Rescued Lives: Myozyme Answers SOS from Pompe Community

The approval of Myozyme in 2006, after decades of research, has transformed Pompe disease from a severely disabling or fatal condition into a treatable, chronic disorder. But responses to the drug vary, its cost is high, and some questions remain unanswered.

by Margaret Wahl on January 1, 2009 - 2:25pm

QUEST Vol. 16, No. 1

Mia Hanley of Cranston, R.I., looks pretty much like any 4-year-old preschooler. She’s a normal height and weight, walks well and has good language skills. In fact, when she started preschool at age 3, her fine motor skills were so good that she didn’t qualify for special services in that area.

Looking at Mia, most people would never suspect she spends every other Friday at Hasbro Children’s Hospital in Providence getting an intravenous infusion of a lifesaving medication, or that some of her nourishment comes through a feeding tube in her abdomen.

Had Mia been born a few years earlier, or if her mother, a nurse, and her pediatrician not been observant and vigilant from the start, it’s unlikely her acid maltase deficiency would have been treated in time to save her life.

A former death sentence

Not long ago, the infantile-onset form of the metabolic muscle disease acid maltase deficiency (also known as Pompe disease and acid alpha-glucosidase deficiency) was a death sentence.

Babies born with this genetic disease have virtually no acid maltase enzyme activity in their skeletal or cardiac muscle cells, and the liver also may be affected. Without acid maltase, a starch known as glycogen builds up in cells and ultimately destroys them. In the past, infants generally died of cardiac or respiratory failure before their first birthdays. Childhood- and adult-onset forms of the disease, in which some residual acid maltase activity remains, usually spare the heart muscle and liver but cause severe weakness and respiratory insufficiency and, without treatment, shorten life.

All that changed radically in 2006, when the U.S. Food and Drug Administration (FDA) and a similar agency in the European Union approved Myozyme, a laboratory-developed acid maltase enzyme manufactured by Genzyme of Cambridge, Mass., for the treatment of Pompe disease.

Since Myozyme became available, the outlook for people of all ages with Pompe disease is much brighter, although the treatment requires regular intravenous infusions of the drug, and several questions — the subject of ongoing research — remain.

The road to understanding

Credit for the first accurate description of Pompe (pronounced either “pom-PAY” or “POM-puh”) disease is generally given to Dutch pathologist Johann Pompe. In Pompe’s 1932 report describing postmortem findings in a 7-month-old girl, he noted pronounced enlargement of the heart, pneumonia and collapse of the air sacs in the lungs. Under the microscope, the heart-muscle cells were so full of glycogen that they were barely recognizable, and abundant glycogen was seen in almost all organs.

For decades, physicians struggled to understand how such massive deposits of the carbohydrate glycogen could exist when other evidence pointed to normal carbohydrate metabolism.

The solution wouldn’t come until 1963, when a group led by investigator Henri-Gery Hers at the University of Louvain in Belgium described a clear correlation between the absence of acid maltase and the large deposition of glycogen in the heart and skeletal muscles of babies with Pompe disease. Hers proposed that a congenital absence of the enzyme was the cause of the symptoms. He also suggested that the disease was not caused by a lack of energy production from glycogen but from the disruption of muscle fibers by the massive glycogen deposits. He speculated that the acid maltase enzyme was confined to cellular structures known as lysosomes. All these speculations would ultimately prove correct, although questions remain about whether energy production is affected.

Replacing the enzyme

Glycogen Buildup in Pompe Disease
In a normal muscle fiber, the lysosomes break down glycogen, the storage form of sugar. In Pompe disease, a deficiency of the acid maltase enzyme prevents the lysosomes from carrying out this function, so they fill up with glycogen and can break open. Over time, the working parts of the fiber (the myofibrils) can be damaged or destroyed.

Salvatore DiMauro, professor of neurology at Columbia University Medical Center in New York and a longtime MDA research grantee, has been seeing patients with Pompe disease for more than 40 years, starting in Italy in the 1960s.

“In adults, they used to recommend respiratory support and physical therapy, but not much more,” he says. “In infants, it was not considered moral to do heroic measures. There was nothing to do for these babies.”

