Coverage Policy Manual
Policy #: 2017022
Category: Pharmacy
Initiated: June 2017
Last Review: January 2024
  Cerliponase Alfa (e.g., Brineura™)
Description:
Cerliponase alfa is an enzyme replacement therapy for the treatment of ceroid lipofuscinosis type 2 (CLN2) disease. It is a recombinant form of human tripeptidyl peptidase-1 (TPP1), which is deficient in individuals with CLN2 disease. Signs and symptoms of this disease usually begin between ages 2 and 4 and may include ataxia, language delay, recurrent seizures, ataxia, and vision loss (Clinical Pharmacology, 2017).
 
Regulatory Status
 
Cerliponase Alfa (e.g., Brineura™) was FDA-approved in April 2017 to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency.  Cerliponase Alfa (e.g.Brineura™) is given as an intraventricular infusion, which is followed by an infusion of intraventricular electrolytes over 4.5 hours.
 
Coding
 
See CPT/HCPCS Code section below.
 
Policy/
Coverage:
Effective April 01, 2018, Prior Approval is required for cerliponase alfa.
 
The use of this drug requires documentation of direct physician (MD/DO) involvement in the ordering and evaluation as well as a signature in the medical records submitted for prior approval.
 
Effective January 10, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Cerliponase alfa meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the below criteria are met:
 
INITIAL TREATMENT (6 month approval)
 
1. Diagnosis is neuronal ceroid lipofuscinosis type 2 (CLN2) (FDA, 2020), confirmed by dried blood spot test confirming TTP-1 enzyme activity deficiency (Schulz, 2017); AND
2. Age ≥ 3 years old and <16 years (Schulz, 2017); AND
3. Symptoms are present, which may include gait symptoms, motor symptoms, swallowing symptoms, speech abnormalities, vision loss, or other symptoms characteristic of CLN2; AND
4. Must be dosed in accordance with FDA label.
 
CONTINUED TREATMENT (12 month approval)
 
1. Individual continues to meet initial criteria listed above; AND
2. Benefit is demonstrated, as shown by not having a greater than 2-category decline in CLN2 Clinical Rating Scale.
 
Dosing and Administration
Dosing per FDA Guidelines
 
Cerliponase alfa is given as an intraventricular infusion.
 
The recommended dosage of cerliponase alfa is 300mg every other week, followed by an infusion of intraventricular electrolytes over 4.5 hours.
 
Cerliponase alfa is available as 150 mg/5 mL solution, two single-dose vials per carton co-packaged with Intraventricular Electrolytes Injection 5 mL in a single-dose vial.
 
Cerliponase alfa should be administered by, or under the direction of a physician experienced in intraventricular administration.  
 
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 cerliponase alfa for any indication or circumstance not described above, does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, Cerliponase alfa, 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 February 2023 to January 9, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
INITIAL TREATMENT (6 month approval)
 
Cerliponase alfa meets member benefit primary coverage criteria that there be scientific evidence of effectiveness and is covered when ALL of the below criteria are met:
 
1. Diagnosis is neuronal ceroid lipofuscinosis type 2 (CLN2) (FDA, 2020), confirmed by dried blood spot test confirming TTP-1 enzyme activity deficiency (Schulz, 2017) AND
2. Age ≥ 3 years old and <16 years (Schulz, 2017) AND
3. Symptoms are present, which may include gait symptoms, motor symptoms, swallowing symptoms, speech abnormalities, vision loss, or other symptoms characteristic of CLN2 AND
4. Must be dosed in accordance with FDA label.
 
CONTINUED TREATMENT (12 month approval)
 
1. Benefit is demonstrated, as shown by not having a greater than 2-category decline in CLN2 Clinical Rating Scale.
 
Dosing and Administration
Dosing per FDA Guidelines
 
Cerliponase alfa is given as an intraventricular infusion.
 
1. The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of 300mg every other week, followed by an infusion of intraventricular electrolytes over 4.5 hours.
2. Cerliponase alfa should be administered by, or under the direction of a physician experienced in intraventricular administration.  
 
