The Team Behind the Treatment

by Marsha A. Green

Yamila Jimenez is a 3-year-old walking miracle. She has Pompe (pronounced pom-PAY) disease, a rare genetic disease that means her body is unable to produce a vital enzyme needed to turn the sugar (glycogen) in her muscles into energy. Had she been born just a few years earlier, her life expectancy would have been 12 months or less. Her muscles would have rapidly weakened, preventing her from moving, swallowing, breathing. Her heart would have become enlarged, inefficient, prone to failure. She, like other babies born with the most severe form of Pompe disease, would have died a tragically early death.

But now, because of Myozyme® — a treatment that people at Duke spent more than a decade shepherding from the molecular biologist’s bench to the patient’s bloodstream — Yamila has a future.

On April 28, 2006, the Food and Drug Administration (FDA) approved Myozyme for treatment of Pompe disease both in infants and for those with later onset of the disease. It is, currently, the only treatment for this devastating disease. Myozyme provides the missing enzyme Yamila’s body needs to break down glycogen in a specialized cell compartment called the lyosome. Although she has to have an infusion of Myozyme every two weeks for the rest of her life, she can walk, talk, swallow, play and live like a normal child.

The miracle of Myozyme has been a long time coming. Like the average new drug, it took almost 15 years to wend its way from the test tube to the treatment room. Along the way, it gathered around it a team of people committed to the project and the lives it saved.


Y.T. Chen, M.D., Ph.D., a pediatrician and former chief of the Pediatrics Division of Medical Genetics at Duke University Medical Center, began studying glycogen storage diseases more than 25 years ago. But in the early 1990s, there was one infant whose plight touched his heart in a new way.

The baby, suffering from Pompe disease, was weak and fragile. The family, desperate to save the child, turned to their community and raised money for a $250,000 bone marrow transplant. Their desperate hope that the new cells would produce the missing enzyme was dashed when the baby died before the transplant could occur.

I went to the funeral in Greensboro, and the pastor talked about how surely God must have had a purpose in having this baby on Earth for such a short time, says Chen. I looked at my colleague and thought — the purpose is to encourage us to go back to the lab and find a treatment.

And so they did.

The researchers used molecular biology techniques to insert the human gene for the missing enzyme (acid alpha glucosidase, or GAA) into a cell grown in the laboratory.

We tried different cell lines, from E-coli to yeast to insect cells to mammalian cells, to see what could make enzymes that could be taken up by humans, says Chen. We ended up with cells from the ovaries of Chinese hamsters.

They turned the lab into a small factory to make enough enzyme for animal experiments.

In 1998, they injected the human enzyme into Japanese quail specially bred to be missing the GAA enzyme. These birds are normally so weak that they cannot fly, and when placed on their backs they cannot right themselves.

The results of the trials were astounding. After seven injections over 18 days, the birds could flip from their backs up onto their feet, and one could even fly a short distance.


Throughout the years, the administration at Duke consistently backed the project. In the 1990s, Michael Frank [then chairman of the Department of Pediatrics] understood the importance of continuing medical genetics as a division, says Chen. Once we moved into the clinical trials, we also received immense support from the administration. Duke leaders made a big investment in this project because they believed it would work.

As possibilities of the new enzyme treatment grew, so did the administrative tasks — submitting a patent request to protect intellectual rights; preparing a protocol for the first clinical trial; finding funding for clinical trials and further research; and licensing the rights to the production of the enzyme to a larger company that could produce more, faster.

Dr. Chen realized that Duke would need to collaborate with a biotech company in order to produce enough enzyme to move forward, says Gil Smith, Ph.D., director of Corporate Research Collaborations of the Duke Office of Science and Technology. We initially worked with Synpac, a British-based Taiwanese company, and then later with the Genzyme Corp., in Boston. Over seven years, Smith has created quite a paper trail for the Pompe project. In addition to working with biotech companies, he handled patent applications (Duke submitted the original application in 2000 and expects to receive the patent later this year), funding agreements, and conflict of interest issues that rose because Chen was both the inventor of the new treatment and the principal investigator. We had to balance the conflict of interest issues with the fact that Duke was the best place to run the early clinical trials, Smith says.

