. "It's one thing to do that when no one knows if a drug is going to work or not, but we know it's working. It seems awfully cruel to not get the real benefit."
Dr. Lewis Waber, an associate professor of pediatrics at UT-Southwestern who oversees the enzyme infusions for Ryan and Spencer, says the treatment should be approved and made available to others who are likely to benefit while additional studies are done.
"Both of these kids have had very, very significant improvement without any bad side effects," Waber says. "We do need more information to be gathered about what the enzyme will do, what exact benefits it will provide, but I think it should be approved."
Although the argument for fast-track approval is compelling, Dr. Stuart Swiedler, vice president for scientific and clinical affairs for BioMarin Pharmaceuticals, the company that is developing the enzyme therapy, says the FDA position is understandable.
"We know this can make a big difference in quality of life for these children. But there is no well-established natural history of these diseases," Swiedler says.
There is no way to know exactly what would happen in each case without the enzyme replacement therapy, because there are many mutations and manifestations of the disorder. MPS is not acutely life-threatening at any one point in the progress of the disease, and no one can be certain of the long-term effects of enzyme therapy, Swiedler says.
"It seems onerous and unfeeling toward the children, but the FDA is requiring two studies for all the treatments being developed for rare, genetic diseases," he says. "Such treatments will be expensive and lifelong. The FDA wants to be certain they are working and have no severe long-term side effects."
Still, Steve Holland and other MPS parents emphasize the importance of arresting the disease as much as possible to buy time until gene therapy or some other alternative is available. The only other current treatment for MPS is a bone marrow transplant, which is also considered experimental and carries a 30 to 40% risk of death, even with a close match. By contrast, hives, which is controlled by a little pre-treatment ibuprofen and Benadryl, is the only known side effect of enzyme replacement.
"We have considered bone marrow transplant, and they have a donor for Spencer, if we decide to do that, but there is still no match for the girls," Amy Holland says. "A doctor at the University of Minnesota (where transplants are done for MPS), who really believes transplants are the answer, told me that if all three of the children receive a transplant, the odds are at least one will not make it. When we see how happy our kids are running around playing with all their friends, looking healthy, it's such a big gamble."
Spencer considers himself to be just like any other child. Just 3 1/2 years ago, he was too weak to walk half a block, but now he skips and runs and skids self-confidently into the treatment room every Friday afternoon. He is grateful for the enzyme, but says his sisters need it, too.
"I want to keep doing all the stuff I get to do now - like shooting baskets," he says. "I couldn't do some stuff before, like basketball and swimming. I wouldn't be able to do a lot of things by now without the enzyme. I can swim real fast."
How fast can he swim? "Probably faster than lightning," Spencer says. "If I stopped the treatment, it (the symptoms) might all come back."
Copyright 2000 The Fort Worth Star-Telegram. All rights reserved.
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