Pompe disease is a rare condition, with a global incidence rate estimated to be between 1 in 40,000 (0.0025%) and 1 in 300,000 (0.0003%) live births.1 According to a study published in 1998, the annual incidence of Pompe disease in New York City was estimated to be approximately 1 in 40,000 births, and approximately 90 babies are assumed born with Pompe disease in the United States annually.2 A similar incidence rate was found in the Dutch population (1 in 40,000 births), a relatively lower rate was found among the Chinese (1 in 50,000 births; 0.0020%), and a higher rate was seen among African Americans (1 in 31,000 births; 0.0032%).2-4
In 1998, the total number of patients with Pompe disease was estimated to be between 1900 and 3000 in the United States.2 By 2004, the estimated number of patients with Pompe disease was between 5000 and 10,000 worldwide.5
Pompe disease is named after Johannes Cassianus Pompe, the physician who was first to identify it as a glycogen storage disease in 1932. Pompe disease is also referred to as glycogen storage disease (GSD) type II (GSD II) or acid maltase deficiency.6 For an infant who contracts the disease, the survival rate to age 12 months is estimated to be 25.7%.7
As an autosomal recessive disease, Pompe disease is caused by an acid alpha-glucosidase (GAA) gene disorder that leads to the GAA deficiency in this disease. GAA is the only enzyme that is active in the acidic milieu of the lysosomes for degradation of glycogen.8 Because the glycogen cannot be broken down effectively into a simpler sugar (glucose), which is the main source of body energy, the accumulation of the glycogen in organs and tissues causes myopathy, with progressive muscle weakness. The heart, liver, respiratory system, and nervous system are all affected.
The goals of this study were to review recent developments in Pompe disease therapies and describe drug utilization and spending trends associated with this disease in the US Medicaid program.
The 2 Forms of Pompe Disease
Depending on whether symptoms occur within the first 6 months after birth or, alternatively, later in life, Pompe disease is classified as infantile-onset or late-onset illness, respectively.3 The late-onset form of the disease progresses more slowly than the infantile-onset and can present in patients as old as age 60 years.
Common signs and symptoms of infantile-onset disease include cardiomegaly, hypotonia (ie, muscle weakness), hepatomegaly, cardiomyopathy, respiratory distress, enlarged tongue (ie, macroglossia), feeding difficulties, and failure to thrive.7 Heart failure and respiratory weakness are the most common causes of death among infants with Pompe disease.3
The primary clinical manifestations of late-onset disease include progressive proximal muscle weakness (especially in the body and legs), exercise intolerance, exertional dyspnea, sleep apnea, and joint contractures. For those who contract the disease in childhood or adolescence, additional symptoms include scoliosis, hepatomegaly, macroglossia, and cardiac hypertrophy.9 The main cause of death for patients with late-onset Pompe disease is respiratory failure.9
Before 2006, there was no effective treatment for Pompe disease, despite several decades of studying potential treatments in clinical trials. Unsuccessful trials involved altering the synthesis of glycogen, bone-marrow transplantation, and administration of unphosphorylated enzyme isolated from Aspergillus niger or from human placenta.10
On April 28, 2006, under priority review, the US Food and Drug Administration (FDA) approved a Biologic License Application for the orphan drug Myozyme (alglucosidase alfa, recombinant human [rh]GAA) for patients with Pompe disease.11 Myozyme received marketing authorization in the European Union slightly earlier, in March 2006.12 Myozyme is an enzyme replacement therapy (ERT) drug, which uses recombinant DNA technology to produce the enzyme from Chinese hamster ovary cells.12 Clinical studies have shown that Myozyme can improve ventilator-free survival in patients with infantile-onset Pompe disease.13 This therapy has several adverse reactions, including pneumonia, respiratory failure and distress, infections, and fever. Myozyme may also be involved in life-threatening allergic reactions, heart or lung failure, and immune-mediated reactions.13 A boxed warning is included in the Myozyme label to caution about possible life-threatening allergic reactions.11
On May 25, 2010, the FDA approved Lumizyme (alglucosidase alfa), the first treatment for late-onset Pompe disease, which is indicated for patients aged ≥8 years (younger children may experience more rapid disease progression while receiving Lumizyme).1 Also using the ERT principle, Lumizyme is believed to work by replacing the deficient GAA enzyme, thereby allowing the breakdown of glycogen in the heart and skeletal muscle cells. However, although both Myozyme and Lumizyme have the same generic ingredient and work by enzyme replacement, the FDA considers the 2 treatments as different drugs, with distinct manufacturing processes, as well as some biologic differences.
