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Horizon BCBSNJ
Uniform Medical Policy ManualSection:Drugs
Policy Number:028
Effective Date: 02/14/2020
Original Policy Date:12/19/2003
Last Review Date:01/14/2020
Date Published to Web: 10/10/2018
Subject:
Agalsidase Beta (Fabrazyme)

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.

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On April 24, 2003, FDA approved Agalsidase beta (Fabrazyme), a recombinant human -galactosidase A (-Gal A) enzyme for use in patients with Fabry disease. Fabry disease is a rare X-linked recessive lysosomal storage disorder that is caused by the deficient activity of -galactosidase A and the resultant accumulation of globotriaosylceramide and related glycosphingolipids. The major debilitating manifestations of Fabry disease result from the progressive accumulation of globotriaosylceramide in the vascular endothelium, leading to ischemia and infarction, especially in the kidney, heart and brain. The disease is panethnic with estimates of incidence range from 1 in 40,000 to 60,000 males. It predominantly affects males, although carrier (heterozygous) females also can be affected to a mild or severe degree because of random X-chromosomal inactivation.

Fabry patients can be divided into three categories of disease severity. In general, the severity of the disease is inversely correlated with enzyme activity.
  • Hemizygotes (and some heterozygotes) with classical Fabry disease beginning in childhood, affecting many organ systems, and resulting in markedly decreased lifespan.
  • Heterozygotes with mild to moderate disease or severe disease confined to a single organ system.
  • Hemizygotes with residual enzyme activity who are diagnosed in the fourth, fifth, or sixth decade of life, when cardiac problems manifest ("cardiac variants").

Diagnosis of Fabry disease is confirmed by assay of -galactosidase activity in leukocytes or plasma. In patients with the classic phenotype, levels of -Gal A activity are very low or undetectable. Patients with detectable -Gal A activity have a milder, variant phenotype. Female carriers can have normal to very low -Gal A activity, therefore, their specific family mutation in the -Gal A gene must be demonstrated. In addition, mutation or genetic linkage analysis may be necessary to establish carrier status. Most kindreds have family specific or private mutations; to date, more than 300 mutations have been identified.

The goal of enzyme replacement therapy is to prevent disease in young patients and both halt disease progression and reverse the underlying pathologic abnormalities and the resultant organ dysfunction in older patients. If plasma globotriaosylceramide levels prove to be a useful marker of disease burden and treatment efficacy, a goal of therapy may be to normalize plasma levels.

Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)

The requirements of the Horizon BCBSNJ Agalsidase Beta (Fabrazyme) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).

1. Please refer to a separate policy on Site of Administration for Infusion and Injectable Prescription Medications (Policy #142) under the Drug Section.

2. Agalsidase beta (Fabrazyme) is considered medically necessary when used in adults and children 8 years of age and older with diagnosis of Fabry disease evidenced by the following:

      • Documentation of
          • α-galactosidase A (α-Gal A) activity in plasma, isolated leukocytes, and/or cultured cells (males only); OR
          • Plasma or urinary globotriaosylceramide(Gb3/GL-3) or globotriaosylsphingosine (lyso-Gb3); OR
          • Detection of pathogenic mutations in the GALA/GLA gene by molecular genetic testing AND
          • Baseline value for plasma GL-3 and/or GL-3 inclusions; AND
          • Must not be used in combination with migalastat; AND
          • Documentation of clinical signs and symptoms of the disease (e.g. acroparesthesias, angiokeratomas, whorls, anhidrosis/hypohidrosis, renal disease, excercise/heat/cold intolerance, etc.); AND
      • The prescriber is a specialist (e.g. endocrinologist, geneticist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis; AND
      • Agalsidase beta (Fabrazyme) will NOT be used in combination with migalastat (Galafold)

[INFORMATIONAL NOTE: In clinical trials, Fabrazyme reduced globotriasylceramide (GL-3) deposition from the interstitial endothelium of the kidney and certain other cell types. The reduction of GL-3 inclusions suggests that Fabrazyme may ameliorate disease expression of Fabry disease; however, the FDA-approved labeling notes that the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.

The FDA approval was based on the results of four clinical studies in individuals with Fabry disease:

Study 1: A phase III double-blind, randomized trial in 58 patients with classical Fabry disease who received infusions of agalsidase beta (1.0 mg/kg) or placebo every 2 weeks for 20 weeks (11 doses) found that renal capillary endothelium GL-3 deposits decreased to normal or near normal in 69% of agalsidase-beta-treated patients and there was no improvement in the placebo-treated patients. Patients treated with agalsidase beta also had marked decreases in vascular endothelial GL-3 deposits in the skin and heart, and plasma GL-3 levels fell to undetectable levels. All 58 patients who completed the trial enrolled in an open-label extension study. After 6 months (former placebo patients) or 12 months (original agalsidase beta patients) of treatment, the percentage of biopsied patients with normal or near normal GL-3 levels in the vascular endothelium of the kidney, skin and heart was 98%, 96% and 75%. Normal or near-normal renal and skin capillary endothelial histology was achieved in 98% of the patients. In the capillary endothelium of the heart, histology scores improved with duration of treatment. Among patients who had heart biopsies, 67% attained normal or near normal histology after 6 months of treatment and 82% attained normal or near normal histology after 12 months. In treated patients followed for up to 30 months, kidney function remained stable.

