Changing Times for CLN2 Disease: The Era of Enzyme Replacement Therapy

Abstract

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a progressive neurodegenerative disease that results in early-onset, severe, progressive, neurological disabilities, leading to death in late childhood or early adolescence. Management has relied on symptomatic care, and supportive and palliative strategies, but the approval of the enzyme replacement therapy cerliponase alfa in the USA and Europe in 2017 brought different treatment opportunities. We describe the natural history of CLN2 disease, its diagnosis and management, and the preclinical and clinical development of cerliponase alfa. A PubMed search was undertaken for cerliponase alfa and rhTPP1 to identify preclinical and clinical studies. The hallmark-presenting symptoms of CLN2 disease are unprovoked seizures and a history of language delay, and progression involves motor dysfunction, and cognitive and visual decline. Cerliponase alfa has shown efficacy and tolerability in mouse and canine models of CLN2 disease when delivered intracerebroventricularly. Administration of cerliponase alfa in patients with CLN2 disease has led to significant reductions in the rate of decline of motor and language functions in comparison with a natural history population. The approval of cerliponase alfa has brought a new era for CLN2 disease, highlighting the need to understand different patterns of disease progression and clinical needs in treated patients.

Keywords: TPP1; cerliponase alfa; late infantile; neuronal ceroid lipofuscinosis type 2; seizures.

Figure 1

The presenting symptoms and progression of CLN2 disease. Reprinted from Lancet Child Adolesc Health; 2(8); Nickel M, Simonati A, Jacoby D, Lezius S, Kilian D, van de Graaf B, Pagovich OE, Kosofsky B, Yohay K, Downs M, Slasor P, Ajayi T, Crystal RG, Kohlschütter A, Sondhi D, Schulz A; Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: An observational cohort study; 582–590; Copyright © 2018 Elsevier Ltd. All rights reserved, with permission from Elsevier. Age ranges represent those typical of the classic late-infantile phenotype. The first circle indicates the age at which the period of rapid progression typically begins (3 years), and the second circle indicates the typical age at diagnosis (approximately 5 years). Atypical phenotypes of CLN2 disease can vary in age of onset, rate of progression, and disease manifestation. Abbreviation: CI, confidence interval.

Figure 2

Timeline showing the preclinical and clinical development of cerliponase alfa and the year of its approval in the USA and Europe. Abbreviations: CNS, central nervous system; ICV, intracerebroventricular; IT-L, intrathecal–lumbar.

Figure 3

Change from baseline in motor and language scores of the CLN2 Disease Clinical Rating Scale in matched pairs of patients treated with cerliponase alfa and historical controls. From N Engl J Med; Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschütter A; CLN2 Study Group; Study of intraventricular cerliponase alfa for CLN2 disease; 378(20); 1898–1907. Copyright © 2018 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.