A treatment for Zoe: Inside the race to build a therapy for a devastating rare disease

Zoe Dewaghe was diagnosed with Sanfilippo syndrome. (Zoe's Medical Expenses/GoFundMe)

CHULA VISTA, Calif. — If Zoe Dewaghe wants ice cream for breakfast, she gets ice cream for breakfast. There’s a different set of rules for her younger brother, Zach: He gets oatmeal instead.

That’s because five-year-old Zoe Dewaghe has a rare genetic disease called Sanfilippo syndrome. Her body can’t metabolize certain sugars properly, leading to progressive brain damage. She’ll gradually lose the ability to speak, to move, to recognize her surroundings. Most patients don’t live into adulthood.

“Once we found out what was wrong with her, we were like, ‘You can eat whatever the heck you want,’” Zoe’s mother, Liz, said ruefully. “Because pretty soon, you won’t be able to eat.”

There’s no approved treatment for Sanfilippo syndrome. But several companies have been testing experimental approaches to re-engineer the faulty genes that cause so much pain. The research has given families a flicker of hope. It’s also sparked disappointment, frustration, even anger.

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In recent months, two drug companies have dropped their Sanfilippo research, unable to get their drugs to work. Another biotech is testing its novel and extraordinarily expensive treatment on just a few children at a time — leaving others to wonder how those families were chosen, when so many other desperate patients are left behind.

The Sanfilippo story is a window into the fraught world of rare disease research. Drug companies increasingly see opportunity in the field, both to alleviate suffering and to reap huge profits. Regulators are under enormous pressure to approve new therapies even with scant evidence that they’re effective. And families seize on every risky trial as a last chance to save a beloved child.

The rare disease patient community pushed hard for the newly enacted 21st Century Cures Act — which passed Congress with huge bipartisan margins — in the hopes that it would boost innovation and speed up regulatory approval of experimental drugs.

But as the Sanfilippo experience shows, drug development is long and slow and full of setbacks; it can be hard even to get patient families, doctors, regulators, and biotech researchers to agree on what constitutes a successful clinical trial. And when a promising treatment emerges, it’s far from certain that patients will be able to get access.

“For families, an effective treatment could never come soon enough,” said Dr. Joseph Muenzer, a professor of pediatric genetics at the University of North Carolina at Chapel Hill. “The reality is that it’s always sometime tomorrow — and they want it yesterday.”

A crushing email

Liz and Thierry Dewaghe started suspecting that something was wrong with Zoe when she was about two. She met early developmental milestones, but barely, and she had phobias. For instance, she was terrified of all men, except her father.

“She was always kind of different than the other kids, but not different enough to think something was really wrong with her,” Liz Dewaghe said. “We just thought she was kind of quirky.”

But at two, her developmental delays really started to show. Her parents, who both work in clinical research for pharmaceutical companies, took her to an array of therapists. The general consensus was that Zoe was on the autistic spectrum. It wasn’t until the summer of 2015 that someone suggested she visit a geneticist. Her parents learned the results by email.

“The geneticist was like, ‘Dear Mrs. Dewaghe, I’m sorry to report that your daughter has Sanfilippo syndrome. Will you please come into my office Friday?’” Liz Dewaghe said. “The whole experience was terrible.”

By the time that Friday rolled around, the Dewaghes already knew — courtesy of Google — that their daughter had a terminal illness. The geneticist had little more to share than that.

Sanfilippo syndrome is a lysosomal storage disorder — a metabolic disease that’s similar, in many respects, to other genetic disease like Tay Sachs and Niemann-Pick. Every human cell is full of little organelles called lysosomes which, roughly speaking, serve as the garbage disposal system. They’re meant to break down a vast array of substances. But the garbage disposal is broken in people with Sanfilippo disease.

They carry a mutation on a gene that codes for an enzyme that’s used to degrade long chains of sugar molecules called glycosaminoglycans, or GAGs. There are actually four types of Sanfilippo syndrome, caused by four different genes. Each mutation triggers the same fault in the enzyme pathway, which leads to the buildup of GAGs.

Although babies with Sanfilippo look normal at first, the symptoms of the disorder tend to start setting in when they’re toddlers, with a noticeable decline in learning abilities around age three or four. Other symptoms include hyperactivity, joint problems, and seizures. As the children get older, symptoms get worse. Those who could once speak typically lose that ability. Many are never toilet trained. There aren’t solid numbers on how many children have the disease, though its estimated incidence is about 1 in 70,000 births

Zoe, an exuberant redhead who can still speak several words — including “momma,” “thank you,” and “bye bye” — is in a hyperactive stage now, with a penchant for ripping up mail and throwing things.

“She’s always on the go,” Liz Dewaghe said. “It’s a phase, and it won’t last forever. But it’s like she takes seven espressos as soon as she wakes up.”