However, he remembers being fascinated by the disease and the “great fervor” of Pompe studies in the 1960s and 1970s. It was during this time that the later-onset forms of the disease were identified and correlated with low, but not absent, activity of the acid maltase enzyme.

In the 1980s, scientists identified the acid maltase gene and studied its structure and function. And by the end of the decade, they had begun to recognize that specific defects in the gene could result in varying levels of acid maltase enzyme production and varying degrees of disease severity.

Attempts were made as early as 1967 to infuse an enzyme to replace the missing acid maltase, but the benefits were minimal.

Then, in 1998, MDA grantee Yuan-Tsong Chen at Duke University, and colleagues, in experiments in acid-maltase-deficient quail, added a key piece of the puzzle. They showed that enzyme replacement could work in Pompe disease if one infused an unprocessed, precursor form of acid maltase.

The fully processed “mature” enzyme, which most earlier investigators had used, can’t enter muscle cells from the bloodstream, the investigators learned. But they found the unprocessed form of acid maltase contains a chemical tag that allows it to enter skeletal and cardiac muscle cells from the blood.

Chen’s enzyme was produced in cells in the laboratory. At about the same time, Dutch researchers pursued a different approach: creating the enzyme by giving rabbits the gene for human acid maltase and then extracting it from their milk.

DiMauro remembers hearing about the rabbit-milk experiments at a meeting in the 1990s and admits he was skeptical. “We kept thinking about all those hapless graduate students milking rabbits,” he says.

But in 2000, a research team coordinated by Ans van der Ploeg at University Hospital Rotterdam in the Netherlands showed infusions of the rabbit-milk enzyme resulted in improvement in skeletal and cardiac muscle function in four babies with Pompe disease.

The early 2000s saw parallel clinical trials of the Duke University cell-based enzyme and the Rotterdam rabbit-based enzyme in patients with Pompe disease.

By the middle of the decade, the large biopharmaceutical company Genzyme had decided to purchase the rights to the cell-based product and develop it for commercial use.

In March 2006, Genzyme announced the results of its trials of Myozyme in babies 6 months old or less and children 6 months to 3 years old. The drug was well-tolerated and resulted in measurable benefit in both trials, although earlier treatment resulted in a better outcome.

On April 28 of that year, the FDA approved Myozyme for all patients with Pompe disease, even though a trial of the drug in older patients had not yet been completed. In December 2007, Genzyme’s trial of Myozyme in patients who were at least 8 years old showed it improved walking endurance and respiratory function in this group.

A cautious beginning

Pediatric nurse practitioner Joanne Mackey was coordinating the metabolic disease clinic at Duke University in 1998 when Chen began preparing for a clinical trial of his modified acid maltase enzyme. “[Chen] knew he couldn’t be at the bedside all the time,” she recalls, “and they wanted to hire a nurse practitioner.” Mackey moved over to the Division of Medical Genetics at Duke in 1999, and some six weeks later, they admitted the first Pompe patient to participate in a clinical trial of Chen’s enzyme.

“We only had enough drug for three patients, so we had to call some patients and tell them it was not available,” Mackey recalls. “It was very difficult. For that trial and the subsequent trial we had to sort through all the kids we knew and see who had contacted us.” The final decision was based on eligibility according to the trial criteria, the date of contact by the family, the condition of the child, and the family’s ability to come to Duke in Durham, N.C., where they would be required to spend six months. (MDA helped provide funds for accommodations.)

“In the earlier trials, we didn’t know what the effect of the enzyme would be,” Mackey recalls. Because of the potential for the body’s immune system to see the enzyme as “foreign” and reject it, she says, “we were worried about the development of antibodies. We knew we were infusing an enzyme that might be recognized as a foreign substance. That carried risks in itself. We did see some mild infusion reactions. We were extremely cautious.”

Of the first three patients, only one survived, but his survival was crucial. “The reason why the enzyme went as far as it did [in development] was because we had this surviving and thriving little boy whose sibling had died. That was our first indication that this was good.”

