Health Technology Review

Cerliponase Alfa for Pediatric Patients With Neuronal Ceroid Lipofuscinosis Type 2 Disease

What Is the Issue?

• Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is an ultrarare, severe, and rapidly progressing lysosomal storage disorder, with a global incidence of approximately 0.15 to 9.0 per 100,000 live births. It has a devastating impact on children and families, leading to rapid functional decline and early death without effective treatment.

• Cerliponase alfa is currently the only disease-modifying therapy approved by Health Canada for CLN2 disease.

• Drug plans have requested an updated evidence review to support reimbursement decisions for cerliponase alfa, with a focus on evaluating their current discontinuation criteria that is based largely on motor-language score changes.

What Did We Do?

• We searched key resources, including journal citation databases, and conducted a focused internet search for relevant studies of benefits and harms, as well as evidence-based clinical practice guidelines published since our previous review in 2019.

• One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included studies and guidelines, and summarized the findings.

• We identified patients, caregivers, and families in Canada with lived experience with CLN2 disease and cerliponase alfa, and gathered their perspectives through semistructured interviews. The insights and priority treatment outcomes that they shared helped to inform our interpretation of the literature and conclusions.

• We engaged 2 clinical experts in the diagnosis and management of CLN2 disease to provide input on the project protocol and draft report, offering clinical context and interpretation of the evidence.

What Did We Find?

• Clinical experts identified improved quality of life (QoL), the mitigation of disease progression, and patient safety as key outcomes in treating people with CLN2 disease. Caregivers shared these priorities and emphasized additional outcomes, including patients’ comfort and happiness. Both groups underscored the importance of shared decision-making in initiating and discontinuing treatment with cerliponase alfa based on patients’ specific needs and goals.

• Three primary clinical studies (2 observational studies and 1 open-label extension study of a single-arm clinical trial) with untreated historical controls and 2 evidence-based clinical practice guidelines met our preidentified inclusion criteria.

• In alignment with our previous review, the 3 identified studies suggested that cerliponase alfa may slow disease progression in patients with CLN2 disease, helping to preserve or delay deterioration of motor-language function and reduce mortality compared to untreated patients. However, methodological limitations (e.g., results presented descriptively without any statistical analysis) limit the ability to make direct inferences to the benefit of cerliponase alfa on these outcomes, and whether these differences are clinically meaningful.

• The evidence identified from the single-arm, open-label trial examining the benefit of cerliponase alfa on health-related quality of life (HRQoL) was variable. Some domains such as emotional functioning and seizure control showed improvement (indicating better HRQoL in these domains), while other domains such as physical functioning and daily activities declined (indicating worsening HRQoL in these domains) over time. Due to the noncomparative nature of the available data, causal inferences cannot be drawn. Observed changes in HRQoL, including seizure control, may reflect the natural progression of the disease, unadjusted confounding factors (e.g., use of antiseizure medications, disease severity, and concurrent illnesses), placebo effects, or the effects of cerliponase alfa.

• Adverse events (AEs) were reported as common but manageable by the included study authors, with no deaths or treatment withdrawals reported due to AEs.

• No studies were identified that met our inclusion criteria on caregiver burden measures.

• No studies conducted subgroup analyses based on disease severity at treatment initiation, time of symptom onset, or patient age group.

• Evidence-based clinical guidelines support the use of cerliponase alfa in patients with CLN2 disease, including patients with early-stage disease or who are presymptomatic, but note that evidence is limited regarding advanced disease and when to stop treatment.

What Does It Mean?

• Findings suggest that early initiation of cerliponase alfa in CLN2 disease may help preserve or delay deterioration of motor-language function, particularly in patients with a motor-language score above 3 (i.e., some functional abilities are still preserved).

• The emerging evidence that suggests a potential benefit of cerliponase alfa on QoL, seizure control, and mortality outcomes — which were deemed important to those with lived experience — has methodological limitations (e.g., lack of concurrent control groups; patients being aware of the treatment they received; and residual confounding factors, such as concurrent use of antiseizure medications and concurrent illnesses) that limit the ability to make definitive conclusions on the relative benefit of cerliponase alfa on these outcomes.

• New evidence from the identified published clinical studies generally aligns with the previous conclusions of our 2019 clinical review.

• The 3 primary studies did not examine the impact of treatment discontinuation on clinical outcomes and provide limited information to inform discontinuation criteria. In addition, 1 evidence-based clinical guideline highlighted a scarcity of data to inform treatment discontinuation.

Introduction and Rationale

Background

What Is CLN2 Disease?

CLN2 disease, also known as late infantile neuronal ceroid lipofuscinoses or Jansky-Bielschowsky disease, is classified under the umbrella term of neuronal ceroid lipofuscinoses (NCLS), collectively referred to as Batten disease. CLN2 disease is a rare, severe, and rapidly progressing lysosomal storage disorder caused by mutations in the TPP1 gene (also known as the CLN2 gene).^1,2 Mutations in the TPP1 gene lead to a deficiency or complete absence of the TPP1 enzyme, which is essential for normal lysosomal function.² The severe deficiency or complete absence of the functional TPP1 enzyme, particularly within neurons of the brain and retina, results in the accumulation of toxic materials, including autofluorescent lipopigments, leading to progressive damage to the nervous system and cell death.^2,3 CLN2 disease causes a decline in cognitive abilities and motor functions, and also causes drug-resistant epilepsy, ataxia (difficulty coordinating movements), vision loss, and a significantly shortened life expectancy.³

CLN2 disease is an ultrarare disease, with an incidence that ranges from approximately 0.15 to 9.0 per 100,000 live births worldwide.⁴ In Canada, Newfoundland has historically reported the highest incidences of CLN2 disease (9.0 per 100,000 live births),⁵ potentially due to founder effects, where certain genetic traits are more common in a population descended from a small number of ancestors.

CLN2 disease most often appears in children between the ages of 2 and 4 years, often beginning with subtle signs, such as delayed language development or the onset of seizures.^1,4 The disease then progresses rapidly, with children losing abilities such as walking, talking, and vision.⁴ By the age of 6 to 7 years, most children with CLN2 disease lose all motor and speech functions, and death usually occurs between the ages of 10 and 15 years.^6-8 Some patients with CLN2 disease present with an atypical (nonclassical) later onset (after the age of 4 years) form of the disease, which presents with slower disease progression of functional decline and more varied behavioural, motor, and vision symptoms compared to typical clinical presentations.^9,10

What Is the Current Treatment Landscape of CLN2 Disease?

Historically, treatment for CLN2 disease focused on supportive care, which involves a multidisciplinary team of health care professionals — including pediatric neurologists, ophthalmologists, physiotherapists, and palliative care specialists — working together to manage symptoms, improve HRQoL, and prevent disease-related complications.^4,8 Supportive care remains essential in managing the complex needs of children with CLN2 disease, including addressing issues such as nutritional difficulties and mobility issues.¹¹ The first disease-modifying therapy for CLN2 disease, cerliponase alfa, was approved by the European Medicines Agency and the FDA in 2017, and by Health Canada in 2018. Cerliponase alfa remains the only approved disease-modifying therapy for people with CLN2 disease. Cerliponase alfa is an enzyme replacement therapy that targets the underlying enzyme deficiency in CLN2 disease, shifting treatment from purely supportive care to care that aims to slow disease progression.⁸

Clinical studies commonly use the CLN2 Clinical Rating Scale to evaluate the treatment effects of cerliponase alfa. The Clinical Rating Scale includes 4 domains: motor, language, vision, and seizures. Each domain is scored from 0 (complete loss of function) to 3 (normal function), yielding a total score ranging from 0 to 12, with higher scores indicating better function.¹² Most studies focus on the combined motor-language score as the primary outcome. This subscore ranges from 0 to 6, where higher values reflect more developed motor and language abilities.¹² One study reported a 1-point change in the combined motor-language score of the CLN2 Clinical Rating Scale to be both measurable and clinically meaningful; however, it was unclear whether this referred to a within-group or between-group change.¹³ The methodology used to establish this threshold remains unclear. It is uncertain whether this value can reliably define the minimal important difference (MID) value, which represents the smallest change in an outcome measure that patients perceive as beneficial or meaningful.