Study 2: Randomized double-blind, placebo-controlled, multi-national, multi-center study of 82 patients (72 males and 10 females), ages 20 to 72 years, all naïve to enzyme replacement therapy. Patients received either 1 mg/kg of Fabrazyme or placebo every two weeks for up to a maximum of 35 months. The reduction in plasma GL-3 levels in the Fabrazyme group compared to the placebo group was statistically significant at one year and at two years.

Study 3 :Pediatric Study an open-label, uncontrolled, multi-national, multi-center study to evaluate safety, pharmacokinetics, and pharmacodynamics of Fabrazyme treatment in 16 pediatric patients with Fabry disease. All patients received Fabrazyme 1 mg/kg every two weeks for up to 48 weeks. At baseline all the males had elevated plasma GL-3 levels. Twelve of the 12 males had observed GL-3 inclusions in the capillary endothelium on skin biopsies. At week 24 and 48 the 12 males with GL-3 inclusions in capillary endothelium at baseline achieved a GL-3 inclusion score of 0.

Study 4 :Open-label, re-challenge study to evaluate the safety of Fabrazyme treatment in patients who had a positive skin test to Fabrazyme or who had tested positive for Fabrazyme-specific IgE antibodies. In this study, six adult male patients, who had experienced multiple or recurrent infusion reactions during previous clinical trials with Fabrazyme, were re-challenged with Fabrazyme administered as a graded infusion, for up to 52 weeks of treatment. Four of the six individuals treated received at least 26 weeks of agalsidase beta (Fabrazyme). Two individuals discontinued prematurely due to recurrent infusion reactions.

A single-center, double-blind, placebo-controlled phase II trial involving 26 patients with neuropathic pain who received 0.2 mg/kg agalsidase beta every 2 weeks for 22 weeks reported that the severity of neuropathic pain improved in 14 patients treated with agalsidase beta and changed little in the 12 patients assigned to the placebo. Mean creatinine clearance did not change substantially for patients receiving agalsidase beta but decreased by 16.1 ml/min for patients receiving placebo. In related studies of the same patients, the elevated regional cerebral blood flow and abnormal cerebrovascular response were significantly reduced or improved after 22 weeks or 18 to 24 months of treatment. A double blind, placebo-controlled trial to measure clinical benefit is in progress.

Currently available expert recommendation is that enzyme replacement therapy in all males with Fabry disease (including those with end-stage renal disease, transplanted patients, children) and female carriers with substantial disease manifestations should be initiated as early as possible.
    Patients younger than 8 years of age were not included in clinical studies. The safety and efficacy in patients younger than 8 years of age have not been evaluated.]

3. When medically necessary, initial agalsidase beta (Fabrazyme) therapy will be approved for a period of 1 year at doses that do not exceed the FDA recommended dose of 1.0 mg/kg body weight infused every 2 weeks as an IV infusion.

[INFORMATIONAL NOTE: The most serious and most common adverse reactions reported with agalsidase beta are infusion-associated reactions. In patients experiencing infusion reactions, pretreatment with an antipyretic and antihistamine is recommended. If an infusion reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administrating additional antipyretics, antihistamines, and/or steroids may ameliorate the symptoms

Additional experience is needed before more specific recommendations can be made on optimal dosing regimens for reversal; maintenance; and prevention of disease manifestations in affected males, symptomatic carrier females, children and patients with compromised renal function.

There are no adequate and well-controlled studies of Fabrazyme use in pregnant women.

Fabrazyme was approved by the FDA under an accelerated or early approval mechanism. The FDA is working closely with Genzyme, the manufacturer of Fabrazyme to make sure that, despite the relatively small number of patients with this disease, all reasonable steps will be pursued to make sure that the product's clinical benefits and long-term safety once it is on the market is learned. One of the requirements of the accelerated approval was that the sponsor completes a postmarket study verifying that patients will benefit from the product. Therefore, enrollment of all patients into Genzyme's Fabry disease registry is strongly recommended.

