Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Enzyme Replacement Therapy for Adenosine Deaminase Severe Combined Immune Deficiency (e.g., pegademase bovine [Adagen®], elapegademase-lvlr [Revcovi™])

Policy #:08.01.26b

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

MEDICALLY NECESSARY

Elapegademase-lvlr (Revcovi) and pegademase bovine (Adagen®) are considered medically necessary and, therefore, covered for the treatment of individuals with adenosine deaminase deficiency with severe combined immunodeficiency (ADA-SCID), when all of the following criteria, including, Dosing and Frequency Requirements, are met:
  • Diagnosis of adenosine deaminase deficiency (ADA) is confirmed by one of the following:
    • Molecular genetic testing that reveals biallelic pathogenic variation(s) of the ADA gene
    • Deficiency or absence of ADA catalytic activity (<1% of normal) in hemolysates (in untransfused individuals) or in extracts of dried blood spots or other cells (e.g., blood mononuclear cells, fibroblasts)
    • An increase above laboratory standard (0.2 ± 0.1 pmol/106 cells) in deoxyadenosine triphosphate (dATP) levels in erythrocytes
  • Individual is not a candidate for, or has failed, bone marrow transplantation
  • Absence of severe thrombocytopenia
  • Dosing and Frequency:
    • Pegademase bovine (Adagen®): Administered as an intramuscular injection every 7 days. The recommended dosing schedule is 10 U/kg for the first dose, 15 U/kg for the second dose, and 20 U/kg for the third dose. The usual maintenance dose is 20 U/kg per week. Further increases of 5 U/kg/week may be necessary, but a maximum single dose of 30 U/kg should not be exceeded.
    • Elapegademase-lvlr (Revcovi): Administered as an intramuscular injection.
      • Individuals transitioning from Adagen® to Revcovi:
        • If weekly Adagen® dose is unknown or is less than 30 U/kg, RevcoviTM minImum starting dose is 0.2 mg/kg once a week.
        • If weekly Adagen® dose is above 30 U/kg, calculate an equivalent weekly RevcoviTM dose (mg/kg) by dividing the Adagen® dose in U/kg by 150.
        • Subsequent doses may be increased by increments of 0.033 mg/kg weekly if trough ADA activity is under 30 mmol/hr/L, trough deoxyadenosine nucleotides (dAXP) are above 0.02 mmol/L, and/or the immune reconstitution is inadequate based on the clinical assessment of the individual.
        • The total weekly dose may be divided into multiple intramuscular (IM) administrations during a week.
      • Adagen®-naïve individuals:
        • The starting weekly dose of Revcovi is 0.4 mg/kg based on ideal body weight, divided into two doses (0.2 mg/kg twice a week), for a minimum of 12 to 24 weeks until immune reconstitution is achieved. After that, the dose may be gradually adjusted down to maintain trough ADA activity over 30 mmol/hr/L, trough dAXP level under 0.02 mmol/L, and/or to maintain adequate immune reconstitution based on clinical assessment of the individual. Further monitoring of levels is required with the possibility of further dosage adjustment.

EXPERIMENTAL/INVESTIGATIONAL

All other uses of elapegademase-lvlr (Revcovi) and pegademase bovine (Adagen®) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

DOSING AND FREQUENCY REQUIREMENTS

The Company reserves the right to modify the Dosing and Frequency Requirements listed in this policy to ensure consistency with the most recently published recommendations for the use of elapegademase-lvlr (Revcovi) and pegademase bovine (Adagen®). Changes to these guidelines are based on a consensus of information obtained from resources such as, but not limited to: the US Food and Drug Administration (FDA); Company-recognized authoritative pharmacology compendia; or published peer-reviewed clinical research. The professional provider must supply supporting documentation (i.e., published peer-reviewed literature) in order to request coverage for an amount of elapegademase-lvlr (Revcovi) and pegademase bovine (Adagen®) outside of the Dosing and Frequency Requirements listed in this policy. For a list of Company-recognized pharmacology compendia, view our policy on off-label coverage for prescription drugs and biologics.

Accurate member information is necessary for the Company to approve the requested dose and frequency of this drug. If the member’s dose, frequency, or regimen changes (based on factors such as changes in member weight or incomplete therapeutic response), the provider must submit those changes to the Company for a new approval based on those changes as part of the utilization management activities. The Company reserves the right to conduct post-payment review and audit procedures for any claims submitted for elapegademase-lvlr (Revcovi) and pegademase bovine (Adagen®).

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

When coverage of elapegademase-lvlr (Revcovi) and pegademase bovine (Adagen®) are requested outside of the Dosing and Frequency Requirements listed in this policy, the prescribing professional provider must supply documentation (i.e., published peer-reviewed literature) to the Company that supports this request.
Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, elapegademase-lvlr (Revcovi) andpegademase bovine (Adagen®) are covered under the medical benefits of the Company’s products when the medical necessity criteria and Dosing and Frequency Requirements listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Elapegademase-lvlr (Revcovi) was approved by the FDA on October 5, 2018 for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult individuals.