What Is Cerliponase Alfa?

Cerliponase alfa, a recombinant form of the human TPP1 enzyme, is designed to replace the missing or deficient TPP1 enzyme in patients with CLN2 disease.⁸ Clinicians administer cerliponase alfa directly into the central nervous system via intracerebroventricular (ICV) infusion.⁸ The standard regimen involves a 300 mg dose (adjusted for younger children) infused over approximately 4 hours, every 2 weeks.⁸ Cerliponase alfa is associated with potential AEs, such as pyrexia (fever), vomiting, seizures, and hypersensitivity reactions, among others.¹⁴ The ICV delivery system also carries potential risks, particularly device-related complications such as infections, which may require antibiotic treatment or device replacement.¹⁴ It is important to note that while enzyme replacement therapy aims to slow disease progression, it does not reverse existing brain damage or cure the disease.¹⁵ Early diagnosis and treatment of CLN2 disease are therefore vital to preserve function and slow decline for as long as possible.¹⁶

Policy Issues

Cerliponase alfa (Brineura) was previously recommended for reimbursement (with conditions) by the Canadian Drug Expert Committee (CDEC) in May 2019 as monotherapy for patients with CLN2 disease.¹⁷ Recommended initiation criteria required a confirmed CLN2 disease diagnosis through TPP1 enzyme testing and genetic testing, with the patient scoring a minimum of 1 in both motor and language domains and a combined motor-language score of 3 or more on the CLN2 Clinical Rating Scale, based on the eligibility criteria of the pivotal single-arm trial. Discontinuation was recommended when the combined motor-language score decreased by 2 or more points, or reached zero after 2 consecutive 24-week assessments, indicating functional decline or complete loss of function, based on the stopping criteria of the pivotal single-arm trial.¹⁷ Drug plans have requested an updated review of the evidence to inform their discontinuation criteria.

Policy Question

What new evidence exists to inform the discontinuation criteria for cerliponase alfa (Brineura) since the 2019 recommendation by CDEC?

Purpose

The objective of this evidence review is to evaluate studies that have become available since the 2019 recommendation by CDEC on the benefits and harms of cerliponase alfa, compared to placebo or best supportive care, in pediatric patients with CLN2 disease. We also aim to identify and summarize relevant evidence-based recommendations published after 2019 about the use of cerliponase alfa in pediatric patients with CLN2 disease.

Research Questions

To address the policy question about evidence to inform the discontinuation criteria for cerliponase alfa, the ideal approach would involve clinical studies comparing the benefits and harms of discontinuing versus continuing treatment among patients with CLN2 disease who are already receiving the therapy. Specifically, such studies would assess patient-important outcomes between those who stopped treatment and those who continued.

However, our preliminary search did not identify any studies meeting these criteria. In the absence of direct evidence, we reviewed indirect evidence by examining studies on the benefits and harms of cerliponase alfa that have become available since the 2019 recommendation by CDEC, as well as evidence-based clinical practice guidelines. Although clinical studies or guidelines may not directly define discontinuation criteria, information on treatment benefits, harms, and evidence-based recommendations may help support these decisions.

The following research questions were identified to address the policy question:

1. What is the clinical effectiveness and safety of cerliponase alfa versus best supportive care, placebo, or no treatment (if no comparative evidence) for pediatric patients with CLN2 disease, based on studies published since 2019?

2. What are the evidence-based recommendations published since 2019 regarding the use and administration of cerliponase alfa for pediatric patients with CLN2 disease?

Methods

Rapid review methodology was used to provide drug programs with timely and pertinent evidence to inform their decision-making.

Literature Search Methods

An information specialist conducted a literature search on key resources including MEDLINE and Embase via Ovid, the Cochrane Database of Systematic Reviews, the International HTA Database, the websites of health technology assessment (HTA) agencies in Canada and major international HTA agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevance. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concept was cerliponase alfa. The search was completed on April 11, 2025, and limited to English-language documents published since January 1, 2019. We limited the review to English-language studies due to resource constraints and published studies since the last 2019 review to align with the scope of the policy question. Only published, peer-reviewed, or publicly accessible studies were included to enhance transparency and reproducibility.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria

AE = adverse event; CLN2 = neuronal ceroid lipofuscinosis type 2; RCT = randomized controlled trial; SAE = serious adverse event; vs. = versus; WDAE = withdrawal due to adverse event.

Note: We considered a review to be systematic if it included the following elements: an objective and research question(s), indications that evidence was searched for in a systematic way (e.g., information on 1 or more of the following: names of databases, search platforms or engines, search date, keywords, or search strategy), and inclusion and exclusion criteria. We considered a guideline to be evidence-based if a systematic search of the literature was undertaken and a guideline panel was involved in informing the recommendations.

Exclusion Criteria

We excluded studies if they did not meet the selection criteria outlined in Table 1, if they were duplicate publications, or if they were published before the 2019 recommendation by CDEC. We excluded all abstracts, including conference abstracts, and did not consider data presented solely in abstract form (e.g., subgroup analyses). We also excluded letters to the editor, commentaries, opinion pieces, narrative reviews, book chapters, publications that were not in English, and guidelines lacking clear methodology.

Critical Appraisal of the Individual Studies

One reviewer extracted data aligned with the research questions and composed a narrative summary of the findings from the included studies. One reviewer critically appraised the methodological quality of included studies using the Downs and Black checklist¹⁸ for primary studies and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument¹⁹ for clinical practice guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively. We considered the findings of the critical appraisals when summarizing study results and drawing conclusions.

Engagement

A call for input on the project scope from interested parties was issued at project initiation through our weekly newsletter and on our website.

Clinical Expert Engagement

Two clinical experts with expertise in the diagnosis and management of patients with CLN2 disease were consulted during our review. Both experts provided input on the project protocol, including the proposed scope, and refinement of the review. The experts also reviewed and provided feedback on the draft report, offering clinical context and interpretation of the evidence, particularly regarding the relevance and applicability of clinical outcomes to the management of CLN2 disease in practice. Their input was used to help inform the interpretation of findings and the identification of key limitations.

Engagement With People With Lived Experience

Semistructured interviews were conducted virtually with people who were willing to share their lived experiences with cerliponase alfa and CLN2 disease. Five caregivers and 1 patient responded to questions about disease history, impact of diagnosis on daily life, treatment decisions, goals of care, and priority health outcomes. Four caregivers and 1 patient had direct experience with cerliponase alfa as a treatment; 1 caregiver’s child had not been treated with cerliponase alfa but the caregiver had extensive knowledge of cerliponase alfa.

Recordings and transcripts generated from the interviews were used by a Canada’s Drug Agency (CDA-AMC) Engagement Officer to summarize patient and caregiver insights. Participants reviewed their interview summaries for accuracy. The summaries were then consolidated and themes were reported. The results of the final report were shared and discussed with participants before the publication of this report.

