Pending Policies - Prescription Drugs


Brineura (cerliponase alfa)

Number:RX501.092

Effective Date:11-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb strength of recommendation or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

Brineura™ (cerliponase alfa) may be considered medically necessary to slow the loss of ambulation in symptomatic pediatric patients 3 to 15 years of age with a diagnosis of late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency, as determined by TPP1 enzyme activity (dried blood spot).

Brineura™ (cerliponase alfa) is considered experimental, investigational and/or unproven for all other indications.

Description:

Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is an inherited disorder that primarily affects the nervous system. In early stages, CLN2 disease is challenging to recognize, and diagnosis is often delayed until after the disease has progressed significantly. The signs and symptoms of this condition typically begin between ages 2 and 4. The initial features usually include recurrent seizures (epilepsy) and difficulty coordinating movements (ataxia). Affected children also develop muscle twitches (myoclonus) and vision loss. CLN2 disease affects motor skills, such as sitting and walking, and speech development. This condition also causes the loss of previously acquired skills (developmental regression), intellectual disability that gradually gets worse, and behavioral problems. Individuals with this condition often require the use of a wheelchair by late childhood and typically do not survive past their teens. BioMarin estimates that between 1,200 to 1,600 children across the globe have this condition, 85 percent of whom may live outside the United States.

CLN2 disease is a rare autosomal recessive lysosomal storage disorder that results from deficient activity of the lysosomal exopeptidase tripeptidyl peptidase 1 (TPP1) enzyme (EC 3.4.14.9) caused by mutations in the TPP1/CLN2 gene. In the absence of newborn screening for CLN2 disease, gene panels are the broadest symptom-based, multiple-disease screening approach with a reasonable diagnostic yield. Laboratory tests to diagnose CLN2 disease are well established. TPP1 enzyme activity can be assessed in several sample types: leukocytes, DBS, fibroblasts, and saliva. The gold standard for laboratory diagnosis is demonstration of deficient TPP1 enzyme activity (in conjunction with normal activity of a control enzyme such as PPT1 and/or β-galactosidase) followed by molecular analysis that detects one pathogenic mutation on each parental allele of TPP1/CLN2. (1)

Brineura (cerliponase alfa)

Brineura (cerliponase alfa) has been approved by the U.S. Food and Drug Administration (FDA) to treat CLN2 disease, a specific form of Batten Disease, which is a rare set of genetic disorders that typically begin in childhood between ages 2 and 4. Brineura is the first treatment approved to treat children with CLN2 disease. Brineura is a purified human enzyme produced by recombinant DNA technology in a Chinese hamster ovary cell line. The active substance is a recombinant human tripeptidyl peptidase-1 (rhTPP1), a lysosomal exopeptidase. The primary activity of the mature enzyme is the cleavage of N-terminal tripeptides from a broad range of protein substrates. Cerliponase alfa contains 544 amino acids with an average molecular mass of 59 kDa. The mature enzyme is 368 amino acids in length. There are 5 consensus N-glycosylation sites on rhTPP1 that contain high mannose, phosphorylated high mannose and complex glycosylation structures. (2)

Recommended FDA Dosage

Brineura and the intraventricular electrolytes must be administered only by the intraventricular route, using the provided administration kit for use with Brineura. The recommended dosage of Brineura in pediatric patients 3 years of age and older is 300 mg administered once every other week by intraventricular infusion. Brineura is administered first followed by infusion of the intraventricular electrolytes each at an infusion rate of 2.5 mL/hr. The complete Brineura infusion, including the required infusion of intraventricular electrolytes, is approximately 4.5 hours. (2)

Regulatory Status

On April 27, 2017, Brineura (BioMarin Pharmaceutical Inc) received Food and Drug Administration (FDA) approval for treatment CLN2 (a specific form of Batten Disease) 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.

Rationale:

The efficacy of Brineura was assessed over 96 weeks in a non-randomized single-arm dose escalation clinical study with extension in symptomatic pediatric patients with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, confirmed by TPP1 deficiency. Brineura-treated patients were compared to untreated patients from a natural history cohort (an independent historical control group). The Motor domain of a CLN2 Clinical Rating Scale was used to assess disease progression. Scores ranged from 3 (grossly normal) to 0 (profoundly impaired) with unit decrements representing milestone events in the loss of motor function (ability to walk or crawl). Due to the inability to establish comparability for the CLN2 Language domain ratings between the clinical study with extension and the natural history cohort, efficacy of Brineura for the Language domain cannot be established.