In 2009, an analysis of registry data of Fabrazyme use in patients with Fabry disease was published in the Lancet. The data analyzed was a 5-year treatment with Fabrazyme in patients with Fabry's disease who were enrolled in the Fabry Outcome Survey observational database (FOS). The data included 181 adults, and 126 of them were males. Serial data for cardiac mass and function, renal function, pain, and quality of life were assessed. Safety and sensitivity analyses were also done. In patients with baseline cardiac hypertrophy, treatment resulted in a sustained reduction in left ventricular mass (LVM) index after 5 years (from 71·4 [SD 22·5] g/m2·7 to 64·1 [18·7] g/m2·7, p=0·0111) and a significant increase in midwall fractional shortening (MFS) from 14·3% (2·3) to 16·0% (3·8) after 3 years (p=0·02). In patients without baseline hypertrophy, LVM index and MFS remained stable. Mean yearly fall in estimated glomerular filtration rate versus baseline after 5 years of enzyme replacement therapy was −3·17 mL/min per 1·73 m2 for men and −0·89 mL/min per 1·73 m2 for women. Average pain, measured by Brief Pain Inventory score, improved significantly, from 3·7 (2·3) at baseline to 2·5 (2·4) after 5 years (p=0·0023). Quality of life, measured by deviation scores from normal EuroQol values, improved significantly, from −0·24 (0·3) at baseline to −0·17 (0·3) after 5 years (p=0·0483). Findings were confirmed by sensitivity analysis. No unexpected safety concerns were identified.]

4. The medical necessity of continued therapy with agalsidase beta (Fabrazyme) will be established yearly thereafter, based on supporting documentation submitted by the prescribing physician. Supporting documentation should show ALL of the following:
      • Absence of unacceptable side effects/toxicity.
      • Response to therapy which is measured by a reduction in plasma GL-3 and/or GL-3 inclusions compared to pre-treatment baseline
      • Agalsidase beta (Fabrazyme) will NOT be used in combination with migalastat (Galafold)

5. The use of agalsidase beta (Fabrazyme) therapy for all indications other than the FDA-approved indication is considered investigational.


Medicare Coverage:
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this drug. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.

**Note: Bullet 1 of the policy section referring to Site of Administration for Infusion and Injectable Prescription Medications (Policy #142) does not apply for Medicare Advantage Products.

Medicaid Coverage:

For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Agalsidase Beta (Fabrazyme)
Fabrazyme (Agalsidase Beta)

References:
1. Fabrazyme. Prescribing Information. Genzyme Corporation. Cambridge , MA. December 2018.

2. Genzyme General Therapeutics. Fabry Disease: Progressive, Destructive, Life Threatening: A lysosomal storage disorder characterized by a-galactosidase deficiency. Genzyme Corporation. 2001.

3. Eng CM, et al. Safety and efficacy of recombinant human -galactosidase A replacement therapy in Fabry’s disease. N Engl J Med 2001; 345: 9-16.

4. Desnick RJ, et al. Fabry Disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 2003; 138: 338-46.

5. U.S. National Institutes of Health. Clinical Trials.Gov. [cited Dec 2019] Available from: URL: http://clinicaltrials.gov/

6. Mehta A, Beck M, Elliott P, et al; Fabry Outcome Survey investigators. Enzyme replacement therapy with agalsidase alfa in patients with Fabry's disease: An analysis of registry data. Lancet. 2009;374(9706):1986-1996.

7. Gal A, Hughes DA, Winchester B. Toward a consensus in the laboratory diagnostics of Fabry disease - recommendations of a European expert group. J Inherit Metab Dis. 2011; 34:509-514.

8. Laney, D.A., Bennett, R.L., Clarke, V. et al. Fabry Disease Practice Guidelines: Recommendations of the National Society of Genetic Counselors J Genet Counsel (2013) 22: 555. https://doi.org/10.1007/s10897-013-9613-3.

9. Eng CM, Banikazemi M, Gordon RE, Goldman M, Phelps R, Kim L, Gass A, Winston J, Dikman S, Fallon JF, Brodie S, Stacy CB, Mehta D, Parsons R, Norton K, O’Callaghan M, Desnick RJ. A Phase 1/2 clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet 2001;68:711-22.

10. Banikazemi M, Bultas J, Waldek S, Wilcox WR, Whitley CB, McDonald M, Finkel R, Packman S, Bichet DG, Warnock DG, Desnick RJ; Fabry Disease Clinical Trial Study Group. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med. 2007 Jan 16;146(2):77-86. Epub 2006 Dec 18.

11. Wraith JE, Tylki-Szymanska A, Guffon N, Lien YH, Tsimaratos M, Vellodi A, Germain DP. Safety and efficacy of enzyme replacement therapy with agalsidase beta: an international, open-label study in pediatric patients with Fabry disease. J Pediatr. 2008 Apr;152(4):563-70, 570.e1. doi: 10.1016/j.jpeds.2007.09.007. Epub 2007 Dec 3.


Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

HCPCS
J0180

* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.

The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy

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