Soon after the first-ever therapy for Batten disease was approved by the U.S. Food and Drug Administration (FDA) in April 2017, Danielle Kerkovich, principal scientist at the Beyond Batten Disease Foundation, started fielding questions from families wondering if their child could take the new treatment.
Kerkovich had to tell parents that they, unfortunately, could not. That’s because the Beyond Batten Disease Foundation works with kids who have the CLN3 form of Batten disease. Brineura (cerliponase alpha), developed by the pharmaceutical company BioMarin, can’t be used for CLN3 — it was designed for patients with the CLN2 form of the disease.
Brineura’s approval, though, did benefit Beyond Batten, and CLN3 patients in another way: “It raised our visibility,” Kerkovich told Batten Disease News.
In Batten, a rare, neurodegenerative disorder, mutations disrupt the normal function of lysosomes, which are responsible for clearing waste material from cells. Fats and proteins build up in neurons and other cells in the body, causing the nervous system to degenerate and leading to seizures, vision loss and neurological impairment.
There are multiple types of the disease, each caused by a mutation to a different gene. Most forms strike in childhood, and children with the disease decline rapidly after symptoms begin — losing their eyesight, their speech, and their ability to walk and move on their own.
The types different enough, though, that they each require their own treatment.
CLN2 is the first form of Batten to have an FDA-approved therapy, but treatments for other types of the disease, including CLN6, CLN1 and CLN3, are moving steadily down the development pipeline. The research community took Brineura’s approval as a positive sign for other upcoming therapies. It’s an exciting time, said Margie Frazier, executive director at the Batten Disease Support and Research Association, by phone from the foundation’s offices in Ohio. “It’s thrilling to have all of these efforts moving forward,” she said.
Enzyme replacement therapy
In the CLN2 form of Batten disease, a genetic mutation prevents cells from properly manufacturing tripeptidyl peptidase 1 (TPP1), an enzyme responsible for breaking down proteins. Brineura fixes that deficiency by infusing a therapy containing working versions of TPP1 through an implanted port directly into the brains of patients with the disease.
In patients with some other forms of Batten, like CLN3, TPP1 is produced normally — other pieces of the waste-clearing mechanism, like different enzymes, or other proteins, are what are malfunctioning. Kerkovich tells parents that giving a child with CLN3 an enzyme replacement therapy like Brineura is like trying to fix a car with broken tires by replacing the steering wheel. “It just has no effect,” she said.
However, it may be possible to treat other forms of Batten that directly affect a particular enzyme using a similar strategy — enzyme replacement therapy had some success in mouse models of CLN1, which affects the enzyme palmitoyl protein thioesterase (PPT1), for example.
As a condition of approval, BioMarin continues to test its therapy in clinical trials. The FDA approved the drug based on data from a Phase 1/2 trial (NCT01907087) in 24 patients, which showed the treatment slowed the progression of disease symptoms. All but one of the participants from that trial are now enrolled in an extension study (NCT02485899), which will continue to track the safety and effectiveness of the drug for up to 240 weeks.
“I get unbelievable darling pictures of kids with CLN2 who are thriving because of the drug,” Frazier said.
But Brineura is not a cure. It only stalls the progression of the disease, holding off the appearance of certain symptoms. Treatment has to be delivered each week, and has a sticker price of more than $700,000 a year, making it one of the most expensive drugs in the world, according to Fortune magazine.
Ron Crystal, MD, chairman of the Department of Genetic Medicine at Weill Cornell Medicine in New York City, started work on gene therapy for the CLN2 form of Batten almost two decades ago, in a project largely driven by the advocacy and donations of Nathan’s Battle Foundation. Gene therapies aim to correct the underlying defect that causes a genetic disorder like Batten, and make use of re-engineered viruses to deliver new, healthy copies of the mutated gene to cells in the body.
The CLN2 gene had just been identified when Crystal began work, so he and his team started largely from scratch — walking the potential therapy through animal and safety studies, and screening children for the CLN2 form of Batten, before starting on the first clinical trial in 2004.
“Screening gave us the opportunity to learn the disease, and get some experience with children and families,” Crystal told Batten Disease News by phone from Weill Cornell. “Over the years, we saw 50 or 60 children, which helped us a lot with understanding disease and developing a therapy.”
During the Phase 1 clinical trial (NCT00151216), the team delivered the therapy directly into the brains of 10 patients between 3 and 10 years old, and followed them for 18 months. Treatment significantly reduced the rate of neurological decline in treated patients, according to the study results, published in the journal Human Gene Therapy in 2008.
Children with CLN2 usually don’t live past the age of 12. Nathan Milto, who received the first round of CLN2 gene therapy, turned 23 last June.
Crystal since has developed a second version of the CLN2 therapy, using a new virus as the delivery system. During the initial research, there was only one virus available for use in gene therapy, AAV2, Crystal said. “We started with that because that was all that was really known, he said. “Now, there are tons to choose from.”
An ongoing Phase 1/2 clinical trial (NCT01414985) is testing the gene therapy using a new virus to deliver it, AAVrh.10.
While gene therapy in CLN2 is the furthest along, a clinical trial for CLN6 (NCT02725580) also is underway at Nationwide Children’s Hospital in Columbus, Ohio. Twelve patients — including Charlotte and Gwenyth Gray, namesakes of the foundation that raised the money for the trial — are receiving the CLN6 gene therapy, which is delivered through a catheter in the spine. The trial is recruiting patients for treatment in Columbus, and the study record shows that it aims to wrap up in March 2019.
“We’re cautiously optimistic,” said Kristen Gray, the girls’ mom and co-founder of the Charlotte and Gwenyth Gray Foundation to Cure Batten Disease, said by phone from Los Angeles, where the family lives.
