On November 27, 2019, NICE issued a guidance which approved the limited use of Cerliponase alfa under a managed access agreement. After reviewing clinical trial data and expert analysis, NICE agreed that the treatment had a significant effect on slowing the progression of Neuronal Ceroid Lipofuscinosis Type 2 in children.
What is Neuronal Ceroid Lipofuscinosis Type 2 (CLN2)?
NCL is an extremely rare neurodegenerative disorder characterised by a progressive loss of motor functions, drug resistant seizures and loss of vision (Ninds.nih.gov, 2019). The pathology of the disease is most often associated with mutations of the CLN2 gene. The subsequent protein, TPP1, is highly expressed in bone marrow, placenta, the lung and lymphocytes. When fully processed and activated, the enzyme’s main function is as a protease in lysosomes, cleaving N-Terminal tripeptides from substrates (Pal et al., 2008). TPP1 has a reduced or no ability to breakdown proteins in CLN2, leading to an accumulation of lipopigments in lysosomes (Bennett and Rakheja, 2013). Whilst lipopigments accrete similarly throughout the body’s cells, cerebral neurons appear to be most affected (Anderson, Goebel and Simonati, 2013). Excessive build-up of these proteins results in atrophy of neurons, which is evident through magnetic resonance imaging of cerebral and cerebellar regions. Symptoms of CLN2 are usually evident around 2-4 years old, with patients not usually surviving beyond 8-12 years old.
How does Cerliponase alfa work?
Until the FDA approved the treatment in 2017, there was no specific treatment for NCL. The drug is an enzyme replacement therapy, which is administered directly to cerebrospinal fluid via an intracerebroventricular infusion. The administration of the drug allows the enzyme to reach cerebral neurons without having to cross the blood brain barrier. Cerliponase alfa, like TPP1, functions as a protease which cleaves tripeptides from larger proteins. Like TPP1, Cerliponase alfa is degraded via proteolysis, and therefore needs to be administered fortnightly. A 48-week trial of the treatment showed a significant reduction in disease progression, measured by motor-language scores, compared to the natural-history cohort (NCT01907087).
NICE managed access agreement approval and conditions
A quality-adjusted life year (QALY) analysis, based on assumptions of disease progression and effects of drug intervention, met the criteria for a QALY weighting of 3. Based on this figure, an incremental cost-effectiveness ratio (ICER) would likely be within the limit of what the NHS deems an acceptable use of resources for rare disease treatments. Due to the high cost of the drug, the uncertainties in clinical evidence, and lack of long-term disease progression data, the drug will be under a managed access under the agreement until a more robust economic evaluation can be made. A final guidance for use of the drug on the NHS will be upon the submission of further clinical data.
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Anderson, G., Goebel, H. and Simonati, A. (2013). Human pathology in NCL. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1832(11), pp.1807-1826.
Bennett, M. and Rakheja, D. (2013). The neuronal ceroid-lipofuscinoses. Developmental Disabilities Research Reviews, 17(3), pp.254-259.
Ninds.nih.gov. (2019). Batten Disease Fact Sheet | National Institute of Neurological Disorders and Stroke.[online]
Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Batten-Disease-Fact-Sheet [Accessed 10 Dec. 2019].
Pal, A., Kraetzner, R., Gruene, T., Grapp, M., Schreiber, K., Grønborg, M., Urlaub, H., Becker, S., Asif, A., Gärtner, J., Sheldrick, G. and Steinfeld, R. (2008). Structure of Tripeptidyl-peptidase I Provides Insight into the Molecular Basis of Late Infantile Neuronal Ceroid Lipofuscinosis. Journal of Biological Chemistry, 284(6), pp.3976-3984.