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 cerliponase alfa for any indication or circumstance not described above, does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes including the following:
 
1. All indications except those listed above.  
2. Age <3 years old or ≥ 16 years old    
 
For members with contracts without primary coverage criteria, Cerliponase alfa, for any indication or circumstance not described above and is considered investigational including for the following:
 
1. All indications except those listed above.
2. Age <3 years old or ≥ 16 years old.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective February 2020 to January 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
INITIAL TREATMENT (6 month approval)
 
Cerliponase alfa meets primary coverage criteria and is covered when ALL of the below criteria are met:
        • Diagnosis is neuronal ceroid lipofuscinosis type 2 (CLN2) (FDA, 2020), confirmed by dried blood spot test confirming TTP-1 enzyme activity deficiency (Schulz, 2017)
        • Age ≥ 3  years old and <16 years (Schulz, 2017)
        • Symptoms are present, which may include gait symptoms, motor symptoms, swallowing symptoms, speech abnormalities, vision loss, or other symptoms characteristic of CLN2
 
CONTINUED TREATMENT (12 month approval)
 
        • Benefit is demonstrated, as shown by not having a greater than 2-category decline in CLN2 Clinical Rating Scale.
 
Dosing and administration:
Cerliponase alfa is given as an intraventricular infusion.
        • The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of 300mg every other week, followed by an infusion of intraventricular electrolytes over 4.5 hours.
        • Cerliponase alfa should be administered by, or under the direction of a physician experienced in intraventricular administration.  
 
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 cerliponase alfa does not meet primary coverage criteria and is considered investigational for the following:
 
        • All indications except those listed above.  
        • Age <3 years old or ≥ 16 years old    
             
Effective February 2019 to January 2020
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
INITIAL TREATMENT (6 month approval)
 
Cerliponase alfa meets primary coverage criteria and is covered when ALL of the below criteria are met:
    • Diagnosis is neuronal ceroid lipofuscinosis type 2 (CLN2), confirmed by dried blood spot test confirming TTP-1 enzyme activity deficiency
    • Age ≥ 3  years old and <16 years  
    • Symptoms are present, which may include gait symptoms, motor symptoms, swallowing symptoms, speech abnormalities, vision loss, or other symptoms characteristic of CLN2
 
CONTINUED TREATMENT (12 month approval)
    • Benefit is demonstrated, as shown by not having a greater than 2-category decline in CLN2 Clinical Rating Scale.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Dosing and administration:
Cerliponase alfa is given as an intraventricular infusion.
    • The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of 300mg every other week, followed by an infusion of intraventricular electrolytes over 4.5 hours.
    • Cerliponase alfa should be administered by, or under the direction of a physician experienced in intraventricular administration.  
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of cerliponase alfa does not meet primary coverage criteria and is considered investigational for the following:
    • All indications except those listed above.  
  •       Age <3 years old or ≥ 16 years old   
 
Effective February 2018 to January 2019
 
Effective April 01, 2018, Prior Approval is required for cerliponase alfa (Brineura ™).
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
INITIAL TREATMENT (6 month approval)
 
Cerliponase alfa meets primary coverage criteria and is covered when ALL of the below criteria are met:
 
    • Diagnosis is ceroid lipofuscinosis type 2 (CLN2), confirmed by dried blood spot test confirming TTP-1 enzyme activity deficiency
    • Age ≥ 3  years old and <16 years  
    • Symptoms are present, which may include gait symptoms, motor symptoms, swallowing symptoms, speech abnormalities, vision loss, or other symptoms characteristic of CLN2
 CONTINUED TREATMENT (12 month approval)
 
    • Benefit is demonstrated, as shown by not having a greater than 2 point decline in CLN2 score
 
Dosing:
The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of 300mg every other week, followed by an infusion of intraventricular electrolytes over 4.5 hours.
 
Cerliponase alfa is given as an intraventricular infusion.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of cerliponase alfa does not meet primary coverage criteria and is considered investigational for the following:
 
    • All indications except those listed above.  
    • Age <3 years old or ≥ 16 years old  
 
Effective Prior To February 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage
Criteria
 
Cerliponase alfa meets primary coverage criteria and is covered when ALL of the below criteria are met:
 
    • Diagnosis is ceroid lipofuscinosis type 2 (CLN2), confirmed by dried blood spot test confirming TTP-1 enzyme activity deficiency
    • Age ≥ 3  years old and <16 years
    • Symptoms are present, which may include gait symptoms, motor symptoms, swallowing symptoms, speech abnormalities, vision loss, or other symptoms characteristic of CLN2
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of cerliponase alfa does not meet primary coverage criteria and is considered investigational for the following:
 
    • All indications except those listed above.
    • Age <3 years old or ≥ 16 years old
 
Dosing:
The prescribed regimen must be in compliance with FDA-approved dosing, with a dosing regimen of 300mg every other week, followed by an infusion of intraventricular electrolytes over 4.5 hours.
 
