Brineura Delays CLN2 Onset, Progression in Case Study of 2 Siblings

Two years of treatment with Brineura (cerliponase alfa) safely and effectively delayed the onset of late-infantile Batten disease in a 23-month-old boy who had not exhibited symptoms when he started treatment, a case study shows.

The same treatment slowed disease progression in his older sister, who received the therapy after symptom onset at 47 months (nearly 4 years) of age.

While preliminary, these findings suggest that Brineura can slow disease progression when late-infantile Batten disease, or neuronal ceroid lipofuscinosis type 2 (CLN2), is already established, and also delay disease onset before symptoms show (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 classic late-infantile neuronal ceroid lipofuscinosis with cerliponase alfa,” was published in the Orphanet Journal of Rare Diseases.

CLN2 is caused by mutations in the TPP1 gene, impairing 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 function. First symptoms usually appear from the ages of 2 to 4.

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

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

Previous clinical trial data showed that Brineura, given every other week, slowed disease progression, particularly motor and language decline, in children with CLN2.

However, “the potential of delaying disease onset when treatment is started in a presymptomatic stage of the disease remains to be shown,” the researchers wrote.

An international Phase 2 trial (NCT02678689) is evaluating Brineura’s safety, tolerability, and effectiveness for a period of nearly three years in 14 children, up to age 17, with CLN2. The trial is expected to conclude in April 2022. Participants may include those treated before symptom onset.

Now, researchers at the University Medical Center Rotterdam, in the Netherlands, reported the effects of two years of Brineura treatment in two siblings with CLN2: the older sibling was a girl with already established disease and the younger sibling was a boy not yet showing symptoms.

The siblings were born of non-related Dutch parents at term after uncomplicated pregnancies and deliveries.

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

These symptoms rapidly progressed in 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 behavior and sleeping problems.

Genetic testing at 44 months of age (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 CLN2 diagnosis, and the patient started Brineura when she was 47 months (nearly 4 years) old.

Her younger brother was diagnosed with CLN2 disease based on her history, and he was found to carry the same TPP1 mutations. The boy was started on Brineura at the age of 23 months (nearly two years), and at that time, he exhibited no symptoms of the disease.

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

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

Her younger brother did not show any motor, language, cognitive, or visual symptoms or seizures throughout the treatment, up to age 4. He would have been expected “to become symptomatic around age 3–3.5 years, also based on symptom onset in his sister,” the researchers wrote.

In particular, his motor and cognitive skills increased over time, as expected for his age, and were superior to those shown by his sister at the same age, suggesting Brineura’s effectiveness on motor and cognitive function.

Moreover, the brain shrinkage observed in the girl when she was 42 months (before treatment) was not observed in her younger brother at 48 months of age (after 2 years of treatment).

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

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

“Our results advocate the start of treatment at an early age before symptom onset, but should be confirmed in a larger cohort study,” they added.

“If disease onset can be delayed for an extended period of time this may pave the road for possible inclusion of CLN2 disease in newborn screening programs and provide a bridge towards the development of innovative treatments, like gene therapy currently under development,” the researchers concluded.