What follows the hyperactivity stage is much, much worse.

“At some point, the kids basically become bedridden, and lose the ability to walk,” said Muenzer. He specializes in a subclass of lysosomal storage disorders known as MPS diseases, which includes Sanfilippo syndrome. Muenzer estimates that he has seen about 500 patients with these rare disorders.

Scientific advances have opened new avenues for possible treatment. And indeed, more and more companies are getting interested in these MPS diseases.

“Fifteen years ago, if I’d talk at national MPS meetings, all we talked about was management —not treatments. As technology is moving forward, that’s changing,” Muenzer said.

“There’s hope in gene therapy,” he added. “To me, it’s the most encouraging experimental option out there.”

A virus brings hope

One of the gene therapies in the works comes from Cleveland-based Abeona Therapeutics.

Its scientists are re-engineering a virus so it carries the gene that patients with Sanfilippo are lacking. The idea is to infect every cell of a patient’s body with that virus — thereby implanting the gene that could fix breakdown in the cellular garbage disposal.

That requires massive doses of the engineered virus. Here’s how Abeona CEO Tim Miller describes it: A typical sneeze releases about 100,000 viral particles into the air.

“For a single dose of gene therapy, you’d have to sneeze 10 million times,” Miller said. “That’s how much virus we give.”

The gene therapy, which has orphan drug designation from the Food and Drug Administration, is being tested at Nationwide Children’s Hospital in Columbus, Ohio. In mice, the results were stunning. With a single dose, enzyme activity was restored in the central nervous system, and throughout the body — and there were broad improvements in cognition and movement. Lifespan was increased substantially, as well.

So far, just three children have been infused with the gene therapy, at a low dose meant primarily to evaluate its safety. At the 30-day mark of the trial, Abeona reported positive signs of biopotency, based on the level of GAGs in both urine and cerebrospinal fluid, and the condition of the liver and spleen. It also announced that there were no safety concerns. In a few months, Abeona will release the six-month results.

Seven-year-old Eliza O’Neill was the first child to receive a dose. She was diagnosed with the disease when she was three and a half — and like Zoe, showed developmental delays and hyperactivity. These days, Eliza has lost almost all of her speech, and quite a bit of her ability to understand her surroundings.

Eliza was dosed with the virus about six months ago, and her parents haven’t yet been told if it’s showing any efficacy. They think they’re seeing an improvement, but it’s hard to say for sure.

“As parents, we feel we’re optimistic. Are we seeing this new connection? A new light in her eyes? We like to think so,” said Glenn O’Neill, Eliza’s father. “But we want the data to come out.”

Glenn O’Neill and his wife, Cara, a special needs pediatrician, run the Cure Sanfilippo Foundation — the most visible of the nonprofits backing research into this disease. Glenn O’Neill, who has a background in marketing, began raising awareness soon after his daughter was diagnosed. That led to a documentary film maker producing a short video about Eliza in 2014.

The video went viral as viewers warmed to the heartbreaking images of a spunky blonde toddler playing while her parents pleaded for help raising money to fund a clinical trial before Eliza’s health deteriorated still further. The O’Neills raised $500,000 in 15 days, and $2 million by the end of the year. Three years in, they’ve brought in $3.5 million for Sanfilippo research. About $1.2 million went to Abeona and Nationwide to jump start the clinical trial.

Other families have questioned why Eliza was given the first dose of the experimental therapy at age 6, when it is believed to have the best chance of helping younger children who haven’t yet had as much brain damage from the disease. CEO Miller said Abeona played no role in choosing who participated in the trial; the doctors running the study selected patients, in part based on their overall health.

For their part, the O’Neills know the treatment might not work. It could even have unanticipated side effects. Yet they were so desperate to try it, they went to the extreme of quarantining the whole family for nearly two years, while preparations for the trial were underway, so that Eliza wouldn’t be exposed to — and develop immunity to — the virus that Abeona engineered to carry the gene therapy.

“I think that’s kind of an out-of-the-box foreign concept to most people who aren’t touched by a terminal rare disease,” Cara O’Neill said. “Our risk tolerance is pretty astronomical — because we know what’s coming, and it’s horrific.”

In the next year, Miller said Abeona will add another three to six patients to its gene therapy trials, offering a higher dose to test more for efficacy.

Zoe Dewaghe is on the waiting list.

“Even right now, we’re crossing our fingers on the Abeona trial — that Zoe will actually get to get the gene therapy,” Liz Dewaghe said. “But who knows where she’ll be in a year.”

Disappointment upon disappointment

Rare disease therapies are increasingly lucrative for drug makers for several reasons. Regulators often move promising products quickly to market, all too aware that patients have no other options. Though the pool of patients is by definition small, drug makers can charge high prices because there is no competition.

