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LOS ANGELES – Intraventricular administration of cerliponase alfa seemed to slow the rate of motor and language decline in an open-label trial of 23 children with neuronal ceroid lipofuscinosis type 2 disease.
Neuronal ceroid lipofuscinosis type 2 disease (CLN2), a form of Batten’s disease, is a rare lysosomal storage disorder that causes progressive dementia in children. Patients have pathogenic variants in the gene encoding lysosomal enzyme tripeptidyl peptidase 1 (TPP1). Without functioning enzyme, lysosomal storage material accumulates in neurons throughout the CNS and retina.
Symptoms start at 2-4 years with seizures and language delays, followed by rapid motor, language, and cognitive declines, and blindness. Children die in early adolescence. Treatment is symptomatic; there are no approved therapies.
The idea of the study was to replace the enzyme in the CNS with cerliponase alfa, a recombinant form of TPP1. Twenty-four children aged 3-16 years received 30 mg, 100 mg, or 300 mg intraventricular infusions every 2 weeks during the dose-finding phase of the open-label trial; they were then switched to 300 mg infused over 4 hours every 14 days for at least 96 weeks. One child dropped out after the first dose in the study, but the others continued.
The investigators used Ommaya or Rickham ventricular reservoirs to deliver the enzyme, which were more convenient than intrathecal administration, said investigator Emily de Los Reyes, MD, a pediatric neurologist at Nationwide Children’s Hospital, Columbus, Ohio.
The primary outcome was the time until a 2-point decline on the motor and language scores of the CLN2 Clinical Rating Scale, with 0 representing no function and 6 representing normal function in both domains. The mean unadjusted rate of decline in the motor-language score per 48-week period was 0.27 points in treated patients, versus 2.12 points in 42 historical controls (P less than .001). The treatment difference at 96 weeks was about 3.3 points. There was also a decrease in seizure severity and frequency.
All but one child experienced convulsions, over two-thirds pyrexia, and almost two-thirds vomiting and hypersensitivity. About half developed upper respiratory tract infections, and about half had increased CSF white-cell counts. There were also cases of device leakage, and two children developed infections detected by CSF monitoring, without symptoms of meningitis. Both continued treatment after removal of the intraventricular device, followed by antibiotics, and device replacement.
Fourteen patients (58%) had at least one grade 3 adverse event, and there was one grade 4 event: status epilepticus deemed unrelated to the study. Side effects resolved on their own or responded to medical management. There were no deaths, study discontinuations, or dose reductions.
The mean age in the study was 60 months, about two-thirds of the patients were girls, and CLN2 diagnosis was confirmed by genotyping. Almost all the children had seizure histories. The majority were moderately advanced at baseline, with motor-language scores of 3 out of 6 in 11 patients.
An audience member asked Dr. de Los Reyes if there would be even more benefit by starting treatment before children became symptomatic. “I think all the neurologists in this group, we know that the earlier the treatment for rare diseases, the better the response,” she said.
The results were published simultaneously in the New England Journal of Medicine.
BioMarin Pharmaceutical funded the work, along with grants from the German Federal Ministry of Education and Research, the European Union’s Horizon 2020 Research and Innovation Program, and the National Institute for Health Research. Several authors were BioMarin employees. Dr. de Los Reyes is a consultant and reported a grant from the company.
SOURCE: Schulz A et al. N Engl J Med. 2018 Apr 24. doi: 10.1056/NEJMoa1712649.
LOS ANGELES – Intraventricular administration of cerliponase alfa seemed to slow the rate of motor and language decline in an open-label trial of 23 children with neuronal ceroid lipofuscinosis type 2 disease.
Neuronal ceroid lipofuscinosis type 2 disease (CLN2), a form of Batten’s disease, is a rare lysosomal storage disorder that causes progressive dementia in children. Patients have pathogenic variants in the gene encoding lysosomal enzyme tripeptidyl peptidase 1 (TPP1). Without functioning enzyme, lysosomal storage material accumulates in neurons throughout the CNS and retina.
Symptoms start at 2-4 years with seizures and language delays, followed by rapid motor, language, and cognitive declines, and blindness. Children die in early adolescence. Treatment is symptomatic; there are no approved therapies.
The idea of the study was to replace the enzyme in the CNS with cerliponase alfa, a recombinant form of TPP1. Twenty-four children aged 3-16 years received 30 mg, 100 mg, or 300 mg intraventricular infusions every 2 weeks during the dose-finding phase of the open-label trial; they were then switched to 300 mg infused over 4 hours every 14 days for at least 96 weeks. One child dropped out after the first dose in the study, but the others continued.
The investigators used Ommaya or Rickham ventricular reservoirs to deliver the enzyme, which were more convenient than intrathecal administration, said investigator Emily de Los Reyes, MD, a pediatric neurologist at Nationwide Children’s Hospital, Columbus, Ohio.
The primary outcome was the time until a 2-point decline on the motor and language scores of the CLN2 Clinical Rating Scale, with 0 representing no function and 6 representing normal function in both domains. The mean unadjusted rate of decline in the motor-language score per 48-week period was 0.27 points in treated patients, versus 2.12 points in 42 historical controls (P less than .001). The treatment difference at 96 weeks was about 3.3 points. There was also a decrease in seizure severity and frequency.
All but one child experienced convulsions, over two-thirds pyrexia, and almost two-thirds vomiting and hypersensitivity. About half developed upper respiratory tract infections, and about half had increased CSF white-cell counts. There were also cases of device leakage, and two children developed infections detected by CSF monitoring, without symptoms of meningitis. Both continued treatment after removal of the intraventricular device, followed by antibiotics, and device replacement.
