BlueCross and BlueShield of Montana Medical Policy/Codes
Enzyme-replacement Therapy for Lysosomal Storage Disorders
Chapter: Drugs - Medical Benefit
Current Effective Date: December 27, 2013
Original Effective Date: December 27, 2013
Publish Date: December 27, 2013
Description

Lysosomal storage disorders are a group of diseases that are characterized by accumulation of waste products in the lysosomes.  These disorders are rare inborn errors of metabolism, with a combined incident of 1 in 1500 to 7000 live births.  Lysosomal enzymes break down macromolecules, either those from the cell itself (eg, when cellular structural components are being recycled) or those acquired outside the cell. (The Merck Manual [2012 April 26] <www.merckmanual.com>.)

Treatment of lysosomal storage disease is by enzyme replacement with placental or recombinant glucocerebrosidase that is effective in types I and III; there is no treatment for type II. The replacement enzyme is modified for delivery to the lysosomes.

Idursulfase (Elaprase) is the first drug approved by the U.S. Food and Drug Administration (FDA) for Hunter’s syndrome.  Elaprase was approved as an orphan drug used to treat, prevent, or diagnose a rare disease; it is manufactured using recombinant DNA technology.  The result is the production of an enzyme that is almost identical to the enzyme produced in the human body.  Treatment allows the body to uptake the enzyme into cellular lysosomes, thereby aiding in the catabolism of accumulated glycosaminoglycans (GAGs).

Hunter syndrome, also known as mucopolysaccharide metabolism disorder with iduronate-2-sulfatase deficiency, is a rare X-linked recessive, inherited and potentially fatal disorder in children.  This syndrome has variable manifestations exhibiting mainly microcephaly, characteristic facies, mental retardation/intellectual disability, short stature, acral skeletal anomalies with occasional craniosynostosis and congenital heart defects.  Clinical characteristics are similar to those in alpha-L-iduronidase (MPS I), except for the absence of corneal clouding and slower progression of the course of disease and central nervous system deterioration.  Retinal degeneration may occur, but the cornea usually remains clear.  Appearance is normal at birth with excessive growth taking place during the first two years of life.  Two types are recognized:

  • A severe form (MPS IIA) which is characterized mainly by mental retardation/intellectual disability and progressive physical deterioration and early death, AND
  • A mild form (MPS IIB) in which patients may survive into adulthood. 

MPS IIA usually occurs between two and four years of age with progressive deterioration, chronic diarrhea, recurrent ear infections, hearing impairment, communicating hydrocephalus with increased intracranial pressure, and death at about 10 to 15 years of age.  Obstructive airway disease, cardiac valvular dysfunction, myocardial thickening, pulmonary hypertension, coronary disease, and myocardial infarction may be superimposed.  MPS IIB is milder with preservation of intelligence.  The symptoms usually include hearing impairment, carpal tunnel syndrome, joint stiffness, discrete corneal opacities, and papilledema.  Death may occur in early adulthood, usually from airway obstruction or cardiac failure.  Only 500 patients in the United States are believed to have the disease, which affects mostly boys.  Hunter syndrome is diagnosed in approximately one in 65,000 to132,000 births.  

Alglucosidase alfa (Myozyme) is the first drug approved by the FDA to treat infantile-onset Pompe disease.  Myozyme has orphan drug status and has been shown to improve ventilator-free survival in patients with infantile-onset Pompe disease as compared to untreated historical control, where use of Myozyme in patients with other forms of Pompe disease has not been adequately studied to assure safety and efficacy.

Myozyme provides an exogenous source of alpha-glucosidase (GAA).  Binding to mannose-6-phosphate receptors on the cell surface has been shown to occur via carbohydrate groups on the GAA molecule, after which it is internalized and transported into lysosomes, where it undergoes proteolytic cleavage that results in increased enzymatic activity.  It then exerts enzymatic activity in cleaving glycogen.