Summary of Engagement With People With Lived Experience

The people with lived experience who participated in our interviews shared their journeys with CLN2 disease, from the onset of symptoms through to diagnosis and treatment, with parents describing the realities of caring for children with a rare, progressive illness. The long process of obtaining and coming to terms with a CLN2 disease diagnosis was universally portrayed as extremely stressful and emotionally devastating, with life-changing impacts to individuals and families. Parents actively researched and pursued treatment and supportive care options, with many transitioning into full-time caregiving immediately after their child's diagnosis. They expressed that the pursuit of any medical intervention was driven by the desire to optimize their child’s QoL; preserve their dignity; and maintain their happiness, safety, and well-being.

For some families, the ability to promptly begin treatment with cerliponase alfa was constrained by drug availability due to regulatory challenges, limited access to clinical trials, and trial eligibility criteria. The parents of children for whom cerliponase alfa was indicated and initiated noted reduced frequency of seizures and a slower decline in motor skills. While they acknowledged that the medication was not curative, it was credited with extending periods of symptom stability, helping to sustain an enhanced QoL, and prolonging survival. Parents described the financial strain of managing CLN2 disease, as caregiving responsibilities often made paid employment difficult while various medical expenses and treatment costs resulted in substantial out-of-pocket spending. Many made major life adjustments to accommodate the economic burden of the disease.

A summary of the engagement with people with lived experience using the Guidance for Reporting Involvement of Patients and the Public (GRIPP2) framework is provided in Appendix 1, Table 2.

Summary of Input From Patient or Clinician Groups or Industry

No submissions were received from patient or clinician groups. Input was received from BioMarin Pharmaceutical, the manufacturer of cerliponase alfa. The manufacturer agreed with the proposed project scope but suggested its expansion to include real-world evidence sources, citing the rarity of CLN2 disease.

The manufacturer submitted references for consideration, including publications, conference abstracts, and summaries from unpublished clinical study reports. All references were screened against predefined inclusion criteria. Several studies had already been identified through the literature search, while others were excluded for not meeting inclusion criteria. Additionally, some submitted data were not included in the review due to a lack of detailed methodologies. Additionally, the manufacturer provided clinician statements and a summary of select discontinuation criteria used in international jurisdictions.

Summary of Engagement With Clinical Experts

According to 2 clinical experts, disease progression and the preferences of patients, caregivers, or families play a crucial role in decisions about discontinuing treatment. The expert suggested treatment may be discontinued if the Clinical Rating Scale (Hamburg) score reaches 0 (complete loss of function) and there is significant caregiver burden, or if the patient experiences repeated central nervous system infections, requiring prolonged hospital admissions and treatment. Other factors that may lead to discontinuation include the need for major procedures, worsening seizures, or deterioration in cognitive function.

Summary of Evidence

Quantity of Research Available

We identified a total of 183 citations in the literature search. After screening titles and abstracts, we excluded 157 citations and retrieved 26 potentially relevant records from the electronic search for full-text review. We also retrieved 9 potentially relevant records from the grey literature search for full-text review. Of these potentially relevant records (35), we excluded 30 for various reasons (refer to Appendix 3 for excluded studies and reasons for exclusion) and included 3 primary studies with natural history controls and 2 clinical practice guidelines that met the inclusion criteria. Given that we identified primary studies with historical controls, we excluded single-arm studies and case series without a control group. We also excluded HTA reports, as these are typically developed by agencies focused on local resource allocation and cost-effectiveness.

Figure 1 (Appendix 2) presents the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)²⁰ flow chart of the study selection. We also screened potentially relevant findings from ongoing clinical studies. No results were available at the time of review. These ongoing clinical studies are listed in Table 3 under the ongoing studies category. We did not find any systematic reviews or randomized controlled trials (RCTs) that met our inclusion criteria.

Summary of Study Characteristics

Primary Studies

Three primary studies^21-23 assessed the effectiveness and safety of cerliponase alfa compared to untreated natural history controls in children with CLN2 disease. Schulz et al. (2025)²² conducted a real-world, multicentre study using the DEM-CHILD registry, comparing prospectively collected data from 21 children treated with cerliponase alfa (whose data were collected prospectively, with a mean follow-up of 106.7 weeks) to 21 matched untreated controls (whose data were collected retrospectively, with a mean follow-up of 76.1 weeks). The study adjusted for baseline combined motor-language score, age, sex, and genotype when analyzing motor-language function outcomes. In a separate study, Schulz et al. (2024)²³ reported on the long-term extension (up to 240 weeks) of a multicentre, open-label single-arm study across Germany, Italy, the UK, and the US, including 24 patients treated with cerliponase alfa and 42 untreated patients from the DEM-CHILD database. The study adjusted for baseline combined motor-language score, age, genotype, and sex in assessing both motor-language function and mortality outcomes. Estublier et al. (2021)²¹ performed a retrospective review of medical records for 8 children treated with cerliponase alfa at 3 hospitals in France (with a mean follow-up of 26 months), compared to historical untreated patients (unclear sample size in this group) from a previous study.⁷ The study did not perform any adjusted analyses for the reported outcomes. In all studies, treated patients received cerliponase alfa via intracerebroventricular infusion at a dose of 300 mg every 2 weeks.

Two studies^22,23 used untreated patients from the DEM-CHILD registry as historical controls. One study²¹ did not report the key details of its control group such as the functional assessment scales used and the sample size. In 1 study,²³ the baseline motor-language score for the natural history cohort was defined as the first score of less than 6 occurring at or after 36 months of age; 2 studies^21,22 did not report on the definition of baseline motor-language score. Details regarding the untreated patients were not reported directly but instead referenced in a separate study.⁷ Based on the external study,⁷ before the development of the motor-language CLN2 Clinical Rating Scale — which was created specifically for the Brineura clinical trials — the motor-language functions of patients in the historical control group were likely assessed using the Hamburg scale. In that study, disease progression was tracked longitudinally in 67 patients. Among the 41 patients with complete assessments across the disease course, motor-language scores on the Clinical Rating Scale (adapted from the Hamburg scale) declined rapidly, from normal (score of 6) to no function (score of 0), at an average decline rate of 1.81 points per year (95% confidence interval [CI], 1.50 to 2.12) over approximately 30 months.

The assessed outcomes included functional outcomes measured by the CLN2 Clinical Rating Scale and AEs in all 3 included studies.^21-23 Schulz et al. (2024)²³ also assessed mortality; MRI changes; biomarkers; HRQoL measured by the PedsQL Parent Report for Toddlers, PedsQL Family Impact Module, and CLN2 Disease-Specific Quality of Life dimension scores; and development milestones measured by the Denver II Developmental Scale Age Equivalent Performance. In this evidence review, we summarized the functional outcomes, mortality, HRQoL measures, and AEs.

In 1 study,²³ HRQoL was assessed every 24 weeks using the PedsQL Parent Report for toddler assessment (21 items across 4 dimensions) and the PedsQL Family Impact Module (36 items across 5 dimensions), both of which were scored on a 0 to 4 Likert scale and transformed to a 0 to 100 scale, with higher scores indicating better HRQoL or better family functioning.^12,24 A CLN2-specific QoL tool developed by the cerliponase alfa manufacturer (BioMarin) included 28 items across 6 dimensions. Scoring for the CLN2-specific QoL tool was performed analogously to that for PedsQL, according to the included study.²³ The study did not report MID values and recall periods for all HRQoL measures.²³ In another study,²⁴ the clinically important difference for within-group change was defined using a distribution-based method for each domain. The distribution-based clinically important differences were reported as follows: seizures (9.08), sleep (12.94), behaviour (6.79), and daily activities (7.67).

