Treatment with Brineura (cerliponase alfa) reduces decline in motor and language function in children with ceroid lipofuscinosis type 2 (CLN2), a subtype of Batten disease, new results from an extension Phase 1/2 trial show.
The findings are in, “Study of Intraventricular Cerliponase Alfa for CLN2 Disease,” published in the New England Journal of Medicine (NEJM).
Similar to other types of Batten disease, CLN2 is caused by genetic mutations that prevent cells from effectively breaking down waste in cellular structures called lysosomes — considered the digestive system of the cell. CLN2 patients have mutations in the TPP1 gene, which lead to the buildup of lysosomal storage material, particularly in the brain and retina.
The U.S. Food and Drug Administration approved Brineura, by BioMarin Pharmaceuticals, to treat children ages 3 and older with late infantile CLN2 in April 2017. The medication also was approved by the European Commission in June. As the disease mainly affects the brain, Brineura is given as an infusion into the cerebrospinal fluid (intraventricular), which fills the brain and spinal cord.
The open-label Phase 1/2 trial (NCT01907087) evaluated the effectiveness and safety of 300 mg of Brineura every two weeks in children with CLN2 disease. Eligible patients, ages 3 to 16, had a combined score of 3-6 on motor and language domains of a CLN2 clinical rating scale (range 0-6, with 0 representing no function and 3 normal function in each of the two domains).
Patients who completed the 48-week study could roll over to a 240-week extension study (NCT02485899) of 300 mg Brineura given every two weeks. This long-term trial is due to conclude in January 2021.
Compared with 42 patients enrolled in the DEM-CHILD NCL Patient Database — a database of children characterizing disease severity and progression — results from the open-label and extension studies in 23 Brineura-treated patients revealed a slower decline in motor and language function.
The median time to a 2-point decline in motor-language score was 345 days (49.3 weeks) in natural history controls. Trial data showed only 9 percent of treated patients had declined by 2 points by this timepoint, demonstrating the treatment’s effectiveness.
Children with CLN2 typically begin experiencing seizures from ages 2 to 4, usually preceded by language development delay. Most lose the ability to walk and talk by age 6.
“To finally have a treatment for CLN2 available is an important step forward in advancing the standard of care for the children affected by this form of Batten disease,” Angela Schulz, MD, the study’s lead author, said in a press release. Schulz added that her hope with these results “is to increase awareness in the medical community of this ultra-rare disease and accelerate the time to diagnosis.”
Emily de los Reyes, MD, director of the Batten Disease Center of Excellence at Nationwide Children’s Hospital in Columbus, Ohio, and one of the trial’s investigators, recently presented an updated analysis of the study at 96 weeks during the 2018 American Academy of Neurology Annual Meeting.
“CLN2 disease is a devastating and rapidly progressing condition that robs children of their motor function, including language and mobility,” de los Reyes said. “The benefits observed with Brineura are “of paramount importance to a child and their families where every day of sustained function is critical.”
The trial’s findings add to the existing knowledge that may advance the standard of care in CLN2, she said, and could be used to develop treatments for other forms of Batten disease.
Hank Fuchs, MD, president of Worldwide Research and Development at BioMarin, said: “Brineura has the potential to change the course of this devastating disease. We continue to study the impact of Brineura and add to the body of scientific knowledge about CLN2.” He added that scientists hope the new data “ultimately benefits the children and families affected by CLN2.”
But, the researchers noted: “The potential uses of intraventricular cerliponase alfa (Brineura) to prevent the onset of symptoms in young patients and to delay or prevent changes in vision warrant further study.”
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