Cerliponase alfa is given as an intraventricular infusion.
Rationale:
The efficacy of cerliponase alfa was evaluated in a non-randomized, single arm dose-escalation study with extension in which 22 symptomatic patients with CLN2, confirmed by genetic testing or dried blood spot testing of enzyme activity, were compared to a natural history cohort of 42 patients.  This clinical trial (NCT01907087) was sponsored by BioMarin Pharmaceutical and was completed in March 2016.
 
Schulz et al (2017) published interim results of this trial. Inclusion criteria for the trial specified that patients be age 3 to 16 years old, have mild to moderate disease as defined by the Hamburg scale, and have the diagnosis confirmed by TPP-1 enzyme activity. Patients were assessed for motor decline using the CLN2 Clinical Rating Scale. Scores range from 3 (grossly normal) to 0 (profoundly impaired).  Decline was defined as having an unreversed 2 point decline or a decline to a score of 0.  Patients were treated with cerliponase (so) 300 mg every other week.  Of the 22 patients treated with cerliponase alfa, 22 did not decline at week 96, as compared to 50% of the untreated historical cohort.  Risks and adverse reactions include pyrexia, ECG abnormalities (71% of patients), vomiting, seizures, and hypersensitivity reactions (46% of patients).  Cerliponase alfa is an intraventricular infusion, and 50% of patients had device-related adverse reactions, including infection.  Hypersensitivity reactions were also common, which included pyrexia, vomiting, and pleocytosis.  One patient experienced hypoxia requiring oxygen administration.   Anti-drug antibodies were detected in 79% of patients, which have not been found to associate to the incidence or severity of hypersensitivity.  Drug neutralizing antibodies have not been evaluated.  
 
2019 Update
An update of the open label study to assess the efficacy and safety of intraventricular cerliponase alfa in children with CLN2 disease from September 2013 through November 2015 was performed by Schultz A, et al. (2018).  Eligible patients were between the ages of 3 and 16 years of age and had received a diagnosis of CLN2 disease.  All of the patients had a combined score of 3 to 6 on the motor and language domains of the CLN2 Clinical Rating Scale and a score of at least 1 in each of the two domains at screening.   Treatment was initiated at a dose of 30 mg, 100 mg, or 300 mg; all the patients then received the 300-mg dose for at least 96 weeks. The primary outcome was the time until a 2-point decline in the score on the motor and language domains of the CLN2 Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function and 3 representing normal function in each of the two domains), which was compared with the time until a 2-point decline in 42 historical controls. Twenty-four patients were enrolled, 23 of whom constituted the efficacy population.
The median time until a 2-point decline in the motor–language score was not reached for treated patients and was 345 days for historical controls. The mean (+SD) unadjusted rate of decline in the motor language score per 48-week period was 0.27+0.35 points in treated patients and 2.12+0.98 points in 42 historical controls (mean difference, 1.85; P<0.001). Common adverse events included convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure of the intraventricular device. In 2 patients, infections developed in the intraventricular device that was used to administer the infusion, which required antibiotic treatment and device replacement. Intraventricular infusion of cerliponase alfa in patients with CLN2 disease resulted in less decline in motor and language function than that in historical controls.
 
Serious adverse events included failure of the intraventricular device and device related infections. Funded by BioMarin Pharmaceutical and others; CLN2 ClinicalTrials.gov numbers, NCT01907087 and NCT02485899.)
 