Lumizyme cannot be used in patients who have cardiac hypertrophy (enlarged heart), because it may cause life-threatening allergic reactions, heart or lung failure, and immune-mediated reactions—the same serious side effects as those associated with Myozyme. Moreover, according to postmarketing experience with Lumizyme therapy, the drug may be involved in cardiorespiratory arrest, respiratory failure, hemothorax, pneumothorax, cardiac failure, sepsis, aortic dissection, cerebrovascular accident, and skin necrosis.14
Lumizyme is available only through a restricted distribution system called the Lumizyme Alglucosidase Alfa Control and Education (ACE) program,1 one of the FDA’s approved risk evaluation and mitigation strategy programs. The primary goal of the ACE program is to ensure that known risks of anaphylaxis and severe allergic reactions associated with Lumizyme are communicated to patients, caregivers, and prescribers.
ERT has been tried for some lysosomal storage diseases, such as Gaucher disease, Fabry disease, and mucopolysaccharidoses (MPS I, MPS II, MPS VI).15 With these first-approved ERTs for Pompe disease (GSD II) comes the hope that ERT may also prove effective for other GSDs as well. The current primary treatment for other GSDs involves control of hypoglycemia.16
The Table summarizes the basic characteristics of Myozyme and Lumizyme therapies.
A retrospective analysis was conducted for the period between the second quarter of 2006 (first approval of Myozyme) and the second quarter of 2011 (the most current data available). The primary data source is the publicly available National Summary Files for the Medicaid State Drug Utilization Data, which are maintained by the Centers for Medicare & Medicaid Services (CMS). The database covers Medicaid beneficiaries in 49 states (all states except Arizona) and the District of Columbia, and it is restricted to outpatient pharmaceuticals.17 The National Summary Files were compiled by aggregating state databases. Because the data are collected as part of the Medicaid Rebate Program, they include fee for service but not managed Medicaid pharmacy claims.
Each data record included the National Drug Code (NDC), drug name, year and quarter of Medicaid expenditure, number of pharmacy claims, number of units, and total pharmacy reimbursement amount, including costs of the drug and its administration. We searched the database for Myozyme and for Lumizyme.
For each drug, quarterly prescription counts and reimbursement amounts were calculated by summing data across individual NDCs for the 2 drugs. Quarterly perclaim pharmacy reimbursement, as a proxy for drug price, was computed for the 2 drugs. Reimbursements are inclusive of the costs for the drug ingredients and administration, but they do not include manufacturer rebates. All of the data analyses were conducted using the SAS software package for Windows (Version 9.1.3; SAS Institute, Inc; Cary, NC).
Prescriptions for Myozyme increased from 1 in 2006 quarter 2 to 127 in 2011 quarter 2, whereas prescriptions for Lumizyme increased from 6 in 2010 quarter 3 to 60 in 2011 quarter 2. During the same period, expenditures rose from $9450 to $930,459 for Myozyme and from $119,691 to $1.16 million for Lumizyme. The average price per prescription was approximately $10,000 for Myozyme and approximately $20,000 for Lumizyme over the study period.
Figure 1 depicts the quarterly trends of utilization for Myozyme and Lumizyme, and Figure 2 describes the quarterly trends of reimbursement (or Medicaid spending) for Myozyme and Lumizyme. As seen in Figure 3, average reimbursement per prescription (or spending per prescription) as a proxy for drug price remained high and stable over time.