Pompe disease is a rare inherited and often fatal disorder that disables the heart and muscles.  It is caused by mutations in a gene that makes an enzyme called GAA.  Normally the body uses GAA to break down glycogen, a stored form of sugar used for energy.  But in Pompe disease, mutations in the GAA gene reduce or completely eliminate this essential enzyme.  Excessive amounts of glycogen accumulate everywhere in the body, but the cells of the heart and skeletal muscles are the most seriously affected.  Researchers have identified up to 70 different mutations in the GAA gene that cause the symptoms of Pompe disease, which can vary widely in terms of age of onset and severity.  The severity of the disease and the age of onset are related to the degree of enzyme deficiency.  The prognosis for individuals with Pompe disease varies according to the onset and severity of symptoms.  Without treatment the disease is particularly lethal in infants and young children.

Infantile Pompe disease is the result of complete or near complete deficiency of GAA.   Symptoms usually begin in the first months of life, with feeding problems, poor weight gain, severe lack of muscle tone, weakness, and an enlarged heart and liver.  Respiratory difficulties are often complicated by lung infections.  The heart is grossly enlarged.  Mental function is not affected.  More than half of all infants with Pompe disease also have enlarged tongues.  Most babies with Pompe disease die from cardiac or respiratory complications before the age of two.

Alglucosidase alfa (Lumizyme) was approved by the FDA in 2010 for use in patients eight years and older with late-onset Pompe disease that has not shown evidence of cardiac hypertrophy.  The safety and efficacy of Lumizyme has not been evaluated in infantile-onset or in patients less than eight years of age with late (non-infantile) onset Pompe disease.  Late-onset Pompe disease differs from infantile principally because of the lack of cardiac involvement and it is only partially deficient of GAA.  Juvenile onset symptoms appear in early to late childhood and include progressive weakness in the respiratory muscles, and lower limbs, and contribute to exercise intolerance.  Adult onset involves muscle weakness and wasting of respiratory muscles in the trunk, lower limbs, and diaphragm.  Intellect is not affected.  A small number of adult patients live without major symptoms or limitations.  The prognosis for individuals with Pompe disease varies according to the onset and severity of symptoms.  Without treatment, the disease is particularly lethal in infants and young children.

Both Myozyme and Lumizyme are manufactured by Genzyme Corporation, but at different manufacturing sites using different manufacturing processes, under separate biologic license applications.  Lumizyme is only available through a restricted distribution program called Lumizyme ACE (Alglucosidase Alfa Control and Education) to ensure its use is restricted to the correct patient group.

NOTE:  Anaphylactoid reactions, which may be life threatening, have been observed in some patients during Elaprase, Myozyme or Lumizyme infusions.  Therefore, appropriate medical support should be readily available when Elaprase, Myozyme or Lumizyme is administered.  Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions.  Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

Enzyme-replacement therapy when utilized for the treatment of lysosomal storage disorders may be considered medically necessary for the specific indications as noted under each of the following enzyme-replacements therapies:       

Idursulfase (Elaprase™) may be considered medically necessary for the treatment of Hunter’s syndrome (mucopolysaccharidosis II [MPS II]).

Idursulfase (Elaprase™) is considered experimental, investigational and unproven for the treatment of all other conditions or diseases.

Alglucosidase alfa (Myozyme®) may be considered medically necessary for the treatment of infantile-onset Pompe disease.

Alglucosidase alfa (Myozyme) is considered experimental, investigational and unproven for the treatment of all other indications, including treatment of persons with other forms of Pompe disease.

Alglucosidase alfa (Lumizyme™) may be considered medically necessary for use in patients eight years and older with late-onset (non-infantile) Pompe disease without evidence of cardiac hypertrophy.

Alglucosidase alfa (Lumizyme™) is considered experimental, investigational and unproven for the treatment of all other indications.

Rationale

Elaprase

Elaprase was approved (July 24 2006) by the U.S. Food and Drug Administration (FDA) after a randomized, double-blind placebo-controlled study of 96 patients with Hunter syndrome showed that the treated participants had an improved capacity to walk at the end of the 53-week trial.  Patients who received Elaprase infusions experienced on average a 38-yard greater increase in the distance walked in six minutes compared to the patients on placebo.