The solution was for Chen to pass the baton on to his colleague, Priya Kishnani, M.D. I turned the clinical trials over to Priya because I knew she would be a good team leader, he says.


I was a fellow in Genetics with Dr. Chen and was seeing patients with Pompe disease in the 1990s, says Kishnani, associate professor of Pediatrics in the Division of Medical Genetics at Duke. I watched the lab develop the enzyme and was part of the whole experience when the birds first flew. Then they started talking about a clinical trial, and I started playing a larger role because of my interest in translational medicine.

Between them, Chen and Kishnani began building the team needed to test the novel treatment on humans. Joanne Mackey, who was a nurse practitioner in Pediatrics, was one of the first to join. Drs. Chen and Kishnani invited me to join the Division of Medical Genetics to be the study coordinator for the first trial in 1999, she remembers. I was the first nurse to ever belong to the division. I was in the clinic when we saw the baby that eventually became the first human being to have the enzyme injected, and I did daily rounds on all the babies once they came to Duke to participate in the trials.

Because the enzyme was difficult to produce, the first clinical trial was restricted to three babies. We didn’t know how much we would need, but we knew that if it worked, we had to keep giving the enzyme to these babies to keep them alive, says Mackey. That created a lot of tension because we had to accept the babies on a first-come, first-served basis. And there were more than three babies with the disease whose families were pleading to be included.

Mackey remembers well the roller-coaster emotions of the first clinical trial. About 10 weeks into the first trial, the first baby was doing really well, she recalls. _He was getting stronger and almost sitting. But then he began to decline after about three months. The second baby followed almost the same pattern.

Both of these patients continued on therapy for several years, but eventually died. We were nervous about enrolling the third baby, says Mackey. But when he had been on the treatment for 10-12 weeks and was still getting better, that’s when we really began to hope that we had something big.

The team still stays in touch with all three families. The third child turned 7 this July, one of the few 7-year-olds with infantile Pompe disease.


The Duke team took time after the first clinical trial to investigate why some of the babies created antibodies against the enzyme and some didn’t. But soon, they were ready to try another clinical trial. However, this couldn’t happen without a partnership with industry.

We needed somebody who could produce large amounts of the enzyme, says Chen.

Turns out, that’s not a simple task.

Genzyme is the company that ultimately served as the engine for the project. There, the three-month cycle to create the enzyme begins with a starter kit of genetically engineered hamster cells (the final production was done with a cell line produced by Genzyme). The cells are put into a stainless steel vat rather like those in microbreweries. Inside the bioreactor, the cells multiply until there are billions churning out the enzyme. Every day, scientists harvest a bit of the fluid and carefully process it to produce a small amount of pure enzyme.

The program to develop Myozyme was the largest in our 25-year history,says Bo Piela, spokesperson for Genzyme. Through 2005 we spent approximately $500 million and had several hundred employees working on it. We added two, 2,000-liter bioreactors at a cost of about $53 million. And were now in the process of adding manufacturing capacity in Europe to ensure that we can produce enough enzyme to treat all the patients who need it. In addition to producing the enzyme, Genzyme administered the clinical trials in seven sites in the U.S., Europe and Asia, with Duke being the first and largest.

Deya Corzo, M.D., medical director of the Myozyme program with Genzyme, believes that the project is a model for partnerships between industry and academia. We were productive, we had tons of publications, and we had a great relationship, she says. _My speed dial is full of Duke numbers. There have been disagreements, but people always saw the bigger goal, and were optimistic that this product could change the course of this horrible disease.


Every clinical trial at Duke has to be approved by the Duke Institutional Review Board (IRB) to ensure that the research is conducted ethically, safely and within regulations. The IRB also ensures that participants are accurately informed of the risks of clinical trials. Kishnani has a special place in her heart for John Falleta, M.D., and James Heller, M.S., C.C.C., a clinical associate in Surgery, who not only helped prepare the paperwork, but followed through quickly when changes were needed for the various Pompe disease clinical trials.