Evidence-Based Guidelines

Two clinical guidelines^25,26 provide recommendations for the diagnosis and management of CLN2 disease. In this evidence review, we focus on using enzyme replacement therapy with cerliponase alfa to manage CLN2 disease. Sampaio et al. (2023)²⁵ developed a guideline to inform the management of CLN2 disease in Brazil. The guideline was informed by a literature review using PubMed, Embase, and SciELO, but the search time frame was not clearly reported. Mole et al. (2021)²⁶ developed an international guideline based on 2 independent systematic reviews conducted in 2019; the search was conducted from PubMed, Google Scholar, and internal databases.²⁶ Both guidelines^25,26 graded the evidence using the Oxford Centre for Evidence-Based Medicine (OCEBM) levels and used structured or modified Delphi processes to reach consensus among a guideline panel of experts. In the guideline developed in Brazil,²⁵ the development group included 9 child neurologists, 1 of whom was also a medical geneticist. The other guideline²⁶ involved a panel of 41 experts who responded to a questionnaire, comprising pediatric neurologists (54%), metabolic specialists (20%), geneticists (9%), neurosurgeons (2%), pediatricians (6%), and others (9%).

Appendix 4 presents additional details regarding the characteristics of the included studies and guidelines.

Summary of Critical Appraisal

Primary Studies

One study²² demonstrated methodological rigour through the use of matched historical controls and appropriate statistical methods; however, it lacked blinding, had a small sample size (n = 21 in each group), and applied retrospectively collected data for controls with different follow-up durations than the intervention group. The small sample size (n = 21 per group) limits the precision of effect estimates and the ability to generalize the results to the broader population of people with CLN2 disease. The use of retrospectively collected data for the control group, with different follow-up durations compared to the intervention group, raises concerns about bias due to confounding and inconsistent outcome measurement.

The extension²³ of the multicentre, open-label, single-arm study was registered and well documented, with detailed outcome reporting. However, it also relied on historical controls with unclear baseline characteristics, lacked blinding, and did not perform a formal sample size calculation. These issues may contribute to bias due to residual confounding and limit the internal validity of the findings. The absence of data on HRQoL and AEs in the control group further restricted the study’s ability to inform on these outcomes, which are important to patients and decision-makers. There was a lack of detailed reporting on missing outcome data. For example, HRQoL scores were missing at study completion for 3 out of 23 participants (13%) to 6 out of 23 participants (26%) across various domains, excluding the “feeding with gastrostomy tube” domain, which was not applicable to all participants. No AE data were reported for the control group. It is also unclear whether patients with more severe disease were excluded from HRQoL assessment, which could potentially lead to an overestimation of the observed improvement and further reduce confidence in the results.

The remaining retrospective study²¹ had several limitations: it involved a very small sample size (n = 8), lacked clear inclusion and exclusion criteria, did not match controls, and did not apply any formal statistical comparisons. Additionally, the intervention details and AE severity were insufficiently reported.²¹ These limitations severely limit the interpretability and reliability of the findings. The absence of methodological safeguards increases the risk of bias due to confounding, selection bias, and reporting bias.

All 3 studies^21-23 had small sample sizes and lacked concurrent control groups, which limits the precision and generalizability of their findings. The extension study²³ of a multicentre, open-label, single-arm study did not implement blinding; in the observational studies, patients were aware of the treatment they received, which may have influenced outcome reporting. Two studies^22,23 attempted to reduce confounding resulting from differences in prognostic factors and treatment effect modifiers across the 2 cohorts by matching patients who received treatment with historical controls based on prognostic factors such as age, baseline motor-language scores, and genotype. They applied this matching either within the main analysis or as part of a sensitivity analysis.^22,23 Although this approach improved comparability between groups, residual confounding likely remained, such as differences in diagnostic methods or supportive care or differences in any additional characteristics that the authors were unable to match. The historical control groups lacked data on HRQoL measures and AEs,^22,23 which limited the external validity of the findings.

All studies did not clearly report how functional scores were assessed for patients in the historical control group.^21-23 It is assumed that the control group’s scores were likely evaluated using the Hamburg scale.⁷ Although the CLN2 Clinical Rating Scale was adapted from the Hamburg scale, the differences in category descriptions between the CLN2 Clinical Rating Scale and Hamburg scale may contribute to bias in the comparison between patients treated with cerliponase alfa and the historical controls.

Evidence-Based Guidelines

Both guidelines^25,26 clearly defined their objectives, target populations (patients with CLN2 disease), and intended users (clinicians). Both guidelines^25,26 searched for relevant evidence and then reached consensus to formulate recommendations. Both guidelines^25,26 conducted literature searches, but the details of the searches were not provided. However, 1 guideline²⁶ did not search Embase, potentially missing relevant evidence due to unclear or incomplete searches.

Both guidelines^25,26 were developed by a team of clinical experts. However, it is uncertain whether a methodology expert was involved in the development of the 2 guidelines. One of the guidelines²⁶ included a patient advocate to seek the views or preferences of the target population. It is unclear whether the perspectives or preferences of the target population were sought or had an influence on the recommendations in the other guideline.²⁵ Therefore, the recommendations regarding cerliponase alfa may not adequately reflect the values and preferences of patients or caregivers.

The 2 guidelines^25,26 used OCEBM criteria to assess the certainty of the evidence. The 2 guidelines used different labels to indicate the level of evidence. For example, 1 guideline used “1b” or “5,” while the other used “B,” “C,” or “D.” However, neither guideline clearly explained what each level of evidence meant.^25,26 The links between the recommendations and the supporting evidence and the strength of recommendations were also unclear in the 2 guidelines.^25,26 Both guidelines^25,26 disclosed the competing interests of their development group. However, several authors in the guidelines had received research grants from industries (e.g., BioMarin), and it is unclear how they addressed these competing interests.^25,26 It is unclear if the competing interests impacted the development of recommendations. One guideline²⁶ provided specific, easily identifiable recommendations, while the other guideline’s recommendations were less clearly presented.²⁵

Appendix 5 presents additional details regarding the strengths and limitations of the included studies and guidelines.

Summary of Findings

Based on the 3 primary studies^21-23 and 2 evidence-based clinical practice guidelines^25,26 included in this evidence review, we have summarized the reported data available since 2019 on the effectiveness and safety of cerliponase alfa in pediatric patients, and relevant recommendations for its use based on guidelines published since 2019. New evidence from published clinical studies since the 2019 review is consistent with the previous clinical review report.¹²

One²³ of the 3 primary studies extended a previous 48-week, single-arm, open-label, multicentre, dose-escalation study²⁷ that compared outcomes of patients treated with cerliponase alfa with historical controls. The original study reported that cerliponase alfa was associated with less decline in motor and language function scores compared with no treatment.²⁷ The extension study²³ suggested that treatment with cerliponase alfa continued to slow CLN2 disease progression over an average of more than 5 years (240 weeks), with safety events that were expected and reported as manageable by the study authors.²³

Appendix 6 presents the summary of findings by different outcomes.

Clinical Effectiveness of Cerliponase Alfa Compared With Untreated Natural History Controls

Unreversed Function 2-Point Decline or a Score of Zero in the Motor-Language Domain on the CLN2 Clinical Rating Scale (Indicating a Noticeable Worsening or Complete Loss of the Person's Ability in Motor and Language Domains, Without Any Recovery)

Two studies^22,23 reported that cerliponase alfa was associated with a reduced hazard of experiencing an unreversed 2-point decline or a score of zero in the motor-language domain on the CLN2 Clinical Rating Scale compared with untreated historical controls, with a mean follow-up of 106.7 weeks in 1 study²² and up to 240 weeks of follow-up in the other study.²³

Two studies^22,23 also reported that cerliponase alfa was associated with a reduced hazard of reaching a score of zero in the motor-language domain of the CLN2 Clinical Rating Scale, compared with untreated historical controls, with a mean follow-up of 106.7 weeks in 1 study and up to 240 weeks of follow-up in the other study.

