Subscribe to eTOC



✓ In an international open-label trial, 18 infants with Pompe disease survived for 18 months or longer after being treated with recombinant human lysomal acid alpha-glucosidase (rhGAA) within the first six months of life.

A recombinant human enzyme approved last April by the FDA safely and effectively countered debilitating motor, cardiac, and respiratory deficits in infants with Pompe disease, a hereditary lysomal storage disorder, which is usually fatal within the first year of life, according to an international open-label study.

Eighteen infants with the disorder survived for 18 months or longer after being treated with recombinant human lysomal acid alpha-glucosidase (rhGAA) within the first six months of life. Some of the treated infants exhibited normal growth and motor development. The drug was well tolerated overall without patients dropping out from the study due to severe adverse events, researchers from 13 hospitals around the world reported in a study published online on Dec. 6, 2006, in advance of the print edition of Neurology.

Lead author and pediatric researcher Priya S. Kishnani, MD, interim chief of the medical genetics division at Duke University Medical Center in Durham, NC, told Neurology Today in a telephone interview that 13 of the children remain alive with ongoing treatment, seven are walking, and three are “sitters.” The eldest child is almost 4 years old.


The open-label trial evaluated the safety and efficacy of the treatment in infants who received either 20 mg/kg or 40 mg/kg rhGAA every other week for at least 18 months, with results analyzed following 52 weeks of treatment after the last infant was randomized. All of the children survived to 18 months, and one group demonstrated not only normal growth but also age-appropriate motor milestones, said Dr. Kishnani. Eleven of the children suffered a total of 164 mild to moderate infusion-related adverse reactions, although none required discontinuation of treatment. The higher dose did not appear to improve response over the lower dose.

Treatment was also tested in the United Kingdom, France, Israel, and Taiwan as primary treatment sites. The researchers noted that the infants' response, which was greater than has been reported in earlier trials, was likely due to the younger age at which treatment was initiated.

A Cox proportional hazards analysis of the data showed treatment reduced 18-month mortality by 99 percent, risk of death or invasive ventilation by 92 percent, and risk of death or any type of ventilation by 88 percent, compared to an historical control group.


Pompe disease, also known as acid maltase deficiency disease, and Glycogen storage disease type II, is a rapidly progressing disorder that causes severe deficits due to accumulation of glycogen in skeletal and cardiac muscles. Early onset or infantile Pompe disease results from complete or near complete deficiency of GAA. Symptoms begin in the first months of life, with feeding problems, poor weight gain, muscle weakness, and head lag. Most babies with Pompe disease die from cardiac or respiratory complications within their first year.

Those with late onset (juvenile or adult) Pompe disease have a partial deficiency of GAA; the primary symptom – muscle weakness progressing to respiratory weakness and failure – can begin in childhood, adolescence, or as late as in the sixth decade. Patients experience steadily progressive debilitation, eventually requiring wheelchairs and artificial ventilation.

Studies dating back to 1999 have shown that rhGAA can increase levels of acid alpha-glucosidase in Pompe disease. This has resulted in stabilization of the disease as well as improvement in motor, respiratory, and cardiac response. “The oldest treated infantile-onset case is now seven years old and in the second grade,” said Dr. Kishnani. “He is completely mainstreamed and is developing normally, although he may not be quite as strong as his peers.”

Whether patients respond to the treatments seems to be related, in part, to the status of their cross-reacting immunologic material (CRIM). Normally, people do not make antibodies (abs) against proteins in their own bodies. However, if a person lacks the protein altogether and is then given an infusion of that protein, antibodies may be generated and the result may have adverse consequences. That happens to some people who lack IgA and are then given intravenous immunoglobulins containing IgA.

Sometimes, a treatment that involves intravenous infusion of a protein may generate an adverse immune response, a problem that raises the question of “cross-reacting immunologic material.” For any enzyme protein, a mutation may negate the biochemical activity and also the three-dimensional shape of the protein, so that it no longer reacts with antibodies against the normal protein.

This issue arises in consideration of replacement therapy for Pompe disease; all patients lack enzyme activity but only some retain CRIM. The authors write that “…increasing evidence suggests that CRIM-negative patients are more likely to develop a higher, more sustained immunologic response against rhGAA than CRIM-positive patients and potentially a more limited duration of clinical benefit after rhGAA administration. In the current study one of the 18 pts developed abs that inhibit in vitro rhGAA enzyme activity.”

