Safety and efficacy of cerliponase alfa in children with neuronal ceroid lipofuscinosis type 2 (CLN2 disease): an open-label extension study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: BioMarin Pharmaceutical.

Therapeutic Management of COVID-19 in a Pediatric Patient with Neurodegenerative CLN2 Disease and ICV-Enzyme Replacement Therapy: A Case Report.

The 12 years old male patient presented here suffers from neuronal ceroid lipofuscinoses 2 (CLN2) (MIM# 204500) and receives intracerebroventricular enzyme replacement therapy (ICV-ERT) every 14 days. After the emergence of the coronavirus disease 2019 (COVID-19) pandemic, routine care of children and adolescents with rare chronic diseases has become challenging. Although, in general, children do not develop severe COVID-19, when severe acute respiratory syndrome coronavirus 2 infection was detected by polymerase chain reaction-screening examination in our CLN2 patient before hospital admission for ICV-ERT, he was regarded to be at risk. Upon diagnosis, the patient developed respiratory deterioration symptoms and was admitted to our pediatric intensive care unit to receive oxygen, remdesivir, and steroids. As far as we know, this is the first CLN2 patient receiving intraventricular enzyme therapy with COVID-19 who required intensive care treatment and specific therapy.

Visual perception and macular integrity in non-classical CLN2 disease.

PURPOSE: Patients with CLN2 suffer from epileptic seizures, rapid psychomotor decline and vision loss in early childhood. The aim of the study was to provide longitudinal ophthalmic data of patients with confirmed genetic mutation and non-classical disease course, marked by later onset, protracted progression and prolonged life span. METHODS: Prospective, observational study to assess visual acuity, retinal features (Weil Cornell Ophthalmic Score), central retinal thickness (CRT) measured by optical coherence tomography and general disease progression (Hamburg CLN2 motor language score) in non-classical CLN2 patients. RESULTS: All patients received intracerebroventricular enzyme replacement therapy with cerliponase alfa. Mean age at last follow-up was 12.4 years; mean follow-up time 2.6 years. All cases demonstrated a stable Hamburg motor language CLN2 Score and Weill Cornell LINCL Ophthalmic Severity Score. Visual function remained stable in 4/6 patients, 2/6 patients showed a decrease, 4/6 cases had a stable CRT and 2/6 showed a reduction of CRT. One patient showed a massive macular thinning and low vision. A correlation with a specific mutation or age could not be verified. DISCUSSION: The presented longitudinal study characterizes the variable ocular involvement in non-classical CLN2 disease and contributes to the natural history description. The functional and morphologic data outline the necessity of regular ophthalmic examination. Ocular phenotyping and description of retinal degeneration in non-classical CLN2 disease.

The Unified Batten Disease Rating Scale (UBDRS): Validation and reliability in an independent CLN3 disease sample.

BACKGROUND: The neuronal ceroid lipofuscinoses (NCLs) are a group of disorders characterized by neurodegeneration and intracellular accumulation of an auto-fluorescent lipopigment. Together, NCLs represent the most common cause of cerebral neurodegenerative disease in children. CLN3 disease, the classic juvenile-onset form (JNCL) due to mutations in CLN3, is characterized by progressive vision loss, epilepsy, dementia, behavioral difficulties, and motor impairment. The Unified Batten Disease Rating Scale (UBDRS) is a disease-specific rating scale that was developed to assess disease severity in 4 domains: physical, behavior, seizures, and functional capability. Validity and reliability of the UBDRS has been established in a large North American cohort of over 130 individuals. The purpose of this study was to determine whether the UBDRS is valid and reliable when tested in an independent sample. METHODS: Over the course of one week, 13 individuals with genetically confirmed CLN3 disease were evaluated with the UBDRS by 5 examiners at the University Medical Center Hamburg Eppendorf (UKE). One rater (JWM), one of the developers of the UBDRS, served as the reference standard. The other 4 raters were physicians with expertise in various forms of Batten Disease. After a formal training session, 13 individuals (age 16.5 ± 5.6 yrs) were evaluated simultaneous in parallel by the 5 raters. Inter-rater reliability of the Physical subscale was assessed with Intra-class Correlation (ICC) analysis. The relationship between age and severity was assessed and compared to previously published data from the North American cohort. FINDINGS: The ICC among the 5 independent raters was 0.92, demonstrating excellent inter-rater reliability. The individual correlations of each UKE rater compared to the reference standard rater were all >0.95. The average UBDRS Physical Subscale score in this sample was 28 ± 21 (mean ± SD) with a range from 1 to 61. When evaluated as a function of participant age, the slope was 3.06 points/year (R2 = 0.66). INTERPRETATION: We have shown excellent interrater reliability for the UBDRS as a clinical rating scale for CLN3 disease in a sample independent from previous work. The results of this study are comparable to those published by Kwon et al., 2011 in a North American cohort showing a slope of 2.86 points per year with a 95% CI of 2.27-3.45 (N = 82). Our results demonstrate excellence inter-rater reliability after training a new group of raters and provide additional evidence for construct validity of the UBDRS. The UBDRS is a valid and reliable rating scale that can used by trained raters to assess the severity and rate of progression of CLN3 disease.