There was always a sense of urgency because we had to get the children signed up for the clinical trials as soon as possible because we knew that the earlier we started the therapy, the better the chance of a good outcome, Kishnani says. That takes a lot of effort. The consent form itself was 25 pages long, and there were always changes that needed to be made based on what we had learned from the babies already enrolled.

When we ran into a rough spot and changed the protocol, we had to change the consent form, inform the families and take it back to the IRB, she explains. Dr. Falletta worked very hard to ensure this was done in a timely fashion so that everything would be available for the next child.


Initially the Pompe team at Duke was quite small — the physicians, scientists and genetic counselors involved in diagnosing the patients and counseling the families; and the clinicians involved in the infusions and assessments. But as the babies lived longer, we had to establish a larger team, says Kishnani. We were learning new aspects of this once lethal disease as we went along.

Because the children were coming from South Africa, United Arab Emirates, Palestine, Peru and all over the U.S., we had to have someone to help deal with the logistics of transporting fragile babies long distances, she says.Because every baby enrolled needed to have a muscle biopsy performed, and this required anesthesia, we needed an anesthesiologist. We had to work closely with the PICU [Pediatric Intensive Care Unit] as we needed a bed for the baby after the muscle biopsy. Because Pompe affects the heart, we needed a cardiologist. Because the babies often needed ventilators, we needed a pulmonologist. Because the weakness affected swallowing, we needed a speech therapist. With each baby, we learned more about the needs these children have, and we added people to the team. And because early treatment is essential, and we couldn’t control when the babies would arrive, we had to find members who were committed to being available at any time.

The team’s dedication was highlighted when a South African family arrived, unannounced, with their baby on July 4, 2000. Unable to obtain a medical visa, the parents brought the child to the U.S. on a tourist visa. Despite the holiday, team members came into the hospital to meet the family, find a bed for the baby, explain the study and obtain consent for participation so the child could be enrolled before the day was over. Today, Abdurraman is a healthy 5-year-old.

Experiences like this helped the team bond and became a source of support not only for the patients and their families, but for each other.

It wasn’t always smooth. There were some very tough times,” says Mackey, who has served as study coordinator for all the clinical trials at Duke. “People had the joy of being in the only place in the world that has successfully treated so many babies with Pompe disease. But there was also sadness.

With a carefully controlled voice, Mackey recalls the story of the first child enrolled in the clinical trial for babies over 6 months of age. We had been following her in clinic, waiting until she was old enough for the trial. When she was finally enrolled, the first thing the protocol called for was a muscle biopsy, which required anesthesia. The baby died while in the operating room. It was devastating.

In addition to the emotional shock, the team had to consider the impact on the trial. We had to rethink the protocol for administering anesthesia, says Kishnani. We worked with Dr. Richard Ing in Anesthesia to create a protocol for safe delivery of anesthesia to critically sick babies with a massive heart. It took time, and it was hard because there were babies ready to be enrolled in the clinical trial, but we couldn’t take them until we had fixed the anesthesia issues. Everyone pulled together as a team to fix the problem, so we could resume the trial and continue to treat babies as soon as possible. We now serve as the international resource for many issues, including anesthesia, for Pompe disease.

Each and every person on the team has been so committed to this mission, she says. I never heard no from anyone. It was always, If I cant do it, I’ll figure out who can. By the end of the last clinical trial, we had a list of more than 50 people who were informed every time a new baby was enrolled.

One of those team members was Laura Case, D.P.T., a board-certified pediatric physical therapist (PT) and faculty member in the doctoral level PT program at Duke, who joined the team in 1999 during the first clinical trial.

I’ve worked for many years with children with progressive motor unit diseases such as muscular dystrophy, she says. The first time I heard Dr. Chen talk about the enzyme, it gave me goosebumps. I knew that if it worked, it wouldn’t just delay the inevitable. It would save these babies lives.

