Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2022002
Category:	Pharmacy
Initiated:	January 2022
Last Review:	January 2025

Plasminogen (e.g., Ryplazim)

Description:

Plasminogen, human-tvmh (e.g., Ryplazim) is plasma-derived human plasminogen indicated for the treatment of individuals with plasminogen deficiency type 1 (hypoplasminogenemia). Glu-plasminogen (> 95% purity) is the native circulating form of plasminogen in the blood. Biological potency of the plasminogen is determined by a chromogenic assay calibrated with a standard.

Congenital plasminogen deficiency is caused by mutations in PLG, the gene coding for production of the zymogen plasminogen, and is an ultrarare disorder associated with abnormal accumulation or growth of fibrin-rich pseudomembranous lesions on mucous membranes. Left untreated, these lesions may impair organ function and impact quality of life. Plasminogen replacement therapy should provide an effective treatment of the manifestations of congenital plasminogen deficiency.

Plasminogen deficiency (PLGD) is subclassified as type I versus type II disease (both are autosomal recessive):

Type I – there is quantitative deficiency due to reduced plasminogen protein production. Both plasminogen protein levels and functional activity are both reduced.

Type II – there is a qualitative deficiency due to production of dysfunctional protein. Plasminogen protein levels may be normal but activity is reduced. (Type II appears to be more common than type I).

These distinctions have major clinical implications, with type I disease causing symptoms and type II disease being asymptomatic.

Regulatory

On June 4, 2021, the U.S. Food and Drug Administration approved plasminogen, human -tvmh (Ryplazim) for the treatment of individuals with plasminogen deficiency type 1 (hypoplasminogenemia).

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

The initial use of this drug requires documentation of direct physician involvement and signature in the ordering and evaluation as documented in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.

Effective January 2025

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Plasminogen (human, tvmh) (e.g., Ryplazim) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the below criteria are met:

INITIAL APPROVAL (6 months):

1. Individual has diagnosis of type 1 plasminogen deficiency (hypoplasminogenemia) confirmed (Shapiro 2018) by submitted documentation of:

a. Plasminogen activity level < 45%; AND

b. Plasminogen antigen (protein levels) < 45%; AND

c. Genetic testing of PLG gene confirming a biallelic pathogenic variant (in those with borderline plasminogen levels); AND

2. Documentation of lesions and symptoms consistent with diagnosis congenital PLGD (e.g. ligneous conjunctivitis, lesions of ears, nose, and/or mouth, characteristic involvement of CNS, skin, orogenital tract, GI, and/or respiratory tract) by a physician with expertise in this ultra rare diagnosis [e.g. hemophilia treatment center (HTC) or academic center of excellence]; AND

3. Individual does not have type 2 plasminogen deficiency; AND

4. Must be dosed in accordance with the FDA label.

CONTINUED APPROVAL for 1 year:

1. Evidence of clinically significant response to treatment such as resolution of lesions or significant improvement; AND

2. Maintenance of a trough plasminogen activity level > 10% above baseline.

Dosage and Administration

Dosing per FDA Guidelines

Dose Determination

The recommended dosage of is 6.6 mg/kg body weight administered intravenously every 2 to 4 days (Q2D to Q4D).

Calculate the total infusion volume of product by using Formula (1), which is based on a final plasminogen concentration of 5.5 mg/mL. Administer the exact infusion volume determined using Formula (1) to the individual. Formula (1): Infusion volume (mL) = body weight (kg) x 1.2

May require more than one reconstituted vial of plasminogen, human-tvmh (Ryplazim) to obtain the infusion volume calculated using Formula (1). Round up the estimated number of vials using Formula (2). Formula (2): Number of vials = Infusion volume (mL) x 0.08.

Plasminogen, human-tvmh (e.g., Ryplazim) is available in a single-dose 50 mL vial containing 68.8 mg of plasminogen as a lyophilized powder for reconstitution with 12.5 mL of Sterile Water for injection. After reconstitution, each vial will contain 5.5 mg/mL of plasminogen.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Plasminogen, human, tvmh (e.g., Ryplazim), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, Plasminogen, human, tvmh (e.g., Ryplazim), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective January 2024 to December 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

The use of plasminogen (human, tvmh) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals with a confirmed diagnosis of congenital plasminogen deficiency (PLGD) type 1 when ALL the below criteria are met:

INITIAL APPROVAL (6 months):

1. Diagnosis of type 1 plasminogen deficiency has been confirmed (Shapiro 2018) by submitted documentation of

a. Plasminogen activity level < 45%, AND

b. Plasminogen antigen (protein levels) < 45%, AND

c. Genetic testing of PLG gene confirming a biallelic pathogenic variant (in those with borderline plasminogen levels), AND

2. Documentation of lesions and symptoms consistent with diagnosis congenital PLGD (e.g. ligneous conjunctivitis, lesions of ears, nose, and/or mouth, characteristic involvement of CNS, skin, orogenital tract, GI, and/or respiratory tract) by a physician with expertise in this ultra rare diagnosis [e.g. hemophilia treatment center (HTC) or academic center of excellence]; AND

3. Individual dose not have type 2 plasminogen deficiency; AND

4. Must be dosed in accordance with the FDA label.

CONTINUED APPROVAL for 1 year:

1. Evidence of clinically significant response to treatment such as resolution of lesions or significant improvement; AND

2. Maintenance of a trough plasminogen activity level > 10% above baseline.

Dosage and Administration

Dosing per FDA Guidelines

Plasminogen, human-tvmh [e.g., RYPLAZIM® ] is available in a single-dose 50 mL vial containing 68.8 mg of plasminogen as a lyophilized powder for reconstitution with 12.5 mL of sterile water for injection (SWFI). After reconstitution, each vial will contain 5.5 mg/mL of plasminogen in a colorless and clear to slightly opalescent solution

Dose Determination

The recommended dosage of is 6.6 mg/kg body weight administered intravenously every 2 to 4 days (Q2D to Q4D).