When the motor and language domains were analyzed separately, 1 study²³ (with up to 240 weeks of follow-up) reported that cerliponase alfa was associated with a reduced hazard of experiencing an unreversed 2-point decline or a score of zero compared with untreated historical controls for both domains.

Rate of Function Decline

Two studies^22,23 reported that patients treated with cerliponase alfa experienced a slower rate of function decline in the CLN2 motor-language score, compared with untreated historical control data, with a mean follow-up of 106.7 weeks in 1 study and up to 240 weeks of follow-up in the other study.

One study (with up to 240 weeks of follow-up)²³ observed similar results when analyzing the motor and language domains separately.

Two studies^21,23 reported that patients treated with cerliponase alfa had higher mean CLN2 Clinical Rating Scale motor-language scores at various time points (week 145, week 289, or their last evaluation) compared with the untreated historical cohort. However, both studies^21,23 presented the data descriptively and did not perform any statistical tests to assess between-group differences.

One study (with up to 240 weeks of follow-up)²³ found smaller changes from baseline across 4 individual CLN2 Clinical Rating Scale domains (i.e., motor, language, vision, and seizures), suggesting a slower functional decline over time in the treatment group compared with the untreated historical cohort. However, the study²³ presented the data descriptively and did not perform any statistical tests to assess between-group differences.

Mortality

No deaths were reported among patients treated with cerliponase alfa in the 3 included studies,^21-23 with up to 240 weeks of follow-up in 1 study.²³

One study (with up to 240 weeks of follow-up)²³ found that treatment with cerliponase alfa was associated with a reduced hazard of death compared to untreated historical controls. The study adjusted for genotype and sex in the unmatched analysis, and further accounted for baseline motor-language score and baseline age in the matched analysis.

One study (with a mean follow-up of 106.7 weeks)²² reported no deaths in the cerliponase alfa group, while 6 deaths occurred in the untreated historical control group (n = 21 for both intervention and control groups). The study did not perform statistical testing for the mortality outcome.

HRQoL Measures

• HRQoL measures were not available for patients in the untreated historical control group.²³

• The extension study²³ of a multicentre, open-label, single-arm study with up to 240 weeks of follow-up reported the HRQoL results for patients treated with cerliponase alfa:

  • In the PedsQL Parent Report for Toddlers, the largest HRQoL decline was observed in physical functioning, followed by school functioning and social functioning, and a slight improvement in emotional functioning at study completion compared to baseline. A decline in within-group HRQoL scores indicates a worsening QoL over time, while an increase reflects better HRQoL.

  • In the PedsQL Family Impact Module, slight mean within-group changes were observed at the study completion compared to baseline.²³

  • In the CLN2 disease-specific HRQoL instrument, within-group changes in seizure scores improved,²⁴ while a within-group change in daily activity scores declined at study completion compared to baseline.²⁴ For sleep, behaviour, and feeding domains, slight mean within-group changes were observed at study completion compared to baseline.²⁴

Caregiver Burden Using Validated Scales

No studies were identified that met our inclusion criteria and reported on caregiver burden measures.

Safety of Cerliponase Alfa Compared With Untreated Natural History Controls

Safety data were not available for patients in the untreated historical control group in all 3 included studies.^21-23

Any Treatment-Emergent AEs

Two studies^22,23 reported treatment-emergent adverse events, with the number of patients who experienced 1 or more AEs reported as 16 out of 24 (66.7%) in 1 study and 24 out of 24 (100%) in the other.

One study²² reported that 7 out of 24 patients (29%) experienced AEs that led to hospitalization.

AEs reported for at least 50% of patients in any of the included studies^21-23 involved upper respiratory tract infection, pyrexia or fever, vomiting, seizure, rhinitis, gait disturbance, dysphagia, constipation, device-related infections, and device end of service.

Any Serious AEs

Two studies^22,23 reported any serious adverse events (SAEs), with the number of patients who experienced 1 or more SAEs reported as 4 out of 24 (17%) in 1 study and 21 out of 24 (88%) in the other.

One study²² that included 24 patients treated with cerliponase alfa reported 4 SAEs of grade 3 or grade 4 severity, all of which led to hospitalization.

SAEs reported in more than 1 participant included²³ product issues (device end of service, device leakage, device malfunction), hypersensitivity, device-related infections, upper respiratory tract infections, dysphagia, gastroenteritis, pleocytosis, dental caries, device deployment issues, epilepsy, bacterial pharyngitis, pyelonephritis, and pyrexia.

Withdrawals Due to AEs

No withdrawals from treatment due to AEs were reported in the 3 included studies.^21-23

Deaths Due to AEs

No deaths due to AEs were reported in the 3 included studies.

Subgroups of Interest

No studies conducted subgroup analyses based on disease severity at treatment initiation, time of symptom onset, or patient age group. Some patients from the included studies^21-23 that were relevant to the disease severity subgroup included the following:

• One study²² reported 5 matched pairs with a baseline motor-language score of 2 or lower. Among them, 1 patient maintained their score, and 2 experienced slower disease progression compared to their matched natural history controls, as measured by motor and language scores. The study also presented patient-level observations of motor and language scores, noting that the results were consistent across different ages at treatment initiation (< 3 years, 3 years to < 4 years, 4 years to < 5 years, 5 years to < 6 years, and ≥ 6 years) as well as across baseline motor and language scores (range, 2 points to 6 points).²²

• Another study²³ included 1 patient with a baseline motor-language score of 1; this patient maintained their score while the matched natural history controls showed a decline.

• A third study²¹ in patients in France (n = 8) included 3 patients with baseline motor-language scores of 2 or lower. All 3 patients experienced a 1-point decline in motor-language score at their final evaluation (mean follow-up: 26 months).

Recommendations for Using Cerliponase Alfa in Patients With CLN2 Disease

Two evidence-based guidelines^25,26 provided the recommendations for using enzyme replacement therapy (cerliponase alfa) in patients with CLN2 disease.

Patient Eligibility

Symptomatic patients with CLN2 disease: Both guidelines recommended enzyme replacement therapy.^25,26 However, 1 guideline aimed at patients in Brazil²⁵ specified that patient eligibility for treatment with enzyme replacement therapy should be children aged 3 years or younger with a Clinical Rating Scale score of 3 or higher, while the other guideline²⁶ did not impose any age-based or score-based restrictions.