Fourteen patients (58%) had at least one grade 3 adverse event, and there was one grade 4 event: status epilepticus deemed unrelated to the study. Side effects resolved on their own or responded to medical management. There were no deaths, study discontinuations, or dose reductions.
The mean age in the study was 60 months, about two-thirds of the patients were girls, and CLN2 diagnosis was confirmed by genotyping. Almost all the children had seizure histories. The majority were moderately advanced at baseline, with motor-language scores of 3 out of 6 in 11 patients.
An audience member asked Dr. de Los Reyes if there would be even more benefit by starting treatment before children became symptomatic. “I think all the neurologists in this group, we know that the earlier the treatment for rare diseases, the better the response,” she said.
The results were published simultaneously in the New England Journal of Medicine.
BioMarin Pharmaceutical funded the work, along with grants from the German Federal Ministry of Education and Research, the European Union’s Horizon 2020 Research and Innovation Program, and the National Institute for Health Research. Several authors were BioMarin employees. Dr. de Los Reyes is a consultant and reported a grant from the company.
SOURCE: Schulz A et al. N Engl J Med. 2018 Apr 24. doi: 10.1056/NEJMoa1712649.
LOS ANGELES – Intraventricular administration of cerliponase alfa seemed to slow the rate of motor and language decline in an open-label trial of 23 children with neuronal ceroid lipofuscinosis type 2 disease.
Neuronal ceroid lipofuscinosis type 2 disease (CLN2), a form of Batten’s disease, is a rare lysosomal storage disorder that causes progressive dementia in children. Patients have pathogenic variants in the gene encoding lysosomal enzyme tripeptidyl peptidase 1 (TPP1). Without functioning enzyme, lysosomal storage material accumulates in neurons throughout the CNS and retina.
Symptoms start at 2-4 years with seizures and language delays, followed by rapid motor, language, and cognitive declines, and blindness. Children die in early adolescence. Treatment is symptomatic; there are no approved therapies.
The idea of the study was to replace the enzyme in the CNS with cerliponase alfa, a recombinant form of TPP1. Twenty-four children aged 3-16 years received 30 mg, 100 mg, or 300 mg intraventricular infusions every 2 weeks during the dose-finding phase of the open-label trial; they were then switched to 300 mg infused over 4 hours every 14 days for at least 96 weeks. One child dropped out after the first dose in the study, but the others continued.
The investigators used Ommaya or Rickham ventricular reservoirs to deliver the enzyme, which were more convenient than intrathecal administration, said investigator Emily de Los Reyes, MD, a pediatric neurologist at Nationwide Children’s Hospital, Columbus, Ohio.
The primary outcome was the time until a 2-point decline on the motor and language scores of the CLN2 Clinical Rating Scale, with 0 representing no function and 6 representing normal function in both domains. The mean unadjusted rate of decline in the motor-language score per 48-week period was 0.27 points in treated patients, versus 2.12 points in 42 historical controls (P less than .001). The treatment difference at 96 weeks was about 3.3 points. There was also a decrease in seizure severity and frequency.
All but one child experienced convulsions, over two-thirds pyrexia, and almost two-thirds vomiting and hypersensitivity. About half developed upper respiratory tract infections, and about half had increased CSF white-cell counts. There were also cases of device leakage, and two children developed infections detected by CSF monitoring, without symptoms of meningitis. Both continued treatment after removal of the intraventricular device, followed by antibiotics, and device replacement.
Fourteen patients (58%) had at least one grade 3 adverse event, and there was one grade 4 event: status epilepticus deemed unrelated to the study. Side effects resolved on their own or responded to medical management. There were no deaths, study discontinuations, or dose reductions.
The mean age in the study was 60 months, about two-thirds of the patients were girls, and CLN2 diagnosis was confirmed by genotyping. Almost all the children had seizure histories. The majority were moderately advanced at baseline, with motor-language scores of 3 out of 6 in 11 patients.
An audience member asked Dr. de Los Reyes if there would be even more benefit by starting treatment before children became symptomatic. “I think all the neurologists in this group, we know that the earlier the treatment for rare diseases, the better the response,” she said.
The results were published simultaneously in the New England Journal of Medicine.
BioMarin Pharmaceutical funded the work, along with grants from the German Federal Ministry of Education and Research, the European Union’s Horizon 2020 Research and Innovation Program, and the National Institute for Health Research. Several authors were BioMarin employees. Dr. de Los Reyes is a consultant and reported a grant from the company.
SOURCE: Schulz A et al. N Engl J Med. 2018 Apr 24. doi: 10.1056/NEJMoa1712649.
REPORTING FROM AAN 2018
Key clinical point: Intraventricular administration of cerliponase alfa seemed to slow the rate of motor and language decline in 23 children with neuronal ceroid lipofuscinosis type 2 disease.
Major finding: The mean unadjusted rate of decline in the motor-language score per 48-week period was 0.27 points in treated patients, versus 2.12 points in 42 historical controls (P less than .001).
Study details: Open-label trial of 23 children.
Disclosures: BioMarin Pharmaceutical funded the work, along with grants from the German Federal Ministry of Education and Research, the European Union’s Horizon 2020 Research and Innovation Program, and the National Institute for Health Research. Several authors were BioMarin employees. The presenter is a consultant to BioMarin and reported a grant from the company.
Source: Schulz A et al. N Engl J Med. 2018 Apr 24. doi: 10.1056/NEJMoa1712649.