However, only three of the 18 were CRIM-negative and, the authors noted, that “the total number of CRIM-negative patients studied to date is quite limited.” As is often the case, experience must be extended to more patients to understand whether CRIM-negative patients are at a greater risk of adverse reactions.

Dr. Kishnani said: “There are a lot of anecdotal reports of older patients improving with treatment, even those with the most severe involvement (on ventilator use and wheelchair dependent). A series of 18 cases ranging in age from 9 to 54 years of age with advanced stage of the disease have shown improvement.”

Dr. Kishnani said four of her late-onset patients were doing better on enzyme therapy. Two who were on ventilator support at the start of treatment are off ventilation for few hours at a time now, she said.

In two women, ages 61 and 45, improvement has been dramatic; they received enzyme treatment for only six months. “They're much stronger, and the older one can now climb stairs. The 45-year-old woman was able to get up from the lying down position much more quickly. In the past it took her 38 seconds to rise from lying flat on the floor to standing, but now she can do it in just eight seconds. This patient was also able to walk more briskly, with no support and also run short distances!”


Pompe disease, which occurs in an estimated 1 in 40,000 persons, has been designated an orphan disease by the US FDA. Last April, the agency granted a seven-year exclusive licensing approval to Genzyme Corp. of Cambridge, MA, for its rhGAA product alglucosidase alpha (Myozyme®).

In announcing its decision last April, the FDA said the drug's safety and efficacy had been evaluated in two separate clinical trials involving 39 infantile-onset patients ranging in age from 1 month to 3.5 years at the time of the first infusion. The agency stressed, however, that there have been life-threatening allergic reactions, and the medicine carries a “black box” warning.

The most serious reactions have been heart and lung failure, while the most common have included pneumonia, respiratory distress, infection, and fever. More than 280 patients in 30 countries are receiving treatment through clinical trials, expanded access programs, or pre-approval regulatory mechanisms.

Dr. Kishnani told Neurology Today that she believes the incidence of Pompe disease may be far greater than current estimates of 1 in 40,000, noting that late onset cases are often misdiagnosed as limb girdle muscular dystrophy.

The diagnosis in the past was made by skin or muscle biopsy. Skin biopsy results can take up to six weeks and muscle biopsy is dangerous for infants because it involves anesthesia, she explained. A rapid blood test (with as little as a 48-hour turnaround time) has been developed needing just a few drops of blood on a filter paper card. This test has the potential for being included in newborn screening. In fact, in Taiwan the test has already been performed on close to 75,000 newborns as part as newborn screening and 3 cases of Pompe disease have been identified.

“I think there is a lot of excitement and a lot still to do in the field of Pompe disease,” she added.


Robert Steiner, MD, assocate professor of pediatrics, molecular, and medical genetics at Oregon Health and Science University School of Medicine in Portland, told Neurology Today in an e-mail: “This is a dramatic advance in the development of a therapy for this disorder, for which no other specific treatment is available at this time. Importantly, this study enrolled only patients less than six months of age, and only three of 18 patients had cross-reacting immunological material-negative forms of the disease.”

Dr. Steiner, vice chairman for pediatric research at Doernbecher Children's Hospital in Portland, said the results are similar to those previously reported and further demonstrate this “as a lifesaving treatment in some patients with Pompe disease.” Dr. Steiner was not involved in the trial.

“Because treatment is more likely to be effective if started early, a strong case for newborn screening for this condition can be made, and indeed technology to allow such screening is available today.”

However, he said it is unclear how effective treatment will be in adult patients, since large clinical trials have not been completed.

“It seems likely from this and other studies, and early experience with treatment of Pompe disease outside of these clinical trials, that not all patients will benefit,” he said. “Specifically, patients are less likely [to respond as well] who begin therapy after six months of age and if they have severe cardiomyopathy or respiratory insufficiency. Furthermore, patients who produce none of the enzyme that is deficient in Pompe disease, so-called CRIM-negative patients, may be less likely to be helped by rhGAA, although further studies are needed.”

However, results of small trials in adults, experience with use of the drug in adults since FDA approval, and the likelihood that late onset Pompe disease patients will be CRIM negative, indicate a strong likelihood that treatment will work well in many patients, he said.


• Kishnani PS, Corzo D, Wraith JE, et al. Recombinant human acid-glucosidase. Major clinical benefits in infantile-onset Pompe disease. Neurology 2006: E-pub 6 Dec. 2006.