Jennifer Miller, MD
Jennifer Miller, MD, a professor of pediatric endocrinology, speaks about her research on Prader-Willi syndrome from her office at the University of Florida in Gainesville. (Photo by Larry Luxner)

Only hours after Jennifer Garzia gave birth to her son, Rocco, doctors diagnosed him with Prader-Willi syndrome (PWS). The baby, who had floppy limbs and underdeveloped lungs, was placed immediately in the neonatal intensive care unit at The Children’s Hospital of Philadelphia in Pennsylvania.

“That early diagnosis really helped my husband Pete and I prepare for this disease,” Jennifer Garzia said. “We came home with oxygen and a feeding tube, because in the beginning, Rocco didn’t want to bottle-feed. We were able to start growth hormones within 6 months.”

But as usually happens with PWS, Rocco Garzia soon went from not wanting to eat to not wanting to stop eating. And that insatiable hunger, a hallmark of this complex disease, has never abated.

Now 19 years old and living in Bradenton, Florida, the young man—who stands 5 feet, 9 inches tall and weighs 190 pounds—is not morbidly obese. However, he would be if his mother didn’t keep the refrigerator and pantry securely locked.

“Food is controlled in our environment. It’s when we go outside that things unravel,” she said. “Rocco is very social, very interested, wants to participate—but the food drives all behavior. And when food security isn’t there, his behavior is explosive.”

Rocco Garzia (far right), 19, who has Prader-Willi syndrome, with his family in Bradenton, Florida. (Photo courtesy Jennifer Garzia)

The hyperphagia, or overeating, associated with PWS is caused by a hypothalamically driven lack of a sense of fullness. People with PWS also suffer from gastrointestinal issues such as chronic constipation, difficulty vomiting, and occasional stomach necrosis and even rupture.

“Rocco’s hierarchy of needs will never be met because of that malfunctioning hypothalamus. You’re in a constant state of fighting to get what your brain is telling you what you need. We are desperate for medication to help the things he can’t control,” Jennifer Garzia said.

“It can go from a verbal outburst with cursing, to throwing chairs or pushing someone,” she added. “He can’t go to school, because when he has outbursts at school, they arrest him. He’s completely ostracized.”

‘Hell on Earth’ for Families During Pandemic

Jennifer Miller, MD, is a professor of pediatric endocrinology at the University of Florida (UF) in Gainesville. Rocco Garzia, who’s been seeing Dr. Miller since the age of 1, is among more than 600 patients with PWS under her care.

She spoke at the Externally-Led Patient-Focused Drug Development meeting held in June by the Prader-Willi Syndrome Association USA, the International Prader-Willi Syndrome Organisation (IPWSO), and the Foundation for Prader-Willi Research (FPWR).

In an interview with Rare Disease Advisor, Dr. Miller explained how the disease—which is diagnosed on average at 1.2 months of age—is initially characterized as a “failure to thrive.”

“You basically have to force‑feed these children or they would die,” she said. “They don’t want to suck. They don’t cry for food. They will sleep through feeds. They will press their lips shut or tongue the bottle out of their mouth if someone tries to feed them. In some countries, they’ll cut the nipple off the bottle and pour milk down a child’s throat to keep them alive.”

But then, by the age of 2 or 3, children with PWS suddenly start craving food. Dr. Miller said that 23 years ago, when she began researching the disease, pretty much everyone with the disease had become obese early in life and remained that way throughout their lives.

“Now, since growth hormone therapy has been approved and we know more about diet and physiology in this syndrome, we’re able to keep a lot of these individuals at normal weight during childhood,” she said. “It becomes much more difficult, of course, once they’re out of their parents’ control. They’ll eat anything and everything. Their parents have to lock the refrigerator and the kitchen, and install motion‑activated cameras on their doors that will alert them if their child tries to escape to go get food or at night. It’s like being in prison in your own house.”

During the height of the pandemic, she said, it was “hell on Earth” for parents of kids with PWS.

“Of course, every person is different. Some individuals with Prader‑Willi did somewhat better at home because it was such a controlled environment. Everything was locked; there was absolutely zero access to food,” she said. “But for most families, it was awful. Their kids had no routine.”

The Root of the Problem: Patients’ Cravings for Food

Dr. Miller’s mentor at UF, Daniel P. Driscoll, MD, PhD, proved the genetic basis for PWS in the early 1990s. In 2000, the US Food and Drug Administration (FDA) approved injectable human growth hormone (HGH) therapy for patients aged 2 years or more with PWS. While it helps improve bone density, body composition, cognition, and metabolism, HGH does nothing to curb patients’ appetites.