Just this week, Biogen set the list price for the first year of treatment with its new therapy for the rare disease spinal muscular atrophy at an eye-popping $750,000. That makes it one of the most expensive medications of all time.

So Abeona isn’t the only company chasing a treatment for Sanfilippo syndrome.

Because the symptoms are caused by the lack of an enzyme, researchers have tried to develop an enzyme replacement therapy. That’s worked for other diseases, but it hasn’t yet proven particularly useful for patients with Sanfilippo syndrome, Muenzer said. Part of the issue is that it’s tough to get any drug in the brain, which is where the bulk of the damage is being done.

Shire Pharmaceuticals recently dropped its enzyme replacement therapy after studying it in a year-long Phase 2 trial among children with Sanfilippo syndrome. The company said the drug wasn’t helping patients more than a placebo. The failure was a major disappointment to patients and researchers.

“I’m still not clear why the Shire trial didn’t work — maybe they didn’t go long enough,” Muenzer said. “Those were early [stage] patients, and I would have thought they would have done better than they did.”

UniQure, another biotech in the field, just last month dropped its own gene therapy for Sanfilippo, after testing it in four children. A representative said the results were inconclusive.

Orchard Therapeutics, a biotech startup based in the UK, is still in the hunt, conducting animal studies of its gene therapy and laying the groundwork for a clinical trial. And then, of course, there’s Abeona.

The record of clinical trials to date shows how difficult it is to test an experimental therapy for a rare disease.

Companies are often wary of testing such a drug too broadly. They may search far and wide for the most promising patients, who are most likely to benefit from a clinical trial, because they don’t want to risk getting a bad result that could hinder their efforts to win regulatory approval.

Cost is a major factor as well.

It can run up to $1.5 million to produce a single, clinical grade gene therapy for a pediatric patient. Animal-grade viral vectors aren’t too expensive to manufacture, but it’s one thing to make low-quality product for a 20-gram mouse, Muenzer said. It’s entirely another to develop a safe and effective therapy to inject into a 20-kilo child.

Still fighting, against all odds

That’s why Patty Taormino may never see her son Jesse in a clinical trial.

He’s 21 and has severe cognitive damage from Sanfilippo. She can’t get a company interested in testing an experimental treatments on patients like him.

“We’ve pushed and pushed to get side-by-side trials done separate for kids who have regressed some, to see if it would have an effect on reversing the disease like it has in the mice,” said Taormino, vice president of the Team Sanfilippo Foundation. She’s had no luck.

It’s tough for drug companies to justify trials on older patients, Muenzer said: “At some point in these brain diseases, there’s a point of no return. Patients continue to deteriorate, because of all these processes that get set in place early.”

Taormino understands that — but she knows, too, that she and other families have been working for years and years to raise money and awareness and spur research into Sanfilippo. Now a potential treatment is in reach, and her son — and so many others — may miss out.

“It’s basically a stab in the back to all of us that had that hope,” she said.

For now, Taormino continues to do what she’s done for Jesse ever since he was first diagnosed: Find ways to make him comfortable, and allay his symptoms as well as she can. She’s set up a sensory table for him in his room, so he can turn the lights and fan on and off, and listen to the radio. He’s got a television set, and toys aimed at children age 3 to 5.

“There’s a man in there somewhere,” Taormino said. “He loves football games on TV, and could watch the Victoria’s Secret fashion show for days.”

Taormino also carefully watches his diet, making sure he doesn’t eat anything that might exacerbate the buildup of complex sugars in his body. She’ll test out new vitamins, supplements, and Chinese medicine on Jesse, as a way to pick up the slack for medical science, which hadn’t advanced enough to reach her son.

“I’m very careful when I try something new — I go low and slow,” she said. “If I see the slightest adverse reaction, I stop.”

Taormino said she’s “as prepared emotionally as one can be” for her son’s death. But she’s still fighting to help him, any way she can. “It’s a hard decision: Do you try and preserve your child from the worst of a disease that you know is going to take them, or do you let them go down the fast track, and go out on their own?” Taormino said. “I used to ask myself: Why am I saving him? I know he’s too old for a cure.”

‘We would do anything’

The Dewaghes aren’t yet at that stage.

Zoe is only five, and she can still play, walk, talk a little. And one of the saving graces of Sanfilippo syndrome, Liz Dewaghe said, is that Zoe doesn’t have any idea of the nature of her disease. She’s a cheerful, affectionate kid.

“She’s innocent; she doesn’t realize anything’s wrong with her. She’s just happy,” she said. “But she’s like a ticking time bomb.”

And so they wait for their chance at a clinical trial. And hold on to hope that modern science can stop Zoe’s disease before it destroys her.

“We would do anything,” Liz Dewaghe said.