Presymptomatic patients with CNL2 disease: Enzyme replacement therapy is recommended for genetically confirmed cases by the guideline aimed at patients in Brazil.²⁵ However, the optimal timing remains uncertain due to the absence of trial data.²⁵

Advanced CLN2 disease (e.g., Clinical Rating Scale score less than 3): The guideline aimed at patients in Brazil stated that no clear benefit of enzyme replacement therapy has been demonstrated for patients with advanced CLN2 disease (i.e., Clinical Rating Scale below 3).²⁵

Patients with atypical (nonclassical) CLN2 disease: Enzyme replacement therapy may be initiated after diagnosis, exclusion of contraindications, and shared decision-making with the patient or caregivers.²⁶

Dosage and Administration

Setting: Perform infusions in a sterile, isolated room with minimal personnel and continuous monitoring. A hospital ward is acceptable if no infectious patients are present.²⁵

A multidisciplinary team — including a child neurologist, neurosurgeon, pediatrician, and nurse — should oversee the procedure.²⁵

Premedication: Administer an antihistamine 30 minutes before infusion to reduce adverse effects.²⁵

Dose: 300 mg (or age-appropriate dose) every 2 weeks via ICV infusion over 4 hours.^25,26

Device handling:

• Use a permanent ICV catheter (e.g., Ommaya reservoir) with a syringe infusion pump.²⁵

• A very experienced pediatric neurosurgeon should place the catheter under general anesthesia.²⁶

• Only trained personnel should access the device to minimize complications.^25,26

Treatment Discontinuation Criteria

The evidence-based clinical practice guideline for patients in Brazil was unable to identify high-quality evidence to support a recommendation on discontinuation criteria for cerliponase alfa.²⁵

Most dosing and administration recommendations or statements were from the guideline aimed for patients in Brazil.²⁵

Limitations

The rapid review methodology used in this review has several limitations that may affect the interpretation of our findings. Study selection, data extraction, and critical appraisal were conducted by a single reviewer, which may increase the risk of errors, bias, and the potential omission of relevant studies. The restricted search strategy excluded studies published before 2019, limiting the comprehensiveness of the evidence base. We also did not perform detailed assessments of risk of bias or evaluate the certainty of the evidence, which limits our ability to contextualize the benefits and harms of cerliponase alfa in children with CLN2 disease. For HRQoL and AEs, data were only available from the treatment arms of the included studies challenging the review team’s ability to draw causal conclusions for these outcomes.^21-23 We did not comprehensively assess whether other single-arm studies reported these outcomes in this patient population. We also did not conduct a comprehensive search for evidence on the psychometric properties or MID values of the reported outcome measures, as this was beyond the scope of the review. The limited availability of such information may affect the ability to fully contextualize the findings.

In this evidence review, we did not identify any systematic reviews, RCTs, or studies with concurrent controls that evaluated the effectiveness and safety of cerliponase alfa. Although we found 3 primary studies,^21-23 1 was an extension of a single-arm trial with up to 240 weeks of follow-up,²³ 1 was a retrospective study²¹ with significant reporting limitations that restricted our ability to interpret its findings. For instance, while the body of evidence suggests that cerliponase alfa may contribute to improved seizure control, this conclusion is limited by the lack of seizure frequency data in control groups, absence of statistical analyses, and failure to adjust for key confounders such as antiseizure medication use, disease severity, and concurrent illnesses. However, given the rarity of the disease, it is unlikely that a randomized trial would be feasible.

We did not find any recommendations that directly addressed our policy question (i.e., treatment discontinuation criteria). One guideline²⁵ noted insufficient data to establish discontinuation criteria for cerliponase alfa in CLN2 disease. While 2 evidence-based guidelines provided recommendations for the use of cerliponase alfa, most were based on expert consensus.^25,26 Neither guideline clearly reported the evidence base for recommendations and the link between recommendations and supporting evidence was also unclear.^25,26 This suggests that the current recommendations may be influenced by clinical opinion in the absence of clear supporting evidence, highlighting the need for cautious interpretation.

We did not identify any evidence-based guidelines developed by Canadian organizations or involving experts from Canadian institutions. Given potential implementation challenges, such as access to treatment and unique patient characteristics in Canada (e.g., higher incidence or specific genotypes in Newfoundland),⁵ the applicability of these recommendations to Canadian settings remains uncertain.

The engagement of people with lived experience faced several limitations. Targeted outreach through specific patient groups restricted broader participation, potentially excluding other interested individuals. Additionally, time and resource constraints limited the number of participants who were able to take part in the project.

Conclusions and Implications for Decision- or Policy-Making

The people with lived experience who were interviewed identified improved QoL, the mitigation of disease progression, and the importance of ensuring patients’ comfort, safety, and happiness as key treatment outcomes for CLN2 disease. Caregivers stressed the importance of early access to treatment, transparent communication regarding treatment expectations, and patient-centred decision-making with their child’s health care providers regarding starting and stopping medications. The 2 clinical experts consulted highlighted that the preferences of patients, caregivers, and families play a crucial role in their decisions about discontinuing treatment.

The accounts of lived experience highlighted the profound impact of CLN2 disease on children and their families. Collectively, they underscore the critical importance of early and accurate diagnosis, as well as the need for comprehensive and coordinated care frameworks for families affected by CLN2 disease. The emotional toll of a CLN2 diagnosis is immense, with parents describing the devastating reality of caring for a child with a progressive illness while urgently seeking effective treatments. Financial hardship compounds these challenges, forcing many families to make difficult personal and economic sacrifices in their efforts to secure appropriate care and maintain their child's well-being. People with lived experience emphasized that while cerliponase alfa is not curative, it slows disease progression, stabilizes symptoms, prolongs life, and preserves QoL.

We identified 3 primary studies^21-23 with natural history controls and 2 evidence-based clinical practice guidelines^25,26 to answer our research questions. The evidence reviewed in this report largely aligns with the conclusions from the previous Reimbursement Review conducted in 2019.¹² More recent findings suggest that early initiation of cerliponase alfa in the disease course may help preserve or delay deterioration of motor-language function, particularly in patients with a motor-language score above 3 (some functional abilities are still preserved). One extension study²³ with up to 240 weeks of follow-up reported slower functional decline in motor, language, vision and seizure among patients treated with cerliponase alfa compared to historical controls. All studies^21-23 reported no deaths among patients treated with cerliponase alfa, while 2 studies^22,23 reported several deaths in historical control groups, including 1 study²³ with up to 240 weeks of follow-up. The emerging evidence on the potential benefit of cerliponase alfa in reducing seizures and mortality outcomes, while promising, has methodological limitations (e.g., results presented descriptively without statistical comparisons, historical controls with unclear baseline characteristics) that limit the ability to make direct inferences on the effects of cerliponase alfa.

Limited evidence from single-arm data²³ suggests that patients with CLN2 disease treated with cerliponase alfa experienced varying mean score changes in HRQoL measures, which were reported as important outcomes by families who shared their lived experiences. Some domains — such as emotional functioning and seizure control — showed improvement (indicating better HRQoL in these domains), while other domains — such as physical functioning and daily activities — declined (indicating worsening HRQoL in these domains) over time. Due to the noncomparative nature of the available data, causal inferences cannot be drawn (e.g., changes in HRQoL may be attributed to natural history, placebo effects, concurrent seizure medications, or the effects of cerliponase alfa).

AEs were common but generally manageable (as noted by the study authors) among CLN2 patients treated with cerliponase alfa.^21-23 No deaths or treatment withdrawals due to AEs were reported.

No studies were identified that met our inclusion criteria on caregiver burden measures. No studies conducted subgroup analyses based on disease severity at treatment initiation, time of symptom onset, or patient age group.

Two clinical guidelines^25,26 support the use of cerliponase alfa in symptomatic and genetically confirmed presymptomatic patients, or patients with atypical (nonclassical) CLN2 disease. The eligibility requirement of being aged at least 3 years, with a Clinical Rating Scale score of 3 or higher was inconsistently reported between the 2 guidelines.^25,26 One guideline²⁵ highlighted the lack of evidence for use in advanced disease (i.e., a motor-language score of ≤ 2). In alignment with the findings from the 3 identified primary studies,^21-23 1 guideline²⁵ highlighted a scarcity of data to inform treatment discontinuation.