A 53-week randomized, double-blind, placebo-controlled Phase II/III trial demonstrated that Elaprase provides clinically important benefits to Hunter syndrome patients.  The primary efficacy endpoint of the trial was a composite analysis of changes from baseline in two clinical measures: a six-minute walk test and percent predicted forced vital capacity.  This endpoint achieved statistical significance compared to placebo.  After one year of treatment, patients receiving weekly infusions of Elaprase experienced a mean increase in the distance walked in six minutes of 35 meters compared to patients receiving placebo.  Treatment with Elaprase was generally well-tolerated by patients in the Phase II/III trial.  Adverse reactions were commonly reported in association with infusions, and were generally mild to moderate.  The Elaprase label includes a boxed warning with information on the potential for hypersensitivity reactions.  Therefore, appropriate medical support should be readily available when Elaprase is administered.  Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to infusion reactions, and require additional monitoring.   

In all phases of clinical study for Elaprase, eleven patients experienced significant hypersensitivity reactions during 19 of 8,274 infusions (0.2%) and no patients discontinued treatment permanently as a result of hypersensitivity reaction.  The most common adverse events observed in >30% of patients during the Phase II/III trial were pyrexia, headache and arthralgia.

Fifty-one percent (32 of 63) of patients in the weekly Elaprase treatment arm in the pivotal clinical study (53-week placebo-controlled study with an open-label extension) developed anti-idursulfase IgG antibodies.

Myozyme

The safety and efficacy of Myozyme (alglucosidase alfa) were assessed in two separate clinical trials in 39 Pompe disease patients, who ranged in age from one month to 3.5 years at the time of the first infusion.

Patient survival without needing invasive ventilatory support was substantially greater in the Myozyme treated infants than would be expected considering the high mortality rate of untreated patients of similar age and disease severity.  According to the FDA, the drug's safety and effectiveness in other forms of Pompe disease have not been adequately studied.

Myozyme, a recombinant form of the human enzyme acid alpha-glucosidase, is currently being used to replace the missing enzyme.  Myozyme helps break down glycogen.  In a study which included the largest cohort of patients with Pompe disease treated with enzyme replacement therapy (ERT) to date findings showed that Myozyme treatment clearly prolongs ventilator-free survival and overall survival in patients with infantile-onset Pompe disease as compared to an untreated historical control population.  Furthermore the study demonstrated that initiation of ERT prior to six months of age which could be facilitated by newborn screening, shows great promise to reduce the mortality and disability associated with this disorder.  The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid alpha-glucosidase in which patients were older

2010 Update

Lumizyme

The safety and efficacy of Lumizyme (alglucosidase alfa) was assessed in 90 patients with late-onset Pompe disease, ages 10 to 70 years, in a randomized double-blind, placebo-controlled study designed to enroll patients age 8-70 years.  The youngest Lumizyme treated patient was 16 years of age, and the youngest placebo treated patient was 10 years of age.  All patients were naïve to enzyme replacement therapy.  Patients were allocated in a 2:1 ratio and received 20 mg/kg Lumizyme (n=60) or placebo (n=30) every other week for 78 weeks (18 months).  The study population included 34 males and 26 females (N=60) in the Lumizyme group and 11 males and 19 females (N=30) in the placebo group.  At baseline, all patients were ambulatory (some required assistive walking devices), did not require invasive ventilator support or non-invasive ventilation while awake and sitting upright, and had a forced vital capacity (FVC) between 30 and 79% of predicted in the sitting position.  Patients who could not walk 40 meters in six minutes or were unable to perform appropriate pulmonary and muscle function testing was excluded from the study.

A total of 81 of 90 patients completed the study.  Of the nine patients who discontinued, five were in the Lumizyme group and four were in the placebo group.  Three patients discontinued the study due to an adverse event; two patients were in the Lumizyme treatment group and one patient was in placebo group.  One patient in the Lumizyme group died.  Four patients discontinued study participation to pursue treatment with commercial therapy, and one patient discontinued the study for personal reasons.