Pegademase bovine (Adagen®) was approved by the FDA on March 21, 1990 for enzyme replacement therapy for adenosine deaminase (ADA) deficiency in individuals with severe combined immunodeficiency (SCID) disease who are not suitable candidates for, or who have failed, bone marrow transplantation. In accordance with the FDA-approved prescribing information, pegademase bovine (Adagen®) is recommended for use in infants from birth or in children of any age at the time of diagnosis. Pegademase bovine (Adagen®) is not intended as a replacement for human leukocyte antigen (HLA) identical bone marrow transplant therapy. Pegademase bovine (Adagen®) is also not intended to replace continued close medical supervision and the initiation of appropriate diagnostic tests and therapy as indicated for intercurrent illnesses.

Description

Severe combined immunodeficiency (SCID) is an inherited heterogeneous group of disorders that affects the development and function of T-cells and B-cells. The classic symptoms of SCID are recurrent severe infections, failure to thrive, and chronic diarrhea. Adenosine deaminase (ADA) deficiency is an autosomal recessive type of severe combined immunodeficiency (SCID) caused by variations in the ADA gene. ADA is an essential enzyme in the metabolism of purine nucleosides. ADA is represented by two isoenzymes: ADA1 and ADA2. The ADA1 isoenzymes are found in all cells, with the highest activity in lymphocytes, whereas ADA2 isoenzymes appear to be found only in antigen-presenting cells.

ADA deficiency accounts for approximately 15 percent of SCID cases; conversely, ADA deficiency leads to SCID in 90% of cases. In lymphocytes, ADA is responsible for breaking down deoxyadenosine, a harmful molecule generated from the breakdown of DNA. A deficiency in ADA leads to a buildup of deoxyadenosine, killing the lymphocytes. Immature lymphocytes in the thymus are especially vulnerable to the toxic buildup and die before reaching maturity, preventing them from helping to fight infections.

Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life and that is fatal within the first two years of life if the underlying defect is not corrected. In a small amount of cases (about 10-15%), the onset of immune deficiency is delayed to between 6 and 24 months of age (delayed onset) or even until adulthood (late onset). Immune deficiency in later-onset cases tends to be less severe, causing primarily recurrent upper respiratory and ear infections. Over time, affected individuals may develop chronic lung damage, malnutrition, and other health problems. Hematopoietic stem cell transplant is the treatment of choice for SCID; if a donor is not possible, or if the individual has failed stem cell transplant, enzyme replacement therapy is the next option.

Pegademase bovine (Adagen®) was approved by the US Food and Drug Administration (FDA) as an orphan drug (a drug used to treat, prevent, or diagnose a rare disease) for enzyme replacement therapy for adenosine deaminase (ADA) deficiency in individuals with SCID who are not suitable candidates for, or who have failed, bone marrow transplantation. It is a modified enzyme that is derived from bovine intestine. Due to production challenges, the pharmaceutical company created elapegademase-lvlr (Revcovi), a recombinant adenosine deaminase, that was approved by the FDA for the treatment of adenosine deaminase severe combined immune deficiency (ADA-SCID) in pediatric and adult individuals.

PEER-REVIEWED LITERATURE

SUMMARY
The safety and efficacy of elapegademase-lvlr (Revcovi) was evaluated in two studies. Study 1 (NCT 01420627) was a Phase 3, open-label, multicenter, single-arm, one-way crossover U.S. study in individuals with ADA-SCID who were stable on pegademase bovine (Adagen®). Six individuals, ages 8 to 37 years, were enrolled in the study. The primary efficacy endpoint assessed was trough deoxyadenosine nucleotide (dAXP) level (metabolic detoxification was defined as a trough erythrocyte dAXP concentration equal to or below 0.02 mmol/L). Five of six individuals reached the 21-week endpoint of the Treatment Phase, and three of six individuals received treatment with elapegademase-lvlr (Revcovi) for over 135 weeks. These three individuals had achieved erythrocyte dAXP concentration equal to or below 0.02 mmol/L.

Study 2 was a single-arm study that was conducted in Japan to assess the safety and efficacy elapegademase-lvlr (Revcovi) in individuals with ADA-SCID. Four individuals 3.4 months to 25 years of age, all Asian, were enrolled in the study and received elapegademase-lvlr (Revcovi). Three individuals received elapegademase-lvlr (Revcovi) for 21 weeks and one individual received elapegademase-lvlr (Revcovi) for 15 weeks. All four individuals achieved and maintained detoxification (trough dAXP [erythrocyte or blood] ≤0.02 mmol/L) throughout their participation in the Treatment Phase of 21 weeks (Dose Adjustment and Dose Maintenance).

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
References


American Hospital Formulary Service (AHFS). Drug Information 2018. Elapegademase-lvlr (Revcovi™). [Lexicomp Online Web site]. 10/29/18. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed December 20, 2018.

ClinicalTrials.gov. NCT 01420627: A Study of EZN-2279 (Polyethylene Glycol Recombinant Adenosine Deaminase [PEG-rADA]) Administered as a Weekly Intramuscular Injection in Patients With Adenosine Deaminase (ADA)-Deficient Combined Immunodeficiency. Available at: https://clinicaltrials.gov/ct2/show/NCT01420627 . Accessed January 7, 2019.