It is important to note that CLN2 disease is an ultrarare disease, and it is unlikely that well-controlled randomized trials would be feasible in this population. While several new studies were identified and reviewed in this report, none directly compared the impacts of cerliponase alfa discontinuation on clinical outcomes or provided additional evidence to inform discontinuation criteria. One evidence-based guideline noted that there are insufficient data to establish such criteria. Given the complexity and progressive nature of CLN2 disease, both clinical experts and people with lived experience emphasized that decisions to initiate, continue, or discontinue cerliponase alfa should be made through a shared decision-making process involving clinicians, patients, and caregivers.

The discontinuation criteria from CDEC in 2019¹⁷ were informed by the stopping criteria of the pivotal trial, which is defined as a decrease of 2 or more points or a score of zero on the combined motor-language scale across 2 consecutive 24-week assessments, indicating functional decline or complete loss of function. The current review did not identify any new clinical evidence since the 2019 CDEC reimbursement recommendation that directly informs when treatment with cerliponase alfa should be discontinued.

Special thanks: CDA-AMC extends our special thanks to the individuals who shared their lived experience with the research team, as well as to patient organizations supporting those with CLN2 disease and their families. We thank Terri Gortnar, Mark Gortnar, Lori Brown, Leah Brochu, and Mike Brochu for providing input on the direction of the research, drawing from lived experience, and providing valuable contributions to this report. A very special thank you to Claire Gortnar, Josef Gortnar, Daniel Brown, and Neil Brochu.

References

1.UptoDate. Neuronal ceroid lipofuscinosis. 2024. Accessed April 29, 2025. https://www.uptodate.com/

2.Fietz M, AlSayed M, Burke D, et al. Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis. Mol Genet Metab. 2016;119(1):160-167. doi: 10.1016/j.ymgme.2016.07.011 PubMed

3.Schaefers J, van der Giessen LJ, Klees C, et al. Presymptomatic treatment of classic late-infantile neuronal ceroid lipofuscinosis with cerliponase alfa. Orphanet J Rare Dis. 2021;16(1):221. doi: 10.1186/s13023-021-01858-6 PubMed

4.Williams RE, Adams HR, Blohm M, et al. Management Strategies for CLN2 Disease. Pediatr Neurol. 2017;69:102-112. doi: 10.1016/j.pediatrneurol.2017.01.034 PubMed

5.Moore SJ, Buckley DJ, MacMillan A, et al. The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland. Clin Genet. 2008;74(3):213-22. doi: 10.1111/j.1399-0004.2008.01054.x PubMed

6.Specchio N, Pietrafusa N, Trivisano M. Changing Times for CLN2 Disease: The Era of Enzyme Replacement Therapy. Ther Clin Risk Manag. 2020;16:213-222. doi: 10.2147/tcrm.S241048 PubMed

7.Nickel M, Simonati A, Jacoby D, et al. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child Adolesc Health. 2018;2(8):582-590. doi: 10.1016/s2352-4642(18)30179-2 PubMed

8.Lewis G, Morrill AM, Conway-Allen SL, Kim B. Review of Cerliponase Alfa: Recombinant Human Enzyme Replacement Therapy for Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2. J Child Neurol. 2020;35(5):348-353. doi: 10.1177/0883073819895694 PubMed

9.Guelbert N, Espitia Segura OM, Amoretti C, et al. Classic and Atypical Late Infantile Neuronal Ceroid Lipofuscinosis in Latin America: Clinical and Genetic Aspects, and Treatment Outcome with Cerliponase Alfa. Mol Genet Metab Rep. 2024;38(no pagination). doi: 10.1016/j.ymgmr.2024.101060

10.Chang H, Soangra R, Bhola R, GrantBeuttler M, Wang RY. A long-term course of gait assessment in the atypical CLN2 patients along with ICV clerliponase alpha treatment. Mol Genet Metab. 2023;138(2):107048. doi: 10.1016/j.ymgme.2022.107048

11.Schulz A, Jain M, Butt T, et al. The challenges of living with and caring for a child or children affected by neuronal ceroid lipofuscinosis type 2 disease: In-Depth family surveys in the United Kingdom and Germany. J Inborn Errors Metab Screen. 2020;8:e20190013. doi: 10.1590/2326-4594-JIEMS-2019-0013

12.CADTH. Drug Reimbursement Review clinical guidance report: cerliponase alfa (Brineura) for CLN2 disease. 2019. Accessed April 28, 2025. https://www.cda-amc.ca/sites/default/files/cdr/clinical/sr0574-brineura-clinical-review-report.pdf

13.Wyrwich KW, Schulz A, Nickel M, et al. An Adapted Clinical Measurement Tool for the Key Symptoms of CLN2 Disease. J Inborn Errors of Metab Screen. 2018;6:2326409818788382. doi: 10.1177/2326409818788382

14.Ammendolia I, Sframeli M, Esposito E, et al. Adverse Reactions to the Orphan Drug Cerliponase Alfa in the Treatment of Neurolipofuscinosis Type 2 (CLN2). Pharmaceuticals (Basel). 2024;17(11):11. doi: 10.3390/ph17111513 PubMed

15.Radic Nisevic J, Kolic I, Kostanjski M, Kovacevic F, Prpic I. Early Symptoms and Treatment Outcomes in Neuronal Ceroid Lipofuscinosis Type 2: Croatian Experience. J Pers Med. 2024;14(8):24. doi: 10.3390/jpm14080783 PubMed

16.Augustine EF, Adams HR, de Los Reyes E, et al. Management of CLN1 Disease: International Clinical Consensus. Pediatr Neurol. 2021;120:38-51. doi: 10.1016/j.pediatrneurol.2021.04.002 PubMed

17.CADTH. Drug Expert Committee Recommendation: cerliponase alfa (Brineura) for CLN2 disease. May 23, 2019. Accessed April 28, 2025. https://www.cda-amc.ca/cerliponase-alfa

18.Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377-384. doi: 10.1136/jech.52.6.377 PubMed

19.Agree Next Steps Consortium. The AGREE II Instrument. AGREE Enterprise; 2017. Accessed April 29, 2025. https://www.agreetrust.org/wp-content/uploads/2017/12/AGREE-II-Users-Manual-and-23-item-Instrument-2009-Update-2017.pdf

20.Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-e34. doi: 10.1016/j.jclinepi.2009.06.006 PubMed

21.Estublier B, Cano A, Hoebeke C, et al. Cerliponase alfa changes the natural history of children with neuronal ceroid lipofuscinosis type 2: The first French cohort. Europ J Paediat Neurol. 2021;30:17-21. doi: 10.1016/j.ejpn.2020.12.002 PubMed

22.Schulz A, Schwering C, Wibbeler E, et al. Real-world clinical outcomes of patients with CLN2 disease treated with cerliponase alfa. Front Neurol. 2025;16:1516026. doi: 10.3389/fneur.2025.1516026 PubMed

23.Schulz A, Specchio N, de Los Reyes E, et al. Safety and efficacy of cerliponase alfa in children with neuronal ceroid lipofuscinosis type 2 (CLN2 disease): an open-label extension study. Lancet Neurol. 2024;23(1):60-70. doi: 10.1016/S1474-4422(23)00384-8 PubMed

24.Due C, Quinn J, Gissen P, et al. Psychometric Validation of the CLN2 Quality of Life Questionnaire in Participants with CLN2 Disease Treated with Cerliponase Alfa. Healthcare (Basel). 2024;12(22):08. doi: 10.3390/healthcare12222229

25.Sampaio LPB, Manreza MLG, Pessoa A, et al. Clinical management and diagnosis of CLN2 disease: consensus of the Brazilian experts group. Arq Neuropsiquiatr. 2023;81(3):284-295. doi: 10.1055/s-0043-1761434 PubMed

26.Mole SE, Schulz A, Badoe E, et al. Guidelines on the diagnosis, clinical assessments, treatment and management for CLN2 disease patients. Orphanet J Rare Dis. 2021;16(1):185. doi: 10.1186/s13023-021-01813-5 PubMed

27.Schulz A, Ajayi T, Specchio N, et al. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med. 2018;378(20):1898-1907. doi: 10.1056/NEJMoa1712649 PubMed

Appendix 1: Summary of Patient and Caregiver Engagement

Please note that this appendix has not been copy-edited.