2020 Update
A literature search conducted through January 2020 did not reveal any new information that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Cerliponase alfa is recombinant human tripeptidyl peptidase 1 (TPP1) delivered by i.c.v. infusion for CLN2, a pediatric neurodegenerative disease caused by deficiency in lysosomal enzyme TPP1. The pharmacokinetics (PK) and pharmacodynamics of cerliponase alfa were reported, the first i.c.v. enzyme replacement therapy, characterized in a phase I/II study. Escalating doses (30-300 mg Q2W) followed by 300 mg Q2W for ≥ 48 weeks were administered in 24 patients aged ≥ 3 years. Concentrations peaked in cerebrospinal fluid (CSF) at the end of ~ 4-hour i.c.v. infusion and 8 hours thereafter in plasma. Plasma exposure was 300-1,000-fold lower than in CSF, with no correlation in the magnitude of peak concentration or area under the concentration-time curve (AUC) among body sites. There was no apparent accumulation in CSF or plasma exposure with Q2W dosing. Interpatient and intrapatient variability of AUC, respectively, were 31-49% and 24% in CSF vs. 59-103% and 80% in plasma. PK variability was not explained by baseline demographics, as sex, age, weight, and CLN2 disease severity score did not appear to impact CSF or plasma PK. No apparent correlation was noted between CSF or plasma PK and incidence of adverse events (pyrexia, hypersensitivity, seizure, and epilepsy) or presence of antidrug antibodies in CSF and serum. There was no relationship between magnitude of CSF exposure and efficacy (change in CLN2 score from baseline), indicating maximum benefit was obtained across the range of exposures with 300 mg Q2W. Data from this small trial of ultra-rare disease were leveraged to adequately profile cerliponase alfa and support 300 mg i.c.v. Q2W for CLN2 treatment. (Kim A, Grover A, Hammon K, et.al., 2021)
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
In a multicenter, open-label study, we evaluated the effect of intraventricular infusion of cerliponase alfa every 2 weeks in children with CLN2 disease who were between the ages of 3 and 16 years. Treatment was initiated at a dose of 30 mg, 100 mg, or 300 mg; all the patients then received the 300-mg dose for at least 96 weeks. The primary outcome was the time until a 2-point decline in the score on the motor and language domains of the CLN2 Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function and 3 representing normal function in each of the two domains), which was compared with the time until a 2-point decline in 42 historical controls. We also compared the rate of decline in the motor–language score between the two groups, using data from baseline to the last assessment with a score of more than 0, divided by the length of follow-up (in units of 48 weeks).
 
Twenty-four patients were enrolled, 23 of whom constituted the efficacy population. The median time until a 2-point decline in the motor–language score was not reached for treated patients and was 345 days for historical controls. The mean (±SD) unadjusted rate of decline in the motor–language score per 48-week period was 0.27±0.35 points in treated patients and 2.12±0.98 points in 42 historical controls (mean difference, 1.85; P<0.001). Common adverse events included convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure of the intraventricular device. In 2 patients, infections developed in the intraventricular device that was used to administer the infusion, which required antibiotic treatment and device replacement.
 
Intraventricular infusion of cerliponase alfa in patients with CLN2 disease resulted in less decline in motor and language function than that in historical controls. (Schulz A, Ajayi T, Specchio N, 2018)
CPT/HCPCS:
J0567Injection, cerliponase alfa, 1 mg
J3490Unclassified drugs
J3590Unclassified biologics
References: BioMarin Pharmaceutical sponsor(2017) NCT01907087. A Phase 1/2 Open-Label Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Intracerebroventricular BMN 190 in Patients With Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN2) Disease. https://clinicaltrials.gov/ct2/show/NCT01907087.

Elsevier.(2017) Cerliponase Alfa [Internet]. c2017- [cited 2017 May 19]. Available from: http://www.clinicalpharmacology.com

Kim A, Grover A, Hammon K, de Hart G, Slasor P, Cherukuri A, Ajayi T, Jacoby D, Schulz A, Specchio N, de Los Reyes E, Gissen P, Henshaw JW.(2021) Clinical Pharmacokinetics and Pharmacodynamics of Cerliponase Alfa, Enzyme Replacement Therapy for CLN2 Disease by Intracerebroventricular Administration. Clin Transl Sci. 2021 Mar;14(2):635-644. doi: 10.1111/cts.12925. Epub 2020 Nov 30. PMID: 33202105; PMCID: PMC7993266.

Schultz A, Specchio N, et al(2018) Study of Intraventricular Cerliponase Alfa for CLN2 Disease. New England Journal of Medicine 2018 May 17;378(20):1898-1907.doi:10.1056/NEJMoa1712649.Epub2018Apr24.

Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschütter A; CLN2 Study Group.(2018) Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med. 2018 May 17;378(20):1898-1907. doi: 10.1056/NEJMoa1712649. Epub 2018 Apr 24. PMID: 29688815.

Schulz A, Specchio N, Gissen P., de los Reyes E, Cahan H, Slasor P, Ajayi T, Jacoby D.(2017) Long-term safety and efficacy of intracerebroventricular enzyme replacement therapy with cerliponase alfa in children with CLN2 disease: interim results from an ongoing multicenter, multinational extension study. Molecular Genetics and Metabolism. January–February, 2017Volume 120, Issues 1-2, Page S120. DOI: http://dx.doi.org/10.1016/j.ymgme.2016.11.311. DOI: http://dx.doi.org/10.1016/j.ymg

U.S. Food and Drug Administration (FDA).(2020) Brineura. Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761052s008lbl.pdf Last accessed September 2, 2021.
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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