May require more than one reconstituted vial of plasminogen, human-tvmh [RYPLAZIM® ] to obtain the infusion volume calculated using Formula (1). Round up the estimated number of vials using Formula (2). Formula (2): Number of vials = Infusion volume (mL) x 0.08.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of plasminogen, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, plasminogen therapy, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective January 12, 2022 to December 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

The use of plasminogen (human, tvmh) meets primary coverage criteria that there be scientific evidence of effectiveness for patients with a confirmed diagnosis of congenital plasminogen deficiency (PLGD) type 1 when ALL of the below criteria are met:

INITIAL APPROVAL (6 months):

Diagnosis of type 1 plasminogen deficiency has been confirmed (Shapiro 2018) by submitted documentation of

a. Plasminogen activity level < 45%, AND

b. Plasminogen antigen (protein levels) < 45%, AND

c. Genetic testing of PLG gene confirming a biallelic pathogenic variant (in those with borderline plasminogen levels), AND

2. Documentation of lesions and symptoms consistent with diagnosis congenital PLGD (e.g. ligneous conjunctivitis, lesions of ears, nose, and/or mouth, characteristic involvement of CNS, skin, orogenital tract, GI, and/or respiratory tract) by a physician with expertise in this ultra rare diagnosis [e.g. hemophilia treatment center (HTC) or academic center of excellence]

Continuation of plasminogen therapy (1 year) meets primary coverage criteria when the following are met:

Evidence of clinically significant response to treatment such as resolution of lesions or significant improvement
Maintenance of a trough plasminogen activity level > 10% above baseline

Dosage and Administration

Plasminogen, human-tvmh [RYPLAZIM® ] is available in a single-dose 50 mL vial containing 68.8 mg of plasminogen as a lyophilized powder for reconstitution with 12.5 mL of sterile water for injection (SWFI). After reconstitution, each vial will contain 5.5 mg/mL of plasminogen in a colorless and clear to slightly opalescent solution

Dose Determination

The recommended dosage of is 6.6 mg/kg body weight administered intravenously every 2 to 4 days (Q2D to Q4D).

Calculate the total infusion volume of product by using Formula (1), which is based on a final plasminogen concentration of 5.5 mg/mL. Administer the exact infusion volume determined using Formula (1) to the patient. Formula (1): Infusion volume (mL) = body weight (kg) x 1.2

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of plasminogen does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any indication or circumstance other than those listed above, including but not limited to type 2 plasminogen deficiency.

For members with contracts without primary coverage criteria, plasminogen therapy is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

Note: Patients receiving plasminogen may have elevated levels of D-dimer in blood. D-dimer levels should be interpreted with caution in patients being screened for venous thromboembolism (VTE), as elevated levels may be associated with the physiological activity of this product (fibrinolysis of ligneous lesions) and not indicative of VTE. The use of other tests other tests to screen for VTE in patients receiving plasminogen should be considered since D-dimer levels lack interpretability.

The efficacy of plasminogen in pediatric and adult patients with plasminogen deficiency type 1 was evaluated in a single-arm, open-label clinical trial (RYPLAZIM Trial 2). A total of 15 patients with plasminogen deficiency type 1 were enrolled. All patients had a baseline plasminogen activity level between <5% and 45% of normal, and biallelic mutations in the plasminogen (PLG) gene. The age range of these patients was 4 to 42 years, including 6 pediatric patients age 4 to 16 years, and 9 adults. Eleven patients were female. All patients were White. All patients received plasminogen at a dose of 6.6 mg/kg administered every 2 to 4 days for 48 weeks to achieve at least an increase of individual trough plasminogen activity by an absolute 10% above baseline and to treat the clinical manifestations of the disease.

Efficacy was established on the basis of overall rate of clinical success at 48 weeks. Overall rate of clinical success is defined as 50% of patients with visible or other measurable non-visible lesions achieving at least 50% improvement in lesion number/size, or functionality impact from baseline. Spirometry was the only test of organ function used and one patient had abnormal spirometry at baseline. This patient had a history of ligneous airway disease with a severe obstructive ventilatory defect (FEV1: 46.7% of predicted normal) at baseline prior to treatment that corrected to normal (FEV1: 89.3% of predicted normal) after 12 weeks of treatment. All patients with any lesion at baseline had at least 50% improvement in the number/size of their lesions: external lesions: Twenty-five of the 32 (78%) external lesions [with sites mainly located in the eyes (ligneous conjunctivitis), nose, gums (ligneous gingivitis), ligneous lesions of the hands and feet] were resolved by the end of Week 48. There were no recurrent or new external lesions in any patient through Week 48; internal lesions: Nine of the 12 (75%) assessed internal lesions were resolved by Week 48. The lesion sites were mainly located in the cervix, bronchus, colon, vagina and uterus. No recurrent or new lesions were found on imaging in any patient through Week 48.

2023 Update

A literature search conducted through January 2023 did not reveal any new information that would prompt a change in the coverage statement.

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

References:

Mehta R, Shapiro AD.(2008) Plasminogen deficiency. Haemophilia 2008; 14:126

Schuster V, Hügle B, Tefs K.(2007) Plasminogen deficiency. J Thromb Haemost. 2007 Dec;5(12):2315-22

Shapiro AD, Nakar C, Parker JM, et al.(2018) Plasminogen replacement therapy for the treatment of children and adults with congenital plasminogen deficiency. Blood. 2018 Mar 22;131(12):1301-1310. doi: 10.1182/blood-2017-09-806729.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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