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Two years of treatment with Brineura (cerliponase alfa) safely and effectively delayed the onset of Batten disease in a 23-month-old boy who had no symptoms when he started treatment, study finds of cases.

The same treatment slowed the progression of the disease in her older sister, who received the treatment after the onset of symptoms at the age of 47 months (almost 4 years).

Although preliminary, these results suggest that Brineura may slow disease progression when Batten disease in late infants, or neuronal ceroid lipofuscinosis type 2 (CLN2), is already established, and also delays disease onset. before the onset of symptoms (pre-symptomatic).

Larger longitudinal studies are needed to confirm the therapeutic value of administering Brineura in pre-symptomatic CLN2 patients, the researchers noted.

The case study, “Presymptomatic treatment of classical neuronal ceroid lipofuscinosis in late childhood with cerliponase alfa, ”Was published in the Orphanet Journal of Rare Diseases.

CLN2 is caused by mutations in the TPP1 gene, altering the production of an enzyme called tripeptidyl peptidase 1 (TPP1). TPP1 deficiency leads to seizures and a rapid decline in cognitive, language, motor and visual functions. The first symptoms usually appear between 2 and 4 years old.

In 2017, BioMarin Pharmaceutical’s Brineura became the first – and currently the only – approved treatment targeting the underlying cause of CLN2 disease in the United States and Europe.

An enzyme replacement therapy, Brineura works by delivering the missing TTP1 enzyme directly into the cerebrospinal fluid using a catheter surgically implanted in the brain. Cerebrospinal fluid is the fluid that surrounds the brain and spinal cord.

Data from previous clinical trials have shown that Brineura, given every two weeks, slows disease progression, particularly motor and language decline, in children with CLN2.

However, “the potential to delay the onset of disease when treatment is started at a presymptomatic stage of the disease remains to be demonstrated,” the researchers wrote.

An international phase 2 trial (NCT02678689) is evaluating the safety, tolerability and efficacy of Brineura over a period of almost three years in 14 children up to the age of 17 with CLN2. The trial is expected to end in April 2022. Participants may include those treated before symptoms appear.

Now researchers at the University Medical Center in Rotterdam, the Netherlands, have reported the effects of two years of Brineura treatment in two siblings with CLN2: the older brother was a girl with an already established disease and the younger brother was a boy without symptoms yet. .

The siblings were born at term to unrelated Dutch parents after uncomplicated pregnancies and deliveries.

At 39 months (just over three years old), the girl began to lose vocabulary and showed tremors in her right arm and hand.

These symptoms rapidly progressed over the following months to a complete loss of the ability to walk or stand independently, produce two-word sentences, name objects, and eat normally. She also developed seizures and problems with behavior and sleeping.

Genetic testing at the age of 44 months (over 3.5 years) revealed the presence of the two most common disease-causing mutations (c.622C> T and c.509-1G> C), confirming a diagnosis of CLN2, and the patient started Brineura when she was 47 months old (almost 4 years old).

His younger brother was diagnosed with CLN2 disease based on his history, and it was discovered that he carried the same TPP1 mutations. The boy started taking Brineura when he was 23 months old (almost two years old), and at that time he was not showing any symptoms of the disease.

After two years of treatment, the girl showed reduced decline in motor and language functions, which was better than previously reported for untreated CLN2 patients. His cognitive decline was also slower than expected based on natural history studies.

She continued to have seizures, consistent with Brineura’s lower likelihood of having an effect on seizures because they stem from existing neurological damage, the team noted. The girl showed no visual problems before treatment and after two years.

Her younger brother did not have any motor, language, cognitive or visual symptoms or seizures throughout the treatment, until the age of 4. He should have “become symptomatic around the age of 3 to 3.5 years, also depending on the onset of symptoms in him.” sister, ”the researchers wrote.

In particular, her motor and cognitive abilities increased over time, as expected for her age, and were superior to those shown by her sister at the same age, suggesting the effectiveness of Brineura on motor and cognitive functions.

In addition, the cerebral narrowing observed in the girl at 42 months (before treatment) was not observed in her younger brother at 48 months (after 2 years of treatment).

Brineura was generally well tolerated by both siblings, with mild and easily resolving infusion-associated reactions. These included rash, fever, nausea, and faster than usual heartbeat; all were consistent with the adverse events reported by the treatment, the team noted.

In these siblings, Brineura was found to be “not only effective in slowing the progression of the disease, but also in prolonging the presymptomatic phase of the disease. [CLN2]The researchers wrote.

“Our results recommend starting treatment at an early age before symptoms appear, but should be confirmed in a larger cohort study,” they added.

“If the onset of the disease can be delayed for a prolonged period, this could pave the way for the possible inclusion of CLN2 disease in newborn screening programs and bridge the development of innovative treatments, such as gene therapy. currently under development, ”the researchers concluded. .

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