Case has been involved in assessing all 27 children at Duke who have received the enzyme — measuring how well they can move against gravity and monitoring when they reach milestones such as crawling, sitting and walking. The PT team at Duke also provides intervention with careful monitoring to improve the patients_ progress as they regain strength and mobility.

These babies are so fragile when they come in — just turning them over in the crib can be a stress that changes their medical status, Case says. But they are so bright eyed. They are eager to face life and do whatever they can. I think it is the responsibility of the adults to meet that, to do anything possible to open doors for those children.


In addition to treating children enrolled in the clinical trials for Myozyme, Duke faculty and staff have been involved in the expanded access program created by Genzyme.

There were many children who didn’t meet the strict criteria for the clinical trials, but for whom we believed Myozyme would be helpful, says Piela, the Genzyme spokesperson. Our expanded access program was approved to provide the therapy to these other patients before the FDA had given their official approval. Many of these patients began their therapy at Duke. That way there was no delay in starting the treatment, and once the local institution was ready, Duke could transfer the patient. The expanded access program was resource intensive. We had to train staff at each institution that agreed to participate. Often that meant submitting a protocol and informed-consent form, and training staff all for one patient, says Piela.

Duke personnel sometimes assisted with the process, traveling to other sites to teach physicians, nurses and social workers about Pompe disease and the Myozyme treatment.


For nearly everyone involved in the project, the most touching part has been witnessing the love that energizes the families. Their dedication and courage continuously astound those who are privileged enough to meet them.

Of the 40 families involved in the clinical trials worldwide, only a few did not have to relocate. While some just moved to a new city, others had to move to a new country or even a new continent. Stephanie DeArmey, M.H.S., P.A.-C, a Duke physician assistant, says that the care provided is much more than medical. She remembers working with the team to help settle a family that moved across the country to Durham with their four children in order to be involved in the trial. Genzyme representatives, Duke social workers and others helped the families relocate to Durham by coordinating apartments and registering children for school, but we were the first contact. We are on page 24 hours a day for these families, not just for medical issues, but social issues as well. We spent a lot of time with the families and celebrated milestones such as birthdays for the kids. We got very attached to each family. I am always in awe of the families dedication, adds Case. They spend months here at Duke for their child because this is where there is hope. On Aug. 24, many of those families will come back to Duke to celebrate what some call the Myozyme miracle, and the fact that the treatment they helped move from bench to bedside is now available to any baby with Pompe disease.

Like most miracles, it is hard to explain to anyone who hasn’t lived through it. In the words of 3-year-old Yamila’s father, Jorge Romero, I can’t find words to express the joy.

TIMELINE of Myozyme Treatment for Pompe Disease

1991-1994 Genetically engineered cell lines to overproduce the necessary enzyme

1995 Established that the enzyme works in cultured cells from Pompe patients

1996 Established that the enzyme works in vivo in an animal model; Japanese quail injected with enzyme overcome muscle weakness. One flies. 1997 Duke obtains FDA Orphan Drug Designation for Pompe therapy. The British-based Taiwanese biotech company Synpac obtains license from Duke to produce enzyme for clinical trials . 1999 First clinical trial of enzyme replacement therapy in humans begins in Duke’s General Clinical Research Center (GCRC). Y.T. Chen, M.D., Ph.D., is principal investigator.

2000 Biotech firm Genzyme obtains license from Synpac to produce enzyme.

2001 Phase II clinical trial begins with 8 patients (5 treated at Duke). Priya Kishnani, M.D., is principal investigator.

2002 Genzyme compares four different methods for producing enzyme and chooses the modified Chinese hamster ovary cell-line product using an existing Genzyme cell line.

2003 Phase III clinical trial for patients with infantile-onset Pompe disease. Priya Kishnani is the principal investigator. 2005 Clinical trials begun for patients with late-onset Pompe disease

2006 Broad label market approval for Myozyme in Europe (March 29) and in U.S. (April 28). Guidelines published for diagnosis and management of Pompe Disease in Genetics in Medicine.

“This article was first printed in the August 21, 2006 issue of INSIDE DUKE MEDICINE, the employee newsletter and Duke University Medical Center. For more information, visit ”