Table 2: Reporting of Patient and Caregiver Engagement Using the GRIPP2 Framework

Appendix 2: Selection of Included Studies

Please note that this appendix has not been copy-edited.

Figure 1: PRISMA²⁰ Flow Chart of Study Selection

PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Appendix 3: List of Excluded Citations and Potentially Relevant Ongoing Studies

Please note that this appendix has not been copy-edited.

Table 3: Excluded Citations and Potential Relevant Ongoing Studies

Appendix 4: Characteristics of Included Studies

Please note that this appendix has not been copy-edited.

Table 4: Characteristics of the Included Primary Studies

AEs = adverse event; CLN2 = neuronal ceroid lipofuscinosis type 2; ERT = enzyme replacement therapy; HRQoL = health-related quality of life; NA = not applicable; NR = not reported.

Table 5: Characteristics of Included Guidelines

AGREE II = Appraisal of Guidelines for Research and Evaluation; ERT = Enzyme Replacement Therapy; HRQoL = health-related quality of life; OCEBM = Oxford Centre for Evidence-Based Medicine.

Appendix 5: Critical Appraisal of Included Studies

Please note that this appendix has not been copy-edited.

Table 6: Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist¹⁸

CI = confidence interval.

Table 7: Strengths and Limitations of Guidelines Using AGREE II¹⁹

AGREE II = Appraisal of Guidelines for Research and Evaluation II.

Appendix 6: Main Study Findings

Please note that this appendix has not been copy-edited.

Table 8: Summary of Findings by Outcome — Unreversed Function 2-Point Decline or a Score of Zero on CLN2 Clinical Rating Scale^a

CI = confidence interval; CLN2 = neuronal ceroid lipofuscinosis type 2; ERT = enzyme replacement therapy; HR = hazard ratio; NE = not estimable; NH = natural history; NR = not reported.

^aA study reported a 1-point change in the CLN2 Clinical Rating Scale motor-language score to be clinically meaningful, although the methodology behind this threshold is unclear and its validity as a minimally important difference remains uncertain.¹³

^bAn HR less than 1 indicates a benefit in favour of ERT.

^cSensitivity analyses using 3 matched variables (baseline age, motor-language score, and genotype) yielded results consistent with the primary analysis based on 2 variables (baseline age and motor-language score).

Table 9: Summary of Findings by Outcome — Unreversed Function Score of Zero in the CLN2 Clinical Rating Scale Motor-Language Score^a

CI = confidence interval; CLN2 = neuronal ceroid lipofuscinosis type 2; ERT = enzyme replacement therapy; HR = hazard ratio; NE = not estimable; NH = natural history; NR = not reported.

^aA study reported a 1-point change in the CLN2 Clinical Rating Scale motor-language score to be clinically meaningful, although the methodology behind this threshold is unclear and its validity as a minimally important difference remains uncertain.¹³

^bAn HR less than 1 indicates a benefit in favour of ERT.

Table 10: Summary of Findings by Outcome — Rate of Function Decline in CLN2 Clinical Rating Scale^a

CI = confidence interval; CLN2 = neuronal ceroid lipofuscinosis type 2 ; ERT = enzyme replacement therapy; MD = mean difference; NE = not estimable; NH = natural history; NR = not reported, SD = standard deviation.

^aA study reported a 1-point change in the CLN2 Clinical Rating Scale motor-language score to be clinically meaningful, although the methodology behind this threshold is unclear and its validity as a minimally important difference remains uncertain.¹³

^bAn MD greater than 0 indicates a benefit in favour of ERT.

Table 11: Summary of Findings by Outcome — Function Scores at Different Time Points in CLN2 Clinical Rating Scale^a

CLN2 = neuronal ceroid lipofuscinosis type 2 ; ERT = enzyme replacement therapy; NH = natural history; NR = not reported, SD = standard deviation.

^aA study reported a 1-point change in the CLN2 Clinical Rating Scale motor-language score to be clinically meaningful, although the methodology behind this threshold is unclear and its validity as a minimally important difference remains uncertain.¹³

^bMean (SD) change from baseline (the beginning of ERT) to the time point in patients with available measurements at both time points; in 1 study,²³ the baseline motor-language score for the NH cohort was defined as the first score of less than 6 occurring at or after 36 months of age; 1 study²¹ did not report on the definition for baseline motor-language score.

Table 12: Summary of Findings by Outcome — Mortality

CI = confidence interval; ERT = enzyme replacement therapy; HR = hazard ratio; NE = not estimable; NH = natural history; NR = not reported.

^aAn HR less than 1 indicates a benefit in favour of ERT.

Table 13: Summary of Findings by Outcome — Quality of Life for Patients Treated With ERT: PedsQL Parent Report for Toddlers

ERT = enzyme replacement therapy; SD = standard deviation.

^aMean change from baseline to study completion in patients with available measurements at both time points; higher score indicates better quality of life; minimal important difference: not reported.

Table 14: Summary of Findings by Outcome — Quality of Life for Patients Treated With ERT: PedsQL Family Impact Module

ERT = enzyme replacement therapy; SD = standard deviation.

Note: A higher score indicates better family functioning; minimal important difference: not reported.

^aMean change from baseline to study completion in patients with available measurements at both time points; HRQoL scores were missing at study completion for 4 out of 23 participants (17%) in various domains.

Table 15: Summary of Findings by Outcome — Quality of Life for Patients Treated With ERT: CLN2 Disease-Specific Quality of Life Dimension Scores^a

CLN2 = neuronal ceroid lipofuscinosis type 2; ERT = enzyme replacement therapy; G-tube = gastrostomy tube; NA = not applicable; SD = standard deviation.

^aA study reported distribution-based clinically important differences for several domains: seizures (9.08), sleep (12.94), behaviour (6.79), and daily activities (7.67).²⁴

^bMean change from baseline to study completion in patients with available measurements at both time points; higher score indicates better quality of lie; minimal important difference: not reported.

Table 16: Summary of Findings by Outcome — AEs for Patients Treated With ERT

AE = adverse event; ERT = enzyme replacement therapy; NA = not applicable; NR = not reported; SD = standard deviation; WDAE = withdrawal due to adverse event.

Table 17: Summary of Findings by Outcome — AEs for Patients Treated With ERT

ERT = enzyme replacement therapy; NR = not reported.

^aIncluding suspected infection.

Table 18: Summary of Findings by Outcome — SAEs for Patients Treated With ERT

ERT = enzyme replacement therapy; SAE = serious adverse event.

Table 19: Summary of Recommendations in Included Guidelines

CLN2 = neuronal ceroid lipofuscinosis type 2; ERT = enzyme replacement therapy; ICV = intracerebroventricular; LE = level of evidence; NR = not reported.

^aIn the discussion section of the guideline, the guideline author mentioned that ERT treatment should be discontinued in patients who are affected by another life-limiting condition or experience severe infusion-related adverse reactions that are not preventable or manageable.