Approval Status: Approved April 2017
Specific Treatments: late infantile neuronal ceroid lipofuscinosis type 2
Brineura (cerliponase alfa) is a hydrolytic lysosomal N-terminal tripeptidyl peptidase.
Brineura is specifically indicated to slow the loss of 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.
Brineura is supplied as an injection for intraventricular administration. Pre-treatment of patients with antihistamines with or without antipyretics or corticosteroids is recommended 30 to 60 minutes prior to the start of infusion.The recommended dosage is 300 mg administered once every other week as an intraventricular infusion followed by infusion of Intraventricular Electrolytes over approximately 4.5 hours. For complete information on preparation, specific intraventricular access device for use, and administration, see the full prescribing information.
The FDA approval of Brineura was based on 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. 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). Twenty-four patients, aged 3 to 8 years were enrolled in the Brineura single-arm clinical study. 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) 2category 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. 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)). 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. To further assess efficacy, the 22 patients from the Brineura clinical study with a baseline combined Motor plus Language CLN2 score less than 6 were matched to 42 patients in the natural history cohort. Patients were matched based on the following covariates: baseline age at time of screening within 3 months, genotype (0, 1, or 2 key mutations), and baseline Motor domain CLN2 score at time of screening. Using the Motor domain of the CLN2 Clinical Rating Scale, decline was defined as having an unreversed 2-category decline or an unreversed score of 0. At 96 weeks, the matched analysis based on 17 pairs demonstrated fewer declines in the Motor domain for Brineura-treated patients compared to untreated patients in the natural history cohort.
Adverse effects associated with the use of Brineura may include, but are not limited to, the following:
- ECG abnormalities
- decreased CSF protein
- increased CSF protein
- device-related infection
- feeling jittery
Mechanism of Action
Brineura (cerliponase alfa) is a hydrolytic lysosomal N-terminal tripeptidyl peptidase. CLN2 disease is a neurodegenerative disease caused by deficiency of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1), which catabolizes polypeptides in the CNS. TPP1 has no known substrate specificity. Deficiency in TPP1 activity results in the accumulation of lysosomal storage materials normally metabolized by this enzyme in the central nervous system (CNS), leading to progressive decline in motor function. Cerliponase alfa (rhTTP1), a proenzyme, is taken up by target cells in the CNS and is translocated to the lysosomes through the Cation Independent Mannose-6-Phosphate Receptor (CI-MPR, also known as M6P/IGF2 receptor). Cerliponase alfa is activated in the lysosome and the activated proteolytic form of rhTPP1 cleaves tripeptides from the N-terminus of proteins.
For additional information regarding Brineura or late infantile neuronal ceroid lipofuscinosis type 2, please visit http://brineura.com/