Plasminogen, Human-tvmh (Ryplazim)

Number: 0976

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses plasminogen, human tvmh (Ryplazim) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of plasminogen, human tvmh (Ryplazim) is required of all Aetna participating providers and members in applicable plan designs. For precertification of Ryplazim, call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.  

1. Criteria for Initial Approval

   Plasminogen deficiency type 1 (hypoplasminogenemia)

   Aetna considers plasminogen, human tvmh (Ryplazim) medically necessary for the treatment of plasminogen deficiency type 1 (hypoplasminogenemia) when all of the following criteria are met:

   1. Member has a baseline plasminogen activity level of 45% or less; and
   2. Member has a documented history of lesions and symptoms consistent with a diagnosis of plasminogen deficiency type 1 (e.g., ligneous conjunctivitis, ligneous gingivitis or gingival overgrowth, vision abnormalities, respiratory distress and/or obstruction, abnormal wound healing).

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of plasminogen, human tvmh (Ryplazim) therapy medically necessary for members with an indication listed in Section I who are experiencing benefit from therapy as evidenced by disease stability or disease improvement (e.g., improvement in lesion number and/or size, absence of new lesion development, improvement in respiratory function, increased quality of life).

Dosage and Administration

Plasminogen, human-tvmh is available as Ryplazim, which is supplied 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, USP. After reconstitution, each vial will contain 5.5 mg/mL of plasminogen. For intravenous infusion.

The recommended dosage of Ryplazim is 6.6 mg/kg body weight administered intravenously every 2 to 4 days.

Source: Prometic Biotherapeutics, 2021

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96365 – 96368	Intravenous infusion administration
HCPCS codes covered if selection criteria are met:
J2998	Injection, plasminogen, human-tvmh, 1 mg
ICD-10 codes covered if selection criteria are met:
E88.02	Plasminogen deficiency

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Ryplazim is plasma-derived human plasminogen indicated for the treatment of patients with plasminogen deficiency type 1 (hypoplasminogenemia).

Plasminogen, human-tvmh, is available as Ryplazim (Prometic Bioproduction, Inc.). Treatment with Ryplazim temporarily increases plasminogen levels in the blood. 

Ryplazim is contraindicated  in patients with known hypersensitivity to plasminogen, or other components of Ryplazim. The label carries warnings and precautions for the following:

• Bleeding: administration may lead to bleeding at lesion sites or worsen active bleeding. 
• Tissue sloughing: respiratory distress due to tissue sloughing may occur in patients with mucosal lesions in the tracheobronchial tree following Ryplazim administration. 
• Transmission of infectious agents: Ryplazim is made from human blood and therefore carries a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob Disease (CJD) agent. 
• Hypersensitivity reactions, including anaphylaxis, may occur. 
• Neutralizing antibodies (inhibitors) may develop, although were not observed in clinical trials. If clinical efficacy is not maintained (e.g., development of new or recurrent lesions), then
  determine plasminogen activity levels in plasma. 
• Laboratory abnormalities: Patients receiving Ryplazim may have elevated blood levels of D-dimer. D-dimer levels will lack interpretability in patients being screened for venous thromboembolism (VTE).

The most frequent (incidence 10% or more) adverse reactions in clinical trials were abdominal pain, bloating, nausea, fatigue, extremity pain, hemorrhage, constipation, dry mouth, headache, dizziness, arthralgia, and back pain.

Plasminogen Deficiency Type 1

Plasminogen deficiency type 1, also referred to as hypoplasminogenemia, is a rare genetic disorder characterized by decreased plasminogen levels that causes formation of fibrin-rich, ligneous ("wood-like") pseudomembranous lesions on mucous membranes that can impair normal tissue and organ function. Overall severity of the disorder can vary greatly from one person to another depending where the lesions, or growths, occur. The most common symptom is ligneous conjunctivitis, which can lead to blindness. However, the condition can affect other areas of the body which can lead to serious complications (e.g., obstruction of the airways).  Plasminogen deficiency type 1 is caused by mutations in the PLG gene, which is inherited in an autosomal recessive pattern. PLG mutations can decrease the amount of plasminogen that is produced, alter its function, or both. When the mutations affect plasminogen levels as well as the activity of the protein, plasminogen deficiency type 1 results. There is currently no screening test available; molecular genetic testing can only confirm a diagnosis. Diagnosis therefore generally relies on clinical symptoms, family medical history, and confirmatory testing. The growths usually recur if they are removed. Replacement therapy increases the plasma level of plasminogen enabling a temporary correction of the plasminogen deficiency and reduction or resolution of extravascular fibrinous lesions (NIH, 2016; NORD, 2016; Prometic Bioproduction, 2021).

On June 4, 2021, the U.S. Food and Drug Administration (FDA) approved Ryplazim (plasminogen, human-tvmh) for the treatment of patients with plasminogen deficiency type 1. FDA approval was based on one single-arm, open-label (unblinded) clinical trial that evaluated the efficacy and safety of Ryplazim in patients with plasminogen deficiency type 1. The clinical trial included a total of 15 patients who had a baseline plasminogen activity level between less than 5% and 45% of normal, and biallelic mutations in the plasminogen (PLG) gene. The age range was 4 to 42 years old, including 6 pediatric patients age 4 to 16 years, and 9 adults. All patients received Ryplazim 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 (FDA, 2021; Prometic Bioproduction, 2021).

The outcome from the trial on patients with external lesions found that 25 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. The outcome from the trial on patients with internal lesions found that 9 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 (Prometic Bioproduction, 2021).

In summary, the effectiveness of Ryplazim was demonstrated by at least 50% improvement of the patient's lesions in all 11 patients who had lesions at baseline, and absence of recurrent or new lesions in any of the 15 patients through the 48 weeks of treatment.

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References