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

Key Messages

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.