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.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests AS and MN have received payments to their institution as a study site according to clinical trial budget, medical writing support, honoraria, and travel support from BioMarin Pharmaceutical. EDLR has received salary support as the primary investigator and salary support for the research personnel, honoraria, and travel support from BioMarin Pharmaceutical and consulting fees from Zogenix. NS has received consulting fees from BioMarin Pharmaceutical, JAZZ Pharma, UCB, Takeda, and Angeun; honoraria from BioMarin Pharmaceutical, JAZZ Pharma, UCB, and Zogenix; travel fees from BioMarin Pharmaceutical and Jazz Pharma; and current research funding from the Italian Ministry of Health. PG has received payments to his institution as a study site according to clinical trial budget and honoraria and travel support from BioMarin Pharmaceutical. MT has received honoraria from BioMarin Pharmaceutical and current research funding from the Italian Ministry of Health. SCA has received research salary support from BioMarin Pharmaceutical, research effort support for a study of erenumab from Amgen, research effort support for a study of rimegepant from Pfizer, grant support for fellowship training from NINDS/Neuronext, and honoraria as associate editor from Pediatric Neurology. DJB and JPD have received contractor fees paid by BioMarin Pharmaceutical for analysing imaging data that appears in the paper. PS is an employee and stockholder of BioMarin Pharmaceutical. SB and AChe are employees of BioMarin Pharmaceutical. JLCP is an employee and stockholder of BioMarin Pharmaceutical and a scientific advisor for NPKUA. ACha, CS, EW, and LMW reported no conflicts of interest.