Fear and inspiration

Mia Hanley
Mia Hanley

Mia Hanley was among the beneficiaries of that first success. Her Pompe disease was diagnosed at 6 months, and within nine days the family had moved to North Carolina from Rhode Island and enrolled in a Myozyme study.

“If we had hung out here in Rhode Island, by the time they got approval [for Myozyme studies], Mia probably would not have been there,” says her mother, Dawn. “It was quicker to get her involved there, and we knew she was in the safest of hands, with the experts right there.”

The Hanleys arrived in Durham on July 4, 2005, and stayed for three months. “As scary as it was, there was a ray of hope, because now there was a treatment,” Dawn says.

From the start, the family had questions, Dawn remembers. “We wondered, what would her quality of life be? Would she be a pin cushion? Would we just be prolonging the inevitable? Reality was setting in. I thought it was a pill; it was an IV infusion. I thought it might be temporary; I found out it’s for the rest of her life.”

Duke put the Hanleys in touch with Joanne Mackey. “They put the nurse practitioner on speaker phone for the whole family to hear,” Dawn recalls. “We wanted to make the right choice. We wanted to either be aggressive or have end-of-life care. We found out Mia was a great candidate for Myozyme. She was relatively in very good shape. We would never have wanted to put her into something so aggressive for the same end result.”

Mackey told them that there had been side effects with Myozyme, but that they had been mild. “They said some kids are non-responders, but many are responders. The oldest child on the enzyme at the time was 5, and he was a typical 5-year-old except he would kind of fatigue during recess and gym class. He’s a typical 8-year-old now. The nurse practitioner asked if they would mind meeting us. Seeing him walk through the door was my inspiration. That got me through it, the thought that there’s hope my child will thrive and do well.”

Dawn had to leave her job as a nurse at a hospital in Providence, and her husband, Sean, left his electrician apprenticeship program. On July 7, at exactly 6 months of age, Mia started on Myozyme.

By 9 months, she was sitting up, and her echocardiogram (an imaging of heart function) was showing improvement. “We knew that Myozyme was working,” Dawn says. (Mia now has normal heart function.)

Remaining questions

Although Myozyme is certainly the first disease-modifying treatment for Pompe disease and has no doubt saved the lives of many infants and improved the lives of many older patients, there remain questions to be answered and obstacles to be overcome.

“Enzyme replacement is attractive but expensive,” says DiMauro. “And it doesn’t work effectively on all forms of Pompe disease. There are some spectacular improvements — nothing short of miracles — in infants when they’re caught in the first weeks or months of life. In adult patients, it’s somewhat useful, but if the disease has run a long course already, it may be less effective. Soon we’ll have enough statistics to say something about this.”

Some physicians have other reservations. Alfred Slonim, a pediatric endocrinologist and clinical professor at Columbia University Medical College in New York, is concerned that once patients get on the “miracle” enzyme, they may slack off on the exercise and high-protein diet he considers crucial to their well-being. He notes, “Studies have demonstrated an increased turnover and utilization of protein in late-onset Pompe disease, justifying the need for high protein intake.”

Despite this reservation, “If patients ask, ‘Should I go on the enzyme?’ I say ‘Yes, go on the enzyme,’” says Slonim, who has been caring for patients with Pompe disease using a careful nutritional and exercise regimen since the 1970s. (See sidebar below, “Skip the potato?”)

“There are a lot of questions,” admits Joanne Mackey. “Not every adult responds in the same way.” For one thing, she notes, there are a “huge number” of mutations in the acid maltase gene that can cause Pompe disease. “It’s not confined to just a few, and that makes it more difficult. There are a few [mutations] they can identify and say this is probably worse than this one, but there are very few like that. The correlation is not yet understood.” Other genes may affect disease severity or response to Myozyme, she notes.

When Mackey talks about Myozyme with parents of a child with Pompe disease, she tells them, “It’s not magic medicine. It may take years for good results, and we can’t guarantee anything.”

A decision by the FDA about a new, large-scale manufacturing process Genzyme used for the late-onset Pompe disease trial, and wants to continue using, could have ramifications for people with Pompe. In October, an advisory committee met to discuss Genzyme’s request to use this manufacturing process without going through additional regulatory approval; a final decision is pending.