Investigating health-related quality of life in rare diseases: a case study in utility value determination for patients with CLN2 disease (neuronal ceroid lipofuscinosis type 2).

BACKGROUND: Utility studies enable preference-based quantification of a disease's impact on patients' health-related quality of life (HRQoL). It is often difficult to obtain utility values for rare, neurodegenerative conditions due to cognitive burden of direct elicitation methods, and the limited size of patient/caregiver populations. CLN2 disease (neuronal ceroid lipofuscinosis type 2) is an ultra-rare, progressive condition, for which there are no published utility data fully capturing all disease stages. This case study demonstrates how utility values can be estimated for ultra-rare paediatric diseases by asking clinicians to complete EQ-5D-5L questionnaires based on vignettes describing the stages of CLN2 disease. METHODS: An indirect elicitation method using proxy-reporting by clinical experts was adopted. Eighteen vignettes were developed, describing nine progressive disease stages as defined by motor and language domain scores of the CLN2 Clinical Rating Scale, in individuals treated with cerliponase alfa or standard care. Eight clinical experts with experience of treating CLN2 disease with cerliponase alfa and current standard care completed the proxy version 2 EQ-5D-5L online after reading these vignettes. Resulting scores were converted to EQ-5D-5L utility values for each disease stage, using UK, German and Spanish value sets. RESULTS: Utility values, which are typically anchored by 0 (equivalent to death) and 1 (full health), decreased with CLN2 disease progression (results spanned the maximum range of the utility scale). Assigned utility values were consistently higher for patients receiving cerliponase alfa than standard care; differences were statistically significant for the 6 most severe disease stages (p < 0.05). Analysis of the individual dimensions of the EQ-5D-5L showed that greatest differences between patients treated with cerliponase alfa and standard care occurred in the pain dimension (differences in mean scores ranged between no difference and 1.8), with notable differences also observed in the anxiety/depression dimension (differences in mean scores ranged between 0.1 and 1.0). CONCLUSIONS: This study demonstrates a feasible methodology for eliciting utility values in CLN2 disease, indicating HRQoL declines with disease progression. Vignettes describing patients receiving cerliponase alfa were consistently assigned higher utility values for the same disease state, suggesting this treatment improves HRQoL compared with standard care. Trial registration NCT01907087, NCT02485899.

Development of the "Hamburg Best Practice Guidelines for ICV-Enzyme Replacement therapy (ERT) in CLN2 Disease" Based on 6 Years Treatment Experience in 48 Patients.

Intracerebroventricular enzyme replacement therapy (ICV-ERT) for CLN2 disease represents the first approved treatment for neuronal ceroid lipofuscinosis (NCL) diseases. It is the first treatment where a recombinant lysosomal enzyme, cerliponase alfa, is administered into the lateral cerebral ventricles to reach the central nervous system, the organ affected in CLN2 disease. If untreated, CLN2 children show first symptoms such as epilepsy and language developmental delay at 2-4 years followed by rapid loss of motor and language function, vision loss, and early death. Treatment with cerliponase alfa has shown to slow the rapid neurologic decline. However, the mode of administration by 4 hour-long intracerebroventricular infusions every 14 days represents a potentially greater risk of infection compared to intravenous enzyme replacement therapies. The Hamburg NCL Specialty Clinic was the first site worldwide to perform intracerebroventricular enzyme replacement therapy in children with CLN2 disease. In order to ensure maximum patient safety, we analysed data from our center from more than 3000 intracerebroventricular enzyme replacement therapies in 48 patients over 6 years with regard to the occurrence of device-related adverse events and device infections. Since starting intracerebroventricular enzyme replacement therapy, we have also developed and continuously improved the "Hamburg Best Practice Guidelines for ICV-Enzyme Replacement Therapy (ERT) in CLN2 Disease." Results from this study showed low rates for device-related adverse events and infections with 0.27% and 0.33%, respectively. Therefore, following our internal procedural guidelines has shown to improve standardization and patient safety of intracerebroventricular enzyme replacement therapy for CLN2 disease.