Twenty-four patients, aged 3 to 8 years were enrolled in the Brineura single-arm clinical study. Sixty three percent of patients were female and 37% were male. Ninety-six percent of patients were Caucasian and 4% were Asian. One patient withdrew after week 1 due to inability to continue with study procedures; 23 patients were treated with Brineura 300 mg every other week for 48 weeks, and continued treatment during the extension period. In the clinical study with extension, patients were assessed for decline in the Motor domain of the CLN2 Clinical Rating Scale at 48, 72 and 96 weeks. Decline was defined as having an unreversed (sustained) 2-category decline or an unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale. Patients’ responses to Brineura treatment were evaluated if at screening a combined Motor plus Language CLN2 score of less than 6 was recorded. Two patients with a combined Motor plus Language CLN2 score of 6 were excluded from the analyses; they maintained that score throughout the study period. The patient who terminated early was analyzed as having a decline at the time of termination. Data used in the analyses from the natural history cohort began at 36 months of age or greater and at the first time a Motor plus Language CLN2 score less than 6 was recorded.

Motor scores of the 22 Brineura-treated patients in the clinical study with extension were compared to scores of the independent natural history cohort that included 42 untreated patients who satisfied inclusion criteria for the clinical study. The results of logistic modeling with covariates (screening age, screening motor score, genotype: 0 key mutations [yes/no], demonstrated the odds of Brineura-treated patients not having a decline by 96 weeks were 13 times the odds of natural history cohort patients not having a decline (Odds Ratio [95% CI]: 13.1 [1.2, 146.9]. (2)

Descriptive non-randomized comparison

In an unadjusted non-randomized comparison, of the 22 patients treated with Brineura and evaluated for efficacy at week 96, 21 (95%) did not decline, and only the patient who terminated early was deemed to have a decline in the Motor domain of the CLN2 Clinical Rating Scale. Results from the natural history cohort demonstrated progressive decline in motor function; of the 42 patients in the natural history cohort, 21 (50%) experienced an unreversed (sustained) 2-category decline or unreversed score of 0 in the Motor domain of the CLN2 Clinical Rating Scale over 96 weeks. Given the non-randomized study design, a Cox Proportional Hazards Model adjusted for age, initial motor score, and genotype was used to evaluate time to unreversed 2-category decline or unreversed score of 0 in the Motor domain. Brineura-treated patients demonstrated fewer declines in walking ability compared to untreated patients in the natural history cohort.

The most common adverse reactions in patients treated with Brineura include fever, ECG abnormalities including slow heart rate (bradycardia), hypersensitivity, decrease or increase in CSF protein, vomiting, seizures, hematoma (abnormal collection of blood outside of a blood vessel), headache, irritability, increased CSF white blood cell count (pleocytosis), device-related infection, feeling jittery and low blood pressure. (5)

The safety and effectiveness of Brineura have not been established in patients less than 3 years of age. The FDA will require the Brineura manufacturer to further evaluate the safety of Brineura in CLN2 patients below the age of 2 years, including device related adverse events and complications with routine use. In addition, a long-term safety study will assess Brineura treated CLN2 patients for a minimum of 10 years. (5)

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

C9014, J0567, J3490, J3590

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. M. Fietz et al. Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis. Molecular Genetics and Metabolism. 119 (2016):160–167.

2. FDA – Label Brineura™ (cerliponase alfa). Food and Drug Administration - Center for Devices and Radiologic Health (2017). Available at <http://www.fda.gov> (accessed May 25 2017).

3. FDA – BLA Approval Letter - Brineura™ (cerliponase alfa). Food and Drug Administration - Center for Devices and Radiologic Health (2017). Available at <http://www.fda.gov> (accessed May 25, 2017).

4. BioMarin Pharmaceutical Inc. Prescribing Information. Brineura™ (cerliponase alfa). Available at <http://brineura.com> (accessed May 2017).

5. FDA – News Release - FDA approves first treatment for a form of Batten disease. Food and Drug Administration - Center for Devices and Radiologic Health. April 26 2017. Available at <http://www.fda.gov> (accessed May 25, 2017).

Policy History:

Date Reason
11/15/2018 Reviewed. No changes.
11/1/2017 New medical document. Brineura™ (cerliponase alfa) may be considered medically necessary to slow the loss of ambulation in symptomatic pediatric patients 3 to 15 years of age with a diagnosis of late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency, as determined by TPP1 enzyme activity (dried blood spot). Brineura™ (cerliponase alfa) is considered experimental, investigational and/or unproven for all other indications.

Archived Document(s):

Title:Effective Date:End Date:
Brineura (cerliponase alfa)11-01-201711-14-2018
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