| Coverage Policy Manual | |
| Policy #: | 2017022 |
| Category: | Pharmacy |
| Initiated: | June 2017 |
| Last Review: | January 2025 |
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| Cerliponase Alfa (e.g., Brineura™) | |
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| 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
In April 2017, cerliponase alfa (e.g., Brineura) was FDA-approved for 3 years of age and older with late 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.
On July 24, 2024, the Food and Drug Administration approved Cerliponase Alfa (e.g., Brineura) for expansion of the treatment population to birth, corresponding updates to indication and usage, dosing and administration, and other sections of the Brineura Prescribing information , as well as new information on infusion-associated reactions in the Warnings and Precautions section.
Coding
See CPT/HCPCS Code section below.
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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 15, 2025
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Cerliponase alfa (e.g., Brineura) 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)
CONTINUED TREATMENT (12-month approval)
Dosing and Administration
Dosing per FDA Guidelines
Cerliponase alfa is given as an intraventricular infusion.
The recommended dosage of Cerliponase alfa (e.g., Brineura):
Age Group: Birth to < 6 months
Dose: 100 mg (every other week)
Volume of Solution: 3.3 mL
Infusion Rate: 1.25 mL/hr
Age Group: 6 months to < 1 year
Dose: 150 mg (every other week)
Volume of Solution: 5 mL
Infusion Rate: 2.5 mL/hr
Age Group: 1 year to < 2 years
Dose: First 4 doses: 200 mg (every other week); Subsequent doses: 300 mg (every other week)
Volume of Solution: First 4 doses: 6.7 mL; Subsequent: doses-10 mL
Infusion Rate: 2.5 mL/hr
Age Group: 2 years and older
Dose: 300 mg (every other week)
Volume of Solution: 10 mL
Infusion Rate: 2.5 mL/hr
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
Cerliponase alfa (e.g., Brineura) 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 (e.g., Brineura), 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 10, 2024 through January 14, 2025
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)
CONTINUED TREATMENT (12 month approval)
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:
CONTINUED TREATMENT (12 month approval)
Dosing and Administration
Dosing per FDA Guidelines
Cerliponase alfa is given as an intraventricular infusion.
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:
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:
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:
CONTINUED TREATMENT (12 month approval)
Dosing and administration:
Cerliponase alfa is given as an intraventricular infusion.
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:
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:
CONTINUED TREATMENT (12 month approval)
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.
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:
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:
CONTINUED TREATMENT (12 month approval)
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:
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:
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:
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.
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| 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)
2025 Update
Trial 3 (NCT02678689) was a Phase 2, open label clinical study designed to enroll symptomatic and presymptomatic CLN2 patients less than 18 years of age. The trial enrolled 14 patients ranging in age from 1 to 6 years at baseline, including 8 patients less than 3 years of age, the median age was 2.7 years. Patients received BRINEURA at the recommended dose every 2 weeks by intraventricular infusion for 144 weeks (1 patient withdrew to receive treatment commercially). Fifty-seven percent of patients were female and 43% were male. All patients were White; for ethnicity, 14% identified as Hispanic/Latino, 86% as non-Hispanic/Latino. The mean baseline CLN2 Motor score was 2.3 (standard deviation (SD) 0.83) with a range from 1 to 3.
Thirteen of the 14 BRINEURA treated patients were matched with up to 3 natural history comparators on the basis of age within 3 months, equal CLN2 Motor score, and genotype (0, 1, or 2 key mutations). None of the BRINEURA treated patients (N=14) had a 2-point decline or score of zero in the Motor scale by Week 169. Among the matched natural history comparators (N=31), 20 subjects (65%) had an unreversed 2-point decline or score of zero by last assessment.
The median time to an unreversed 2-point decline in Motor score or score of 0 was 133 weeks among the natural history comparators and was not reached by last assessment (Week 169) in patients treated with BRINEURA.
In patients below 3 years of age, none (0%) of the BRINEURA treated patients (N=8) had a 2-point decline or score of zero in the Motor score by Week 169. Among the 8 treated patients, 7 were matched to 18 untreated patients from the natural history cohort. Among the matched natural history comparators (N=18), 11 subjects (61%) had an unreversed 2-point decline or score of zero in the Motor score by last assessment. All seven of the treated patients below 3 years of age with a motor score of 3 at baseline remained at a motor score of 3 at the last measured timepoint, which represents grossly normal gait. In this population BRINEURA treated patients showed a delay in disease onset. (Brineura, 2024)
Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 (TPP1) enzyme replacement therapy for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2 disease), which is caused by mutations in the TPP1 gene. We aimed to determine the long-term safety and efficacy of intracerebroventricular cerliponase alfa in children with CLN2 disease.
This analysis includes cumulative data from a primary 48-week, single-arm, open-label, multicentre, dose-escalation study (NCT01907087) and the 240-week open-label extension with 6-month safety follow-up, conducted at five hospitals in Germany, Italy, the UK, and the USA. Children aged 3-16 years with CLN2 disease confirmed by genetic analysis and enzyme testing were eligible for inclusion. Treatment was intracerebroventricular infusion of 300 mg cerliponase alfa every 2 weeks. Historical controls with untreated CLN2 disease in the DEM-CHILD database were used as a comparator group. The primary efficacy outcome was time to an unreversed 2-point decline or score of 0 in the combined motor and language domains of the CLN2 Clinical Rating Scale. This extension study is registered with ClinicalTrials.gov, NCT02485899, and is complete.
Between Sept 13, 2013, and Dec 22, 2014, 24 participants were enrolled in the primary study (15 female and 9 male). Of those, 23 participants were enrolled in the extension study, conducted between Feb 2, 2015, and Dec 10, 2020, and received 300 mg cerliponase alfa for a mean of 272·1 (range 162·1-300·1) weeks. 17 participants completed the extension and six discontinued prematurely. Treated patients were significantly less likely than historical untreated controls to have an unreversed 2-point decline or score of 0 in the combined motor and language domains (hazard ratio 0·14, 95% CI 0·06 to 0·33; p<0·0001). All participants experienced at least one adverse event and 21 (88%) experienced a serious adverse event; nine participants experienced intracerebroventricular device-related infections, with nine events in six participants resulting in device replacement. There were no study discontinuations because of an adverse event and no deaths.
Cerliponase alfa over a mean treatment period of more than 5 years was seen to confer a clinically meaningful slowing of decline of motor and language function in children with CLN2 disease. Although our study does not have a contemporaneous control group, the results provide crucial insights into the effects of long-term treatment. (Schulz, 2024)
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| CPT/HCPCS: | |
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| 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. |
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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.
CPT Codes Copyright © 2025 American Medical Association. |
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