Abeona Therapeutics is in the final preclinical stages of work on gene therapies for both the CLN1 and CLN3 forms of Batten. According to chief operating officer Jeff Davis, it should wrap up the last of those studies by the middle of the year. “We have a goal of filing IND [investigational new drug] applications with the FDA for CLN1 and CLN3 later this year, and then getting right into human clinical trials,” he said.
Both therapies were designated as orphan drugs by the FDA, which can help accelerate clinical testing, and provides tax credits for the research.
Abeona acquired its CLN1 gene therapy, ABO-202, from Steven Gray, PhD, an associate professor at UT Southwestern Medical Center in Dallas, Texas. Gray is continuing work on Batten disease, and has preclinical studies underway on gene therapies for both the CLN5 and CLN7 forms of Batten, he said in a telephone interview.
The approach to gene therapy is similar for all types of Batten, because the underlying technology is the same. But it’s more challenging for some forms of the disease than others, Gray said. In CLN1 and CLN2, for example, the new gene only needs to get to some cells, and then the correction will spread from there. But in other forms of Batten, like CLN3, the replacement gene takes effect only in the cells it hits directly.
Because gene therapy corrects the problem that causes Batten, many families are hopeful these treatments will prove to be a cure, Frazier said.
“There’s a lot of intrigue around gene therapy,” she said. “We have to see how well it works, at what age, at what level of disability. There are so many questions. That’s why they call it a trial.”
Small molecules and other approaches
Another potential path to treatment, small molecule therapy, includes compounds that don’t act directly on the proteins or genes that are malfunctioning in the various forms of Batten disease. Instead, they target other, surrounding cellular systems in the body in the hope of repairing the overall function of cells.
A group of researchers at Texas Children’s Hospital, funded in part by the Beyond Batten Foundation, is working to bring a small molecule therapy for CLN3 to clinical trial. The proposed treatment targets transcription factor EB (TFEB), a molecule that activates a cascade of reactions within a cell that enhances the activity of lysosomes, which clear out cellular waste.
“Our theory is that children with Batten and other lysosomal storage diseases have lysosomes that work, but are inefficient,” Kerkovich said. A therapy that jump-starts the lysosomes, then, may help restore function to cells. In mice with a Batten-like disease, activating TFEB led to a drop in neural degeneration and prolonged the lives of the animals, according to research published in the journal Nature Communications in 2017.
Though the therapy was developed for CLN3, targeting TFEB potentially could benefit patients with other forms of Batten, or other lysosomal storage disorders, Kerkovich said. “The amount of benefit would be different, though.”
Patients with Batten tend to have high levels of inflammation throughout the nervous system, which contributes to the damage and death of neurons. So, some researchers are looking to treat the disease with immunosuppressants to calm inflammation and protect brain cells.
In mouse models of the CLN3 form of Batten, the immunosuppressant drug Cellcept (mycophenolate mofetil), approved to prevent rejection after an organ transplant, improved motor performance, according to research published in the Journal of Neuroimmunology in 2012. A clinical trial (NCT01399047) testing that drug in 19 patients with Batten ended in 2015, but the results aren’t available yet.
One benefit of small molecule therapies, Kerkovich said, is that they’re tiny enough to more easily cross through the blood-brain barrier. Unlike most gene therapies and enzyme replacement, they don’t have to be delivered directly into the central nervous system — instead, patients can take the drug orally, or through an intravenous injection.
Though Bruneria is a treatment only for CLN2, its approval put Batten disease on the map for researchers, pharmaceutical companies, and biotechnology companies.
“Any time you have an FDA approval, that gets the attention of researchers, and people in industry, and elsewhere,” Frazier said. “This is how science and innovation goes — one thing builds on another.”
For Abeona, Brineura’s approval was a promising sign that the FDA is willing to work with companies with rare disease therapies in the pipeline. “BioMarin had a relatively small trial, a small number of patients, and few sites, but had a very accommodative pathway to approval,” Davis said. “We’re hoping we have the same sort of atmosphere as we move forward.”
While the goal is to find a cure, Frazier noted that anything that helps treat some of the symptoms of Batten can be innovative and helpful for patients, too.
“Anytime we have a new and efficacious seizure medication, or advances in respiratory care, physical therapy — all of that is very important in the day-to-day lives of these families,” she said.
With options emerging, families of children with Batten have to make decisions about which, if any, to pursue. “As little as five years ago, we often saw parents struggling whether to spend time with their child and ignore the noise, or to go for things that might be really aggressive, that could affect quality of life now and extend it later,” Kerkovich said. “Now, we seem to have a different landscape.”
Families are balancing risks and fears of gene therapy against its potential to be a permanent fix, deciding on clinical trials to pursue, or sitting back and waiting for small molecules to move into the clinic. It’s still early to tell what treatment strategies families will gravitate toward, Kerkovich said. “We’ll know better how families are leaning once more drugs are available,” she said.
As treatments come online, Gray said that combining approaches might be the best way to help patients. “I favor an all-of-the-above strategy. We’d like gene therapy to be the be-all, end-all, but right now I would consider it a treatment, and not a cure,” he said. “In the space of devastating diseases like Batten, everything is on the table.”
Technologies to screen for Batten, and diagnosing patients earlier, also become more critical as therapies emerge, Gray said. “Treating early is going to be just as important as anything else. Newborn screening, early identification — those might have as great of an impact on our ability to treat the disease as the therapies.”
At the end of the day, said Frazier, families just want what works. “They want a living, happy, healthy child,” she said. “And that’s what we’re moving toward.”