Even now, Gary D. Clark, MD, is struck by the unmistakable impact of BioMarin Pharmaceutical Inc.’s Brineura, the first treatment ever approved by the US Food and Drug Administration to treat a form of Batten disease, a rare set of lysosomal storage disorders.
“There’s just such a definite treatment effect in this disorder,” said Dr Clark, the chief of neurology at Texas Children’s Hospital, in Houston. “It’s not subtle.”
In those with Batten disease, a genetic mutation disables the patient’s ability to clear waste from cells, resulting in a catastrophic series of problems: loss of speech, loss of mobility, and, usually by around age 12, death.
Prior to Brineura’s approval in April 2017, a diagnosis of late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) Batten disease essentially was the starting point of an unstoppable journey of rapid neurodegeneration and an unwanted entrance into a small club of parents and researchers pushing desperately for scientific breakthroughs.
BioMarin’s enzyme replacement therapy changed all of that.
“The clinical trial was probably one of the most impressive things I’ve seen in medicine,” Dr Clark said. “Once the child was fully on the enzyme replacement in the brain there was a complete cessation of the decline in function.”
It’s the kind of miracle that no physician who works in rare diseases would take for granted. And yet, for parents whose children have 1 of the other 13 forms of the disease, it’s merely a spark of light keeping alive hope that one day there will be a treatment for their children, too.
A Novel Approach
The different types of Batten disease are numbered, CLNs 1 through 14. Each type is different—its own disease—though there are similarities. Overall, an estimated 2 to 4 children per 100,000 will have the disease.
“In the case of kids with CLN2 and other kids with Batten, they have seizures of varying kinds, they lose the ability to walk and talk, and they lose their vision in time,” said Margie Frazier, PhD, executive director of the Batten Disease Support and Research Association. “And sadly, they lose their life way too early.”
The genetic mutation is autosomal recessive, meaning both parents must have the mutation in order for the child to have Batten. In some cases, that means families have multiple children with the disease.
Two forms of Batten—CLN1 and CLN2—involve a deficient enzyme; that’s where the opportunity to treat CLN2 came into play. In CLN2, the deficient enzyme is called TPP-1.
BioMarin developed a recombinant form of the TPP-1 suitable for use in enzyme replacement therapy, but there was a problem. Although most enzyme replacement therapies are delivered through intravenous infusion, Dr Clark said that wouldn’t work with Batten.
“These Batten diseases primarily affect the nervous system, and if you give an enzyme in the blood it doesn’t get into the nervous system because of the barrier between the blood and the brain,” he explained.
BioMarin had a different idea, one Dr Clark describes as both brilliant and gutsy. They hypothesized that they could bypass the blood-brain barrier by injecting the enzyme replacement therapy solution directly into the cerebrospinal fluid in the brain using a surgically implanted reservoir and catheter in the head.
Emily C. de los Reyes, MD, a pediatric neurologist who oversaw the US clinical trial site for Brineura at Nationwide Children’s Hospital, said the leap from gutsy idea to proven strategy relied on finding a suitable animal model. In this case, they found one in dachshunds.
The results from the canine model were striking.
“Canines were able to tolerate the drug infusion that they had,” Dr de los Reyes said. “The brain was able to have good uptake and it cleared the lysosomal storage material.”
The effect of the therapy was essentially to stop the disease in its tracks.
The first trials were conducted in Europe, so by the time trials came to the United States, optimism was high.
“The Europeans already had an experience by the time it came to the United States, so we knew it was safe in the children but at the same time we still follow the protocol, which is to [evaluate] safety and tolerability,” she said.
In order to participate in the trial, families from around the country literally left everything behind to move to the Columbus area.
“These families are phenomenal,” Dr de los Reyes said.
Those trials helped Brineura win an approval from the US Food and Drug Administration (FDA) in April of 2017. The drug’s official indication is for the treatment of the slow loss of walking ability in symptomatic CLN2 patients age 3 and older.
Brineura won’t cure CLN2; patients will need to be on the drug for the rest of their lives. However, it opens up the possibility that with early detection, the disease could be stopped before it starts to cause major damage.
“The earlier the diagnosis, the better the outcome,” Dr de los Reyes said.
Other Patients Must Keep Waiting
As of now, there are nearly 20 centers across the country where patients can receive Brineura infusions, according to Debra Charlesworth, MS, a spokesperson for BioMarin. The company declined to say how many patients are receiving the therapy.
The life-changing news for families of CLN2 patients has provided an emotional boost for patients with other forms of Batten, according to Frazier.
“I think it provides an example that this can get done,” she said. “A lot of these rare diseases, they’re very tough, and having this make it through the FDA approval process has been a real boost to the entire community, even with those who are working on different forms of the disease.”
That said, Frazier said there are times when families mistakenly believe Brineura could be a treatment for their child. Sometimes, it falls to her to break the news.
“For us that’s the heartbreaking part having to tell a family who’s just been diagnosed, that indeed, there’s not a treatment for them,” she said. “That’s the most heartbreaking call you’ll ever take.”
However, she said there is a strong and active support community, particularly on social media sites, and they help to share resources and spread accurate information. For families with non-CLN2 Batten, treatment can still help manage the symptoms and improve quality of life, though it can’t stop, what, at the moment, is inevitable.
