Single Gene Therapy Injection May Stabilize CLN6 Batten Disease in Children, Early Phase 1/2 Data Show

Amicus Therapeutics‘ investigational gene therapy for CLN6 Batten disease may halt disease progression in children, according to interim results from a Phase 1/2 clinical trial.

Early data showed that a single injection of the AAV-CLN6 gene therapy stabilized the decline in children’s motor and language abilities while remaining well tolerated and safe.

“These interim clinical data suggest that our gene therapy in CLN6 Batten disease has the potential to halt the progression of this devastating fatal disease that untreated destroys brain function and kills children,” John F. Crowley, chairman and CEO of Amicus, said in a press release.

“It is remarkable that most children in this study appear to show stabilization, particularly the younger children who were able to maintain high baseline motor and language scores for up to two years,” Crowley added. “We know that brain damage here is irreversible, and early intervention will be critical to preserve the ability to speak and walk.”

Neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, comprise a group of fatal childhood neurodegenerative disorders. The diseases, which affect the nervous system, have a wide range of symptoms, including vision loss, lack of motor coordination, and impaired cognition.

These conditions can be caused by mutations in 14 different genes (CLN1 to CLN14), all of which lead to the accumulation of toxic insoluble waste deposits, called lipofuscins, inside cells. One of these genes is CLN6, which provides instructions to make the CLN6 protein, whose function is still not fully understood.

Amicus’ AAV-CLN6 gene therapy uses an inactive adeno-associated virus (AVV) as a vector to deliver a functional copy of the CLN6 gene into the cells of patients with CLN6 Batten disease. The therapy is delivered intrathecally, that is, injected directly into the spinal canal.

This strategy has been found safe and effective in delivering genes to treat other diseases of the central nervous system, including spinal muscular atrophy.

The therapy’s safety and efficacy is being evaluated in a Phase 1/2 trial (NCT02725580) in CLN6 Batten disease patients. Sponsored by Amicus Therapeutics, the trial is enrolling by invitation only at Nationwide Children’s Hospital in Ohio.

The study is expected to enroll  a total of 13 participants, ages 1 and older, who are ambulatory or able to walk with assistance. More information can be found here.

Safety data available from 12 children showed that the AAV-CLN6 therapy was generally well tolerated. Most of the side effects were reported to be mild in severity and unrelated to the treatment, including no cases of an immune response against the gene therapy.

Interim efficacy data are available for the first eight children with CLN6 Batten disease for up to two years after treatment with AAV-CLN6 gene therapy.

Researchers used the Hamburg Motor & Language Score to evaluate mobility and speech abilities. This scale separately measures performance of mobility on scale of zero to three and speech on the same scale, where zero represents no ability to walk or speak and three represents normal ability, to give a cumulative score of zero to six. Usually, children with CLN6 Batten disease show a rapid decrease in the Hamburg score (from six to zero) within the first three to four years of life.

In seven of the eight patients (ages 1.5 to 5.5 years at the time of treatment), AAV-CLN6 was found to stabilize the disease 1.3 to two years after treatment.

These patients’ Hamburg score was either maintained or improved slightly before stabilizing. The remaining patient who was treated at a later age (6.5 years) showed no improvements and had a two-point decline in the Hamburg score.

These positive results were also observed when patients were compared with a natural history data set from Nationwide Children’s and to their untreated siblings. The natural history data set on untreated patients showed that they all had disease progression, with at least a two- to three-point decrease in their Hamburg score over two years following the initial point of decline.

Siblings often show similar progression of diseases. For three treated patients, disease stabilization was seen compared with their untreated siblings who showed decreased motor and language ability, or died during the same time period.

Furthermore, in two cases where both the siblings were treated with AAV-CLN6 gene therapy, the younger sibling’s Hamburg score increased or stabilized while the older sibling’s scores initially decreased before stabilization was observed.

“Comparing the data collected during the CLN6 Batten disease clinical trial with the natural history data collected for Batten’s disease patients, I am pleased with the progress of this trial. It is powerful to have pairs of siblings as clinical trial participants since siblings are expected to have similar progression of the disease,” said Emily de los Reyes, MD, PhD, the trial’s principal investigator.

The gene therapy was initially developed by Brian Kaspar and his colleagues at Nationwide Children’s, in collaboration with researchers at Sanford Research. Kaspar was also involved in the development of what is now Zolgensma, the first gene therapy approved to treat SMA.

“We look forward to presenting additional data throughout this year and continuing to advance our CLN6 and other Batten disease gene therapy programs that all apply the same AAV technology platform developed by Dr. Brian Kaspar and his former colleagues at Nationwide Children’s. Early intervention is crucial, so we move forward with a great sense of urgency here for these children and their families,” Crowley said.

“I believe this AAV-CLN6 gene therapy has the potential to make a very meaningful impact for children with CLN6 Batten disease, and provides great promise to address many types of Batten disease and other neurologic disorders,” Kaspar said.