At study entry, the mean percentage predicted FVC in the sitting position among all patients was about 55%.  After 78 weeks, the mean percentage predicted FVC increased to 56.2% for Lumizyme-treated patients and decreased to 52.8% for placebo-treated patients indicating a Lumizyme treatment effect of 3.4 % (95% confidence interval: [1.3% to 5.5%]; p=0.004).  Stabilization of percentage  predicted FVC in the Lumizyme-treated patients was observed. 

At study entry, the mean six minute walk test (6MWT) among all patients was about 330 meters.  After 78 weeks, the mean 6MWT increased by 25 meters for Lumizyme-treated patients and decreased by three meters for placebo-treated patients indicating a Lumizyme treatment effect of 28 meters (95% confidence interval: [-1 to 52 meters]; p=0.06).

The effectiveness of Lumizyme has not been established in infantile-onset patients.  Descriptive data from infantile-onset patients who have received Lumizyme commercially outside the U.S. have been collected in the Pompe Registry.  The Pompe Registry is a multi-center, multi-national, voluntary, observational disease registry.  Fifteen infantile-onset patients enrolled in the registry were matched to the baseline characteristics of an untreated historical control cohort.  These patients were diagnosed with Pompe disease and received treatment with Lumizyme prior to six months of age (range 0.6 to 6 months).  The median duration of treatment was 15 months (range 3 to 48 months).  Estimated survival in Lumizyme treated patients was 57% at 18 months and 37% at 36 months, compared to the 2% survival in the historical control group at both time points.  The median age of death or last follow-up was 19 months (range 5 to 51 months).  Descriptive clinical data from patients with infantile-onset Pompe disease in the Pompe Registry were used to verify the overall effectiveness of Lumizyme for patients eight years and older with late-onset Pompe disease.

Lumizyme is available only under a restricted distribution program called the Lumizyme ACE (Alglucosidase Alfa Control and Education) Program.  The purpose of the program is to ensure that the known risks of anaphylaxis and severe allergic reactions and the potential risks of severe cutaneous and systemic immune complex-mediated reactions associated with the use of Lumizyme are communicated to patients, caregivers, and prescribers.  In addition, the purpose of the program is to mitigate the potential risk of rapid disease progression in infantile-onset Pompe disease patients and late (non-infantile) onset Pompe disease patients less than 8 years of age for whom the safety and effectiveness of Lumizyme have not been evaluated.  Under this program, only trained and certified prescribers, and healthcare facilities enrolled in the program are able to prescribe, dispense or administer Lumizyme, and only patients who are enrolled in and meet all the conditions of the Lumizyme ACE Program may receive Lumizyme.

2012 Update

A search of peer reviewed literature through March 2012 identified no new clinical trial publications or any additional information that would change the coverage position of this medical policy.