Dr Clark said patients who are still ambulatory at diagnosis receive treatment and therapy designed to maintain that function as long as possible. Patients also receive medication to control seizures. He said the goal is to find a treatment that controls the seizures without sedation and allows the child to live as normal a life as is possible.
“There’s a lot of hard work that the families are doing to maintain function,” he said of non-CLN2 families.
New Scientific Avenues
While Brineura is specific to CLN2, Dr Clark said the technique of delivering enzyme replacement therapy directly to the brain could be replicated for other similar disorders.
“I think we are, I guess, energized in the field by this treatment because it gives us hope that we can challenge and fix some of the other disorders as well,” he said.
However, it’s not immediately clear whether the Brineura breakthrough will translate into new therapies for other forms of Batten.
At first glance, the most obvious next step for Batten treatment would be CLN1 since it also deals with a deficient enzyme.
However, Dr de los Reyes said CLN1 and CLN2 are very different, and Brineura is specifically built to treat the latter.
“It’s very, very specific to CLN2,” she said.
Dr Charlesworth agreed, saying it’s “unlikely” that Brineura itself could be used to treat CLN1, though she said they are building on Brineura’s success in other ways.
“While we don’t have any other programs for Batten disease,” Dr Charlesworth said, “we do have a program in the clinic for Sanfilippo B, which is an enzyme replacement therapy that is administered directly to the brain in a similar way that Brineura is.”
Though BioMarin does not have another Batten therapy in its pipeline, Frazier said other companies are undertaking Batten-therapy trials.
“We have lots of trials in the pipeline,” she said, including gene therapy trials for various forms of Batten, and small molecule efforts for CLN2 and CLN3.
“I think we’re in a new era of development,” she said. “And so, I think that we have a different outlook now that we have an approval and we have all of these toter things moving forward.”
Dr de los Reyes is involved in a study of a gene therapy for CLN6. She said there is also research looking into drugs that could be neuroprotective, as well as research dedicated to finding out if it’s safe to give Brineura to patients under the age of 3.
The Financial Case for Therapy
While Brineura has shone a light on the scientific path forward, it has also painted a compelling picture for companies considering developing their own rare disease therapies.
“Pharmaceutical companies in the past were only interested in the more common [conditions],” Dr de los Reyes said. “As a clinician and a researcher, it is extremely gratifying that there is a big pipeline for rare diseases right now.”
According to Dr Clark, regulatory changes and incentives seem to have made a difference in that regard. Coupled with scientific breakthroughs, he said there’s plenty of reason to be optimistic.
“Right now, in child neurology there’s a lot of very interesting things happening,” he said. “It’s probably the most hopeful time that I’ve seen in my career in child neurology. And I’ve been at it for quite a while.”
Frazier said the success of Brineura also attracts drug developers to Batten specifically, since it shows that they will find an active and engaged patient community. She noted that part of the reason CLN2 became a target of BioMarin’s was as a result of advocacy efforts by Batten families.
She believes that makes an impression on other drug companies.
“I think it is easier to bring companies on board because we have proven as a community that we work together and that we are able as an organization to help recruit and educate families about the trial process,” Frazier said.
One aspect of launching a successful rare disease therapy is getting insurers to pay for it. Brineura debuted with a list price of $702,000 per year, though the company said it has made extensive discounts available.
Frazier said insurance coverage has not been a major problem thus far.
“We all know that cost perspectives are very important,” she said. “Having said that we find that because this is the only treatment available for children who can be very, very disabled by this disease, the insurance companies have picked it up, some of them more quickly than others, but we are not seeing them deny.”
She said that holds true for Medicaid, where most states have quickly approved the treatment.
She added that it will be interesting to see if any of that changes over time. With such expensive treatment, companies will want to see a long-term, quantifiable impact and while the results of Brineura have been impressive, the therapy has not been around long enough to show long-term results.
“It’s gonna be very interesting to see over time how and what demands the insurance companies will make in terms of noticeable improvement in patients and those kinds of things,” she said. “But so far from where I sit I’ve been pleased at the approvals.”
Dr Clark also cautioned that there could be other impacts of the disease, or the treatment, over the long term.
“We don’t know what else might be affected in the body once the brain is essentially fixed by replacing the enzyme,” he said. “It’s possible that we’re going to see some other manifestations of this genetic disorder, mostly because children haven’t lived long enough to manifest anything else.”
For now, though, Dr Clark said physicians have an opportunity to dramatically alter and extend patients’ lives if they can detect CLN2 early. He said the first symptom is usually a language delay.
“Not every child with a language delay has this disorder,” he said, “but it is a child with language delay that has early onset of seizures that probably could have this particular disorder and should have the genetic testing for it.”
Dr de los Reyes hopes physicians won’t hesitate to perform genetic testing in possible Batten cases. She noted that the cost of genetic testing continues to fall, and the cost of testing pales in comparison to the costs of ICU visits if the untreated disease takes its toll.
Frazier said even though Brineura isn’t for every Batten patient, it’s changed the conversation for the entire community.
“It’s just a wonderful thing to be able to tell newly diagnosed parents that there is some hope for them and make some referrals to at least have a discussion with a physician,” she said.
Frazier said she finds herself doing a lot more media interviews these days, something that rarely happened a few years ago.
“It’s thrilling to talk to reporters because we want families to know about us and about the disease,” she concluded. “Even if there isn’t a treatment for their child yet, there is a community to surround them and support them and help them raise their children.”