Because Myozyme and Lumizyme are the first 2 therapies to be approved by the FDA for Pompe disease, the increase in their utilization is not surprising. Moreover, because of the higher proportion of infants and children among Medicaid beneficiaries than among the population as a whole, some incidence of Pompe disease is certainly expected. The price per prescription for Lumizyme was essentially double the price for Myozyme. This difference is likely a result of the higher dosages required for older/larger patients with late-onset Pompe disease compared with small infants with Pompe disease (see Table). The price for both medications is high and is expected to remain so. The 2 therapies were approved as orphan drugs, which are usually priced higher than drugs with a large target market.
Given patent protection, coupled with the complexity of production procedures for biologic therapies, it is unlikely that another company will compete anytime soon with Genzyme, the manufacturer of both drugs. The high cost of the medication, and the potential for off-label use and serious adverse events related to heart or lung failure, argue for careful monitoring of these medications by Medicaid, as well as by other payers.
Potential Future Treatments
In the United States, currently 18 clinical trials are studying Pompe disease and its treatment and are recruiting patients.18 Among them is a study about the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of BMN-701 (GILT-tagged rhGAA) in patients with late-onset Pompe disease. BMN-701, which is manufactured by BioMarin, is an rhGAA. It can increase the number of mannose-6-phosphates that provide better delivery of GAA to the lysosome, where it causes Pompe disease, thereby improving efficacy, with less enzyme.19 Because the enzyme for Pompe disease needs life-long infusions, a limitation of ERT is the high cost of the recombinant enzyme and the extremely high doses of the drug.8 BMN-701 may solve this problem by requiring lower enzyme doses, at a lower cost, which is a big improvement over ERT.
Gene therapy is another possibility for the treatment of Pompe disease. The idea is to create a permanent GAA source through the use of adenoviral (Ad), adenoassociated (AAV), or hybrid Ad-AAV vectors to introduce a correct sequence coding gene for the deficient enzyme into cells. The first clinical trial for recombinant AAV-mediated gene-based therapy for Pompe disease achieved some success.20
Nutrition and exercise therapy may help patients with late-onset Pompe disease to increase muscle protein synthesis and muscle fibers.21 According to Schoser and colleagues, nutrition and exercise therapy includes a combination of a high-protein, low-carbohydrate diet and daily conditioning aerobic exercise.8 Among all known treatments for Pompe disease, it is the only therapy that can slow the progressive deterioration in muscle function.22
This study has a number of limitations. First, patient-specific information was not available in the national Medicaid pharmacy file provided by CMS. Therefore, it was not possible to determine the cost per patient and/or indication for medication use.
In addition, adherence to medication therapy could not be assessed. As with all database studies, misclassification bias may be present if the CMS data contain reporting errors. All data are prerebate; hence, to some degree (that we cannot measure), they overstate the actual acquisition cost to the US Medicaid program.
Moreover, the results of this study are specific to the Medicaid population, which is heavily comprised of low-income women and children. Hence, they do not necessarily represent utilization and expenditure trends in other populations.
Finally, comparing the pricing data among states, as well as exploring data regarding utilization trends in the commercial population, are beyond the scope of this article.
Medicaid spent $3.6 million in 2010 on Myozyme and $1.8 million in 2011 on Lumizyme, the only 2 FDA-approved therapies (both ERTs) for the treatment of Pompe disease. ERT has been a major breakthrough in the treatment of patients with Pompe disease. It can change the course of the disease and can prolong a patient’s survival, although there are still many challenges. Other promising treatments for Pompe disease that are currently under study may expand the treatment options in the near future.
Author Disclosure Statement
The authors have no conflict of interest concerning this research. They did not receive any consulting fees, grants, honoraria, patents, royalties, stocks, or other financial or material gain that may involve the subject matter of the article. Dr Jeff J. Guo and Dr Kelton have received research grants from Novartis, Johnson & Johnson, and Eli Lilly. Miss Jing Guo has nothing to disclose.