Cerliponase Alfa for the Treatment of Atypical Phenotypes of CLN2 Disease: A Retrospective Case Series.

BACKGROUND: The classic phenotype of CLN2 disease (neuronal ceroid lipofuscinosis type 2) typically manifests between ages 2 and 4 years with a predictable clinical course marked by epilepsy, language developmental delay, and rapid psychomotor decline. Atypical phenotypes exhibit variable time of onset, symptomatology, and/or progression. Intracerebroventricular-administered cerliponase alfa (rhTPP1 enzyme) has been shown to stabilize motor and language function loss in patients with classic CLN2 disease, but its impact on individuals with atypical phenotypes has not been described. METHODS: A chart review was conducted of 14 patients (8 male, 6 female) with atypical CLN2 phenotypes who received cerliponase alfa. Pre- and posttreatment CLN2 Clinical Rating Scale Motor and Language (ML) domain scores were compared. RESULTS: Median age at first presenting symptom was 5.9 years. First reported symptoms were language abnormalities (6 [43%] patients), seizures (4 [29%]), ataxia/language abnormalities (3 [21%]), and ataxia alone (1 [7%]). Median age at diagnosis was 10.8 years. ML score declined before treatment in 13 (93%) patients. Median age at treatment initiation was 11.7 years; treatment duration ranged from 11 to 58 months. From treatment start, ML score remained stable in 11 patients (treatment duration 11-43 months), improved 1 point in 1 patient after 13 months, and declined 1 point in 2 patients after 15 and 58 months, respectively. There were 13 device-related infections in 8 patients (57%) and 10 hypersensitivity reactions in 6 (43%). CONCLUSIONS: Cerliponase alfa is well tolerated and has the potential to stabilize motor and language function in patients with atypical phenotypes of CLN2 disease.

An Ophthalmic Rating Scale to Assess Ocular Involvement in Juvenile CLN3 Disease.

PURPOSE: Juvenile CLN3 disease, the most prevalent form of Batten disease, is a progressive neurodegenerative disorder resulting from mutations in the CLN3 gene. The objective of this study was to design an ophthalmic rating scale for CLN3 disease in order to quantify disease progression. DESIGN: Retrospective, cross-sectional study. METHODS: Patients underwent ophthalmic evaluations including visual testing, optical coherence tomography and fundus imaging. Patients were also assessed using the Hamburg Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) scoring system. Ophthalmic findings were divided into grades of severity ranging from 0 to 3, and the association between the extent of ocular disease and neurological function and age was assessed. RESULTS: Forty-two eyes of 21 patients were included. The mean age at the time of examination was 13.2 years (range, 5.3-21.9 years). The mean ophthalmic severity grade was 2.4 (range, 0-3). The mean neurological severity score was 9.9 (range, 4-14). Ophthalmic manifestations increased in severity with increasing age of the patients (r = -0.84; P < .001), and a strong correlation was found between the CLN3 ophthalmic rating scale score and the Hamburg JNCL score (r = 0.83; P < .001). CONCLUSIONS: Ophthalmic manifestations of CLN3 disease correlate closely with the severity of neurological symptoms and age of the patient. The newly established Hamburg CLN3 ophthalmic rating scale may serve as an objective marker of ocular disease severity and progression and may be valuable tool for the evaluation of novel therapeutic strategies for CLN3 disease.

Best practices for the use of intracerebroventricular drug delivery devices.

For decades, intracerebroventricular (ICV), or intraventricular, devices have been used in the treatment of a broad range of pediatric and adult central nervous system (CNS) disorders. Due to the limited permeability of the blood brain barrier, diseases with CNS involvement may require direct administration of drugs into the brain to achieve full therapeutic effect. A recent comprehensive literature review on the clinical use and complications of ICV drug delivery revealed that device-associated complication rates are variable, and may be as high as 33% for non-infectious complications and 27% for infectious complications. The variability in reported safety outcomes may be driven by a lack of consensus on best practices of device use. Numerous studies have demonstrated that employing strict aseptic techniques and following stringent protocols can dramatically reduce complications. Key practices to be considered in facilitating the safe, long-term use of these devices are presented.