LOS ANGELES — Treatment with intraventricular cerliponsase alfa (Brineura, BioMarin International) may decrease motor and language function declines in children with infantile neuronal ceroid lipofuscinosis type 2 (CLN2), new research suggests.
CLN2 is a rare lysosomal storage disorder that causes affected children to have seizures and progressive loss in motor, language, visual, and cognitive skills within 2 to 4 years.
The open-label study included 23 children and adolescents aged 3 to 16 years who were diagnosed with CLN2. All received a 300-mg-dose infusion of cerliponase alfa over about 4 hours every 2 weeks for at least 96 weeks.
Results showed that mean time until a 2-point decline in score on the CLN2 Clinical Rating scale in the motor and language (ML) domains, the primary outcome measure, was almost a year for the comparator group of untreated "historical controls" but was never reached by the treated group up to the 96-week assessment point.
In addition, the decline rate per 48-week period was significantly less for the treated than for the untreated group.
"Having an 87% response rate at 96 weeks surprised me," co-investigator Emily de Los Reyes, MD, Nationwide Children's Hospital and Ohio State University, Columbus, told Medscape Medical News before her presentation here at the American Academy of Neurology (AAN) 2018 Annual Meeting.
"This is the first in-human trial for intracerebroventricular enzyme replacement. So I did not expect such a robust and wonderful result, especially because this is a neurodegenerative disease that is like a death sentence for these children," said de Los Reyes.
She added that this is "a real breakthrough" in the treatment of these young patients. "Advances in science and in genetic testing have brought us forward in regards to, hopefully, early identification and early diagnosis so we can impact the outcome of these children in the future," said de Los Reyes.
The findings were simultaneously published online in the New England Journal of Medicine.
"13-Fold Risk Reduction"
CLN2, a form of Batten disease, is characterized by a deficiency in enzyme tripeptidyl peptidase-1 (TPP1) that leads to a buildup of protein deposits and to progressive degeneration of the brain and retina. Children with this disorder often die between the ages of 8 and 12 years.
After granting priority review, and based in part on results from this study, the US Food and Drug Administration (FDA) approved cerliponase alfa in April 2017 for the slowing of walking disability in children at least 3 years of age.
The treatment, which is a recombinant form of TPP1 and does not cross the blood-brain barrier, also received marketing authorization throughout the European Union in 2017. It is administered into the lateral cerebral ventricles using a Rickham or Ommaya device.
In the original study, 24 patients were enrolled and treated for 48 weeks, with 1 discontinuation. The remaining participants continued into the extension study (62% girls; mean age, 4.3 years). For both primary and secondary outcome measures, these children were compared with 42 patients with CLN2 who were registered in a natural history database (control group).
At 96 weeks, the time until 2-point decline in ML score was 345 days for the control group and was not reached for the treated group.
When the investigators measured rate of decline in ML score between baseline and last assessment, the decline rate per 48-week period was 0.27 points vs 2.12 points for each group, respectively (P < .001). At the 48-week mark, the difference was 1.8 points in favor of the treatment group; at 96 weeks the difference was 3.3 points in their favor.
Compared with the patients receiving the study drug, the control group was "13 times more likely to have experienced an unreversed 2-point decline" in ML score (hazard ratio, 0.075; P ≤ .0001), reported de Los Reyes. In other words, "there was a greater than 13-fold reduction in risk of a 2-point loss" in the score for those who received treatment.
After 48 weeks of treatment, the difference in total score change from baseline to 48 weeks was 2.2 points in favor of the treatment group and was 5.1 points in their favor at 96 weeks. "So the treatment benefit is persistent," said de Los Reyes.
Common adverse events (AEs) included pyrexia (46%), convulsions, vomiting, and hypersensitivity reactions.
There were 30 device-related AEs, with all but 3 considered as grade 1 in severity. Grade 3 AEs included 2 Propionibacterium infections and 1 Staphylococcus epidermidis infection related to the device, occurring in 2 of the children. Antibiotic treatment was then administered and their devices were replaced. Overall, there were 0.06 infections per patient per patient-year.
"Infections were successfully treated and subjects continued on the study drug," said de Los Reyes.
While 22 patients reported having a history of epilepsy or seizures, 23 had seizures during the study time period; 88% of these seizures were mild to moderate (grade 1 or 2). One child had 1 serious episode of status epilepticus.
Grand mal seizure subscore improved from 1.7 points at baseline to 2.3 points at 96 weeks.
"There was persistent treatment benefit and fewer and less severe seizures reported over time," noted de Los Reyes. Intraventricular infusions of cerliponase alfa "may be an effective and safe route for treatment of lysosomal storage disorders that have tropism for the brain," she added.
Asked about the clinical impact of the findings, de Los Reyes said, "we're changing the face of this disease. We are changing the natural history, which shows a decline in kids' motor and language scores." With treatment, "these children will continue to maintain a better quality of life and better seizure control, and they'll hopefully be able to go to school like other children."
She reported that all of the children are now in an open-label extension study, "so we are continuing to collect data." Also, because cerliponase alfa was approved by the FDA for use only in patients older than 3 years, de Los Reyes said the investigators want to collect data on younger children.
First Ray of Hope?
During the postpresentation question-and-answer session, de Los Reyes was asked whether it would be beneficial to start treatment prior to children becoming symptomatic, or to even possibly give it on the basis of at-birth screening for genetic abnormalities.
"Yes, absolutely," she replied. "I believe in that and we are currently in a study for children less than 3 years old. I think for all the neurologists in this room, we know that the earlier the treatment for any of our rare diseases, the better the response."
Afterward, session co-moderator Holly E Hinson, MD, assistant professor of neurology and emergency medicine at Oregon Health & Science University, Portland, told Medscape Medical News that de Los Reyes' entire presentation "was profoundly moving," including a series of heart-breaking videos showing the progression of decline in an untreated young boy with CLN2.
"This is a universally lethal condition. Even though it only affects around 20 children in the US each year, it's devastating," said Hinson. "The idea that this disease could be modified in any way provides the first ray of hope in a very dark and disabling condition."
She added that she's excited to see where this treatment might lead.
"Potentially, this type of approach might be used for other disease states, including perhaps those that do not have the same genetic mutation but share some of the same [characteristics]. It could lead as a model for other genetic diseases," concluded Hinson.
The study was funded by Biomarin Pharmaceutical and by 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. Dr de Los Reyes reports having received grants from the Charlotte and Gwyneth Gray Foundation, which was "outside the submitted work." A full list of disclosures for the other study authors is in the original article. Dr Hinson has disclosed no relevant financial relationships.
American Academy of Neurology (AAN) 2018 Annual Meeting. Clinical Trials Plenary Session. Presented April 24, 2018.
N Engl J Med. Published online April 24, 2018. Abstract
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Cite this: Cerliponase Alfa May Slow Symptoms of CLN2 Disease in Children - Medscape - Apr 25, 2018.