Coding

Disclaimer for coding information on Medical Policies           

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

271.0, 277.5

ICD-10 Codes
E74.00 - E74.09, E76.01 - E76.9
Procedural Codes: J0220, J0221, J1743, J3490, J3590
References
  1. Van den Hout, H., Reuser, A.J., et al: Recombinant human alpha-glucosidase from rabbit milk in Pompe patients.  Lancet (2000) 356(9227):397-8.
  2. Amalfitano, A., Bengur, A.R., et al: Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial.  Genet Med (2001) 3(2):132-8.
  3. O'Grady, N.P., Alexander, M., et al: Guidelines for the prevention of intravascular catheter-related infections.  Centers for Disease Control and Prevention.  MMWR Recomm Rep (2002) 51(RR-10):1-29.
  4. van den Hout, H.M., Hop, W., et al.  The natural course of infantile Pompe’s disease: 20 original cases compared with 133 cases from the literature.  Pediatrics (2003 August) 112(2):332-40.
  5. Hunley, T.E., Corzo, D., et al: Nephrotic syndrome complicating alpha-glucosidase replacement therapy for Pompe disease. Pediatrics (2004) 114(4):e532-5.
  6. Klinge, L., Straub, V., et al.  Enzyme replacement therapy in classical infantile Pompe disease: results of a ten-month follow-up study.  Neuropediatrics (2005 February) 36(1):6-11.
  7. Klinge, L., Straub, V., et al.  Safety and efficacy of recombinant acid alpha-glucosidase (rhGAA) in patients with classical infantile Pompe disease: results of a phase II clinical trial.  Neuromuscular Disorders (2005 January) 15(1):24-31.
  8. Hagemans, M.L., Winkel, P.A., et al.  Clinical manifestation and natural course of late-onset Pompe’s disease in 54 Dutch patients.  Brain (2005 March) 128:671-7.
  9. Genzyme Corporation.  Myozyme® (alglucosidase alfa).  Prescribing Information.  Cambridge, Massachusetts: Genzyme:  (2006 April).   http://www.myozyme.com .  (accessed - 2007 November 19).
  10. FDA - FDA approves first treatment for Pompe disease.  U.S. Food and Drug Administration (FDA).  FDA News. Rockville, Maryland: FDA; April 28, 2006. Available at: http://www.fda.gov .  (accessed - 2007 November 20).
  11. Muenzer, J., Wraith, J.E., et al.  A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome).  Genetic Medicine (2006 August) 8(8):465-73.
  12. MedlinePlus.  Medical encyclopedia.  Hunter Syndrome.  http://www.nlm.nih.gov .  (accessed - 2007 November 19).
  13. FDA—Center for Drug Evaluation and Research.  Elaprase™.  Food and Drug Administration.  http://www.fda.gov .  (accessed - 2007 November 19).
  14. Shire Human Genetic Therapies, Inc.  Elaprase™ (idursulfase) http://www.elaprase.com .  (accessed – 2007 November 19).    
  15. Wagner, K.R.  Enzyme replacement for infantile Pompe disease: the first step toward a cure.  Neurology (2007 January 9) 68(2):88-9.
  16. NINDS – NINDS Pompe Disease Information Page. National Institute of Neurological Disorders and Stroke.  (2007, July 25 update). http://www.ninds.nih.gov .  (accessed - 2007 November 19).
  17. Kishnani, P.S., Corzo, D., et al.  Recombinant human acid [alpha]-glucosidase: Major clinical benefits in infantile-onset Pompe disease. Neurology (2007) 68(2):99-109.
  18. Genetics Home Reference.  Hunter Syndrome. Published 2007 November 13. http://ghr.nlm.nih.gov .  (accessed – 2007 November 19).
  19. Product Information: Myozyme® IV injection, alglucosidase alfa IV injection. Genzyme Corporation, Cambridge, MA. (2009).
  20. FDA—Center for Drug Evaluation and Research.  Lumizyme™.  Food and Drug Administration. http://www.fda.gov . (accessed – 2012 April 26).
  21. U.S. Food and Drug Administration: FDA Approves New Treatment for Late-Onset Pompe Disease.  U.S. Food and Drug Administration. Silver Spring, MD. (2010). Available: http://www.fda.gov . (accessed - 2012 April 26).
  22. U.S. Food and Drug Administration: FDA Approves New Treatment for Late-Onset Pompe Disease.  U.S. Food and Drug Administration. Silver Spring, MD. (2010). Available: http://www.fda.go .  (accessed – 2012 April 26).
  23. Product Information: Lumizyme™ intravenous infusion, powder for solution, alglucosidase alfa intravenous infusion, powder for solution. Genzyme Corporation, Cambridge, MA. (2010).
  24. van der Ploeg, A.T., Clemens, P.R., et al.  A randomized study of alglucosidase alfa in late-onset Pompe's disease.  N Engl J Med (2010 Apr 15) 362(15):1396-406.
History
December 2013  New 2013 BCBSMT medical policy.  Combined the "Alglucosidase alfa intravenous infusion (Myozyme)" and "Idursulfase (Elaprase)" medical policies to create "Enzyme-replacement Therapy for Lysosomal Storage Disorders".  Added coverage criteria for Lumizyme.  Added codes  J0221, J1743, and J3590.
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Enzyme-replacement Therapy for Lysosomal Storage Disorders