Miss Jing Guo is a PhD student at James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center; Dr Kelton is Professor, College of Business, University of Cincinnati; and Dr Jeff J. Guo is Professor, James L. Winkle College of Pharmacy, University of Cincinnati Academic Health Center, OH. A version of this work was presented at the 17th Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research in Washington, DC, June 4-6, 2012.
- FDA approves new treatment for late-onset Pompe disease [news release]. Silver Spring, MD: US Food and Drug Administration; May 25, 2010. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2010/ucm213282.htm. Accessed May 9, 2012.
- Martiniuk F, Chen A, Mack A, et al. Carrier frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet. 1998;79:69-72.
- Di Rocco M, Buzzi D, Tarò M. Glycogen storage disease type II: clinical overview. Acta Myologica. 2007;26:42-44.
- Ausems MG, ten Berg K, Kroos MA, et al. Glycogen storage disease type II: birth prevalence agrees with predicted genotype frequency. Community Genet. 1999;2:91-96.
- Werber Y. Lysosomal storage diseases market. Nat Rev Drug Discov. 2004;3:9-10.
- Kishnani PS, Steiner RD, Bali D, et al. Pompe disease diagnosis and management guideline. Genet Med. 2006;8:267-288.
- Kishnani PS, Hwu WL, Mandel H, et al. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr. 2006;148: 671-676.
- Schoser B, Hill V, Raben N. Therapeutic approaches in Glycogen Storage Disease type II (GSDII)/Pompe disease. Neurotherapeutics. 2008;5:569-578.
- Winkel LP, Hagemans ML, van Doorn PA, et al. The natural course of non-classic Pompe’s disease; a review of 225 published cases. J Neurol. 2005;252:875-884.
- Kishnani PS, Howell RR. Pompe disease in infants and children. J Pediatr. 2004; 144(5 suppl):S35-S43.
- FDA approves first treatment for Pompe disease [news release]. Silver Spring, MD: US Food and Drug Administration; April 28, 2006. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108645.htm. Accessed May 9, 2012.
- Erasmus MC Pompe Center. Treatment. www.erasmusmc.nl/klinische_genetica/research/pompe_center/behandeling/?lang=en. Accessed May 9, 2012.
- Myozyme [prescribing information]. Cambridge, MA: Genzyme Corporation; 2006.
- Lumizyme [prescribing information]. Cambridge, MA: Genzyme Corporation; 2010.
- Neufeld EF. Enzyme replacement therapy—a brief history. In: Mehta A, Beck M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford, England: Oxford PharmaGenesis; 2006.
- Hendriksz CJ, Gissen P. Glycogen storage disease. Paediatr Child Health. 2011;21:84-89.
- Centers for Medicare & Medicaid Services. State Drug Utilization Data. www.cms.hhs.gov/MedicaidDrugRebateProgram/SDUD/list.asp#TopOfPage. Accessed December 9, 2011.
- ClinicalTrials.gov. Pompe trials. www.clinicaltrials.gov/ct2/results?term=pompe. Accessed May 23, 2012.
- BioMarin Company. BMN-701: IFG2-GAA for Pompe. www.bmrn.com/patients-physicians/pompe-disease.php. Accessed May 9, 2012.
- Byrne BJ, Falk DJ, Pacak CA, et al. Pompe disease gene therapy. Hum Mol Genet. 2011;20(R1):R61-R68.
- Slonim AE, Bulone L, Minikes J, et al. Benign course of glycogen storage disease type IIb in two brothers: nature or nurture? Muscle Nerve. 2006;33:571-574.
- Slonim AE, Bulone L, Goldberg T, et al. Modification of the natural history of adult-onset acid maltase deficiency by nutrition and exercise therapy. Muscle Nerve. 2007;35:70-77.