As of late 2008, Genzyme only was able to provide the drug to affected children ages 17 and younger, as well as to anyone who already is being treated, and to participants in a Genzyme-sponsored study of late-onset Pompe disease. For now, though, new adult patients who aren’t in those categories can’t get Myozyme. FDA approval of the revised production process could greatly increase the amount of available Myozyme.

Then there’s the almost unimaginable expense of the lifelong treatments — about $30,000 a year for an infant and about $300,000 a year for an adult. Myozyme is now covered by most — but not all — private insurance plans and by government programs.

“Sometimes,” Mackey says, “people look at the cost and say, ‘I’m going to wait. I’m not bad enough.’ And clinicians are making that evaluation too.” So far, she’s been able to help patients get financial coverage for the drug. But as for whether that will be permanent, she says, “You never know.”

New directions

Although Myozyme has proved a reasonably safe and effective treatment for Pompe disease, other research avenues are being pursued.

Among them is therapy using the acid maltase gene, rather than the protein, which could give patients a much longer interval between treatments, since the protein potentially could be continuously manufactured in the body. MDA has funded some of this work.

On another front, Amicus Therapeutics, a Cranbury, N.J., biopharmaceutical company, is developing and testing a small molecule so far known only as AT2220, which is designed to stick to an acid maltase enzyme that’s the wrong shape and coax it to fold into the proper shape. This approach could work for people with Pompe disease who have certain types of genetic mutations. Several MDA clinic physicians are among the investigators in a multicenter clinical trial of this experimental drug, and Joanne Mackey is the study coordinator at her center at Duke University. “There’s plenty of room” for further research, she says.

Meanwhile, Myozyme itself may undergo some changes. Seng Cheng, group vice president of genetic diseases science at Genzyme, says the company is developing what it hopes will be a new, improved Myozyme. In mice with a Pompe-like disease, one new version of the enzyme reduced tissue glycogen levels as effectively as the currently approved product but required much lower dosages. “We are continuing to evaluate the relative merits of [the newly modified enzyme] and are hopeful that we can move this into development in the future,” Cheng says.

Genzyme is also conducting several studies involving the current formulation of Myozyme. (See Clinical Trials.)

Lecita Moore, a 32-year-old mother living in Tucson, Ariz., says she was always a little slow at running and gym activities but didn’t begin to notice a real problem with exercise until she was in her early 20s.

When she was 21 and working at a desk job at a hospital in Georgia, she began to experience more fatigue than she thought was normal and decided she needed to start going to a gym. “I thought I was just out of shape,” she says.

But the gym workouts didn’t help. “I got even more fatigued. It got so I had to nap after work before doing anything.”

Unfortunately, the medical attention she eventually sought led her down the wrong path (a not uncommon experience for people with Pompe disease). Her condition was misdiagnosed as polymyositis, an inflammatory disease in which the immune system mistakenly attacks muscle tissue, and she was put on prednisone and methotrexate to suppress her immune system.

By 2003, Moore’s condition hadn’t improved, but side effects of the medications had caused her to gain 35 pounds and lose her hair.

In June of that year, her weakness caused her to stop working, and in August she had to leave a bachelor’s degree nursing program she had started.

“I wanted to be a labor and delivery nurse,” she says.

When her husband, Kevin, who’s in the U.S. Air Force, learned he was being sent to Korea, Lecita moved back to her parents’ home in Jackson, Miss., where she had grown up.

“Between 2003 and 2005 I was pretty much in bed,” she says. “I was very weak and unable to do much. I wasn’t able to climb stairs. I couldn’t sort clothes on the floor, because I couldn’t get up. I wasn’t able to take a bath, because I couldn’t get in and out of the tub. I couldn’t even get in and out of bed without difficulty. Washing my hair was a problem. Going to the grocery store was a task. I had to do it with help and take breaks.”

But help was on the way. Moore started seeing a doctor in Jackson who suspected she didn’t have polymyositis and repeated the muscle biopsy that had led to her diagnosis.