Elapegademase-lvlr (Revcovi) Leadiant Biosciences, Inc., Gaithersburg, MD. 10/05/2018. Available at: https://revcovi.com/ . Accessed December 20, 2018.

Elsevier’s Clinical Pharmacology Compendium. Elapegademase-lvlr (Revcovi). 10/11/18. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed December 20, 2018.

Elsevier’s Clinical Pharmacology Compendium. Pegademase bovine (Adagen®). 05/07/15. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed December 20, 2018.

Hershfield M. Adenosine deaminase deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews [Internet]. Seattle, WA: 2017. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1483/. Accessed January 9, 2019.

Hirschhorn R, Tzall S, Ellenbogen A. Hot spot mutations in adenosine deaminase deficiency. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6171-5.

Hoffman R, Benz E, Silberstein L. Congenital disorders of lymphocyte function. In:Pai S, Notarangelo L,eds. Hematology: Basic Principles and Practices. 6th ed. Philadelphia, PA: Elsevier Saunders; 2013.

Hutton JJ, Wiginton DA, Coleman MS, et al. Biochemical and functional abnormalities in lymphocytes from an adenosine deaminase-deficient patient during enzyme replacement therapy. J Clin Invest. 1981;68(2):413–421.

Leadiant Biosciences. Leadiant Shows Rare Dedication to Patients With Recent FDA Approval of Revcovi™. 11/201/8. Available at: http://leadiant.com/leadiant-shows-rare-dedication-patients-recent-fda-approval-revcovi/ . Accessed January 4, 2019.

Lexi-Drugs Compendium. Elapegademase-lvlr (Revcovi). 12/04/18. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed December 20, 2018.

Lexi-Drugs Compendium. Pegademase bovine (Adagen®). 11/27/18. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed December 20, 2018.

National Center for Advancing Translational Sciences (NIH). GARD: Genetic and Rare Diseases Information center. Adenosine deaminase deficiency. 11/28/2018. Available at: https://rarediseases.info.nih.gov/diseases/5748/adenosine-deaminase-deficiency . Accessed February 4, 2019.

National Institutes of Health (NIH). Genetics Home Reference. Adenosine deaminase deficiency. Reviewed 07/2013. Available at: https://ghr.nlm.nih.gov/condition/adenosine-deaminase-deficiency#sourcesforpage . Accessed January 4, 2019.

Pegademase bovine (Adagen®). Leadiant Biosciences, Inc., Gaithersburg, MD. 11/2017. Available at: http://www.adagen.com/ . Accessed December 20, 2018.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Elapegademase-lvlr (Revcovi). 10/26/18. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed December 20, 2018.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Pegademase bovine (Adagen®). 08/29/17. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed December 20, 2018.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Drug details: Elapegademase-lvlr (Revcovi). [FDA Web site]. 10/05/2018. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/ . Accessed December 20, 2018.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Drug details: Pegademase bovine (Adagen®). [FDA Web site]. 06/05/2014. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/ . Accessed December 20, 2018.

Yanovich OO, Titov LP, Dyusmikeeva MI, Shpakovskaya NS. Evaluation of adenosine deaminase (ADA) and ADA1 and ADA2 isoenzyme activities in patients with pulmonary tuberculosis and tuberculous pleurisy. International Journal of Mycobacteriology. March 2015;4(1):93-94. Available at: https://www.sciencedirect.com/science/article/pii/S2212553114002118 . Accessed February 4, 2019.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

D81.31 Severe combined immunodeficiency due to adenosine deaminase deficiency




HCPCS Level II Code Number(s)



J2504 Injection, pegademase bovine, 25 IU

THE FOLLOWING CODES ARE USED TO REPRESENT ELAPEGADEMASE-LVLR (REVCOVI):
C9399 Unclassified drugs or biologicals

J3590 Unclassified biologic



Revenue Code Number(s)

N/A

Coding and Billing Requirements

BILLING REQUIREMENTS

If there is no specific HCPCS code available for the drug administered, then the drug must be reported with the most appropriate unlisted code along with the corresponding National Drug Code (NDC).

Cross References


Policy History

Revisions from 08.01.26b
10/01/2019This policy has been identified for the ICD-10 code update, effective 10/01/2019.

The following ICD-10 code has been removed from this policy:
D81.3 Adenosine deaminase [ADA] deficiency

The following ICD-10 code has been added to this policy:
D81.31 Severe combined immunodeficiency due to adenosine deaminase deficiency

Revisions from 08.01.26a
06/03/2019This policy has been updated to revise the coverage criteria for pegademase bovine (Adagen®). Additionally, the coverage criteria was added for the newly FDA-approved drug, elapegademase-lvlr (Revcovi™). The dosing and frequency requirements are a component of the coverage criteria for both agents.

Revisions from 08.01.26
06/06/2018This policy has been reissued in accordance with the Company's annual review process.


Effective 10/05/2017 this policy has been updated to the new policy template format.
Version Effective Date: 10/01/2019
Version Issued Date: 10/03/2019
Version Reissued Date: N/A

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