The second biopsy, in May 2004, showed Pompe disease, and Moore was referred to a specialist in neuromuscular disorders, who confirmed the diagnosis.

The specialist took her off prednisone and methotrexate, and she began feeling better. Unfortunately, he told her, no treatment was available for Pompe disease.

“When they told me they didn’t have anything, I didn’t know where my life was headed,” Moore says. “The unknown will kill you.”

The following year, the couple transferred to Tucson, where Moore started seeing neurologist Tim Miller, director of the MDA Clinic at Children’s Clinics for Rehabilitative Services. The timing was good, because Miller was very much involved in testing Myozyme and was eager to get her into a trial of the experimental drug. (He’s now employed parttime at Genzyme.)

“Myozyme was approved in 2006, as they were getting the paperwork done, so I never did go into a trial,” Moore recalls. Instead, she started treatment with the enzyme at the Fasseas Cancer Clinic in Tucson in May 2006 as soon as the drug was approved.

“I started noticing a difference about four months into treatment,” she says. “I started noticing increased strength and stamina and less fatigue.” Gradually, her strength returned, and she was able to climb stairs, get in and out of the bathtub and get up from the floor by herself.

Her treatments are paid for by Medicare and by Tricare, an insurance plan for military personnel and their families.

In April 2007, she and Kevin adopted a baby, Maiyah.

“Having the baby has been wonderful,” Moore says. “I wouldn’t trade it for the world. I had been worried about not being able to do things in the future that other mothers can do with their kids, but now I’m able to do those things.” Myozyme, she says, has changed her life.


When Myozyme first became available in 2006, Vincent DaSilva was 20 years old, attending college in upstate New York and not at all sure he wanted to try a new drug for his Pompe disease.

The reason? He was doing very well with a diet and exercise program prescribed by Alfred Slonim, a metabolic disease specialist then practicing at North Shore University Hospital in Manhasset, N.Y. While some physicians advise people with Pompe disease to ingest carbohydrates for a “quick fix” of usable sugars to burn when they’re active, Slonim believes high carbohydrate intake exacerbates muscle glycogen storage problems over time. DaSilva had followed Slonim’s high-protein, low-carbohydrate diet since childhood and was regularly working out at a gym.

But a couple of years ago, he began experiencing increasing fatigue, so much so that he had to reduce his class schedule and limit his daily exercise. DaSilva, with his parents and Slonim, decided to try Myozyme “before anything could get out of hand,” he says, hoping to regain some stamina and improve the lethargy.

In late 2007, DaSilva started receiving Myozyme infusions every two weeks at Albany Medical College. Since then, he says, “That extreme fatigue and lethargy has subsided quite significantly. I’m back to a full-time credit load and have more energy than I did before.”

DaSilva says being on Myozyme has made him even more appreciative of the important role of diet and exercise in managing his disease. At a Myozyme group meeting a few months ago, he realized that Pompe patients who hadn’t followed a diet and exercise regimen were more severely affected by the disease.  That led him to give a few talks about his regimen at events around the state.“After seeing me, and listening to both Dr. Slonim and myself, they were appreciative and welcoming of the idea of trying a more high-protein, low-carb diet, and exercising to the best of their ability,” he says. Two people since have told him the diet-and-exercise plan seems to allow Myozyme to do its job better.

DaSilva walks three to four miles a day and goes to his college gym about five times a week, where he lifts light weights.

As for his diet, DaSilva says his original plan still works well for him. “That doesn’t mean I don’t sneak some ice cream or pasta every now and then,” he says. “Most people don’t realize that a high-protein, low-carb diet allows for a huge range of variety and choice.”

He says he’s not convinced that Myozyme alone can do what diet and exercise can do, and that unless he learns otherwise, he’s going to stick with what works for him, with or without the drug.

(For more on diets in metabolic disease, see “What Not to Eat,” November-December 2007.)
Enter “Pompe” in the search box. for the Pompe disease community for the Myozyme community Pompe Registry site Select Groups; then enter Pompe disease in the search box. Select Popular Support Groups and then Pompe disease.

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