That’s the focus of Dr. Miller’s current research: how to fix the one thing HGH can’t.

While several rare diseases—including spinal muscular atrophy, retinal dystrophy, hemophilia B, and most recently Duchenne muscular dystrophy—now have approved gene therapies to treat them, PWS is a different story.

“Of course, there’s always a chance it could work. Research is currently being done on that. The problem is that this syndrome affects 10 genes on chromosome 15. That makes it more difficult to be amenable to gene therapy because so many genes are involved,” Dr. Miller said. “And even though this disease has been described for a very long time and has been known as a genetic disease since the 1970s, the function of each of those genes is still not completely known.”

Jennifer Miller, MD, a professor of pediatric endocrinology at the University of Florida, poses with 3 of the boys in her research study on Prader-Willi syndrome. (Photo courtesy of Jennifer Miller)

Dr. Miller is currently involved in a phase 2 trial of setmelanotide, being developed by Rhythm Pharmaceuticals. The study of 40 obese patients with PWS involves once-a-day injection of setmelanotide—a melanocortin-4 receptor (MC4R) agonist—in a randomized, double-blind, placebo-controlled pilot study being carried out at 5 sites in California, Florida, Kansas, New York, and Tennessee.

On August 3, 2023, Aardvark Therapeutics announced that it had received the Rare Pediatric Disease Designation for its ARD-101 investigational therapy for PWS. Previously, Aardvark had enrolled 12 patients in a phase 2 study of twice-a-day oral ARD-101 led by Diane Stafford, MD, at Stanford Children’s Health in Palo Alto, California, and Shawn McCandless, MD, at Children’s Hospital Colorado in Denver.

One of those patients was Rocco Garzia, whose mother called the ARD-101 trial “a really great experience.”

“Rocco did really well on that medication,” Jennifer Garzia said. “While he was on it, he was in school for 30 days. No phone calls, no tantrums, no food problems. It was remarkable to see how quickly he responded. As soon as he was off, he was arrested for throwing a chair.”

She added: “We have played all our cards, and we now need medication to control this.” 

Could DCCR Tablets Be the Answer for Desperate Families?

Another promising therapy, Dr. Miller said, is diazoxide choline continuous-release (DCCR) tablets, developed by Soleno Therapeutics. The Redwood City, California-based company says these tablets—derived from a crystalline salt of diazoxide—activate the KATP channel in the brain, pancreas, and fat tissue. That not only helps regulate appetite and reduce hyperphagia, but also reduces resistance to insulin as well as accumulation of excess body fat.

Dr. Miller said the original 13-week trial has been completed but failed to meet its primary endpoint due to COVID-19, “although the secondary outcome measures were statistically positive.”

In a phase 3 trial of DCCR, half of the participants who had been on the medication for 4 years were randomly given placebo for a further 4 months, while the other half remained on DCCR. While official results won’t be known until September 2023, she said that during the open-label extension period, “it completely changed the natural history” of PWS for patients and their families.

“It not only decreased hyperphagia, it decreased the food‑stealing episodes. People were able to unlock [their refrigerators and pantries] and turn their cameras off,” Dr. Miller said. “It allowed them to be typical kids. They were able to attend sports events outside their school, and travel on a bus, and stay in a hotel with their peers, which was never going to happen before with this.”

In a particularly moving letter to Soleno’s CEO, Anish Bhatnagar, MD, made available by Dr. Miller, a mother describes the anguish she went through with her son after years of clinical trials and disappointments—and how his participation in the DCCR study had finally given her hope.

“When your child is 300 pounds and close to 6 feet tall, it can be difficult and dangerous to control him,” she wrote. “But then things began to change. He began to eat slower. His entire life, he’d shovel in his food so quickly, he couldn’t possibly have chewed it. As days passed, he began to wait patiently to eat with the family. He started to remind us to lock the refrigerator and ask us if there was too much food on his plate. We were able to have snacks on the table as everyone swam in the pool. That wouldn’t have even remotely been a possibility before.”

The woman’s son eventually lost 40 pounds; he now rides his bike several miles per day and also works out regularly.

“The arguing and screaming about who accidentally left the pantry or refrigerator unlocked has subsided. We are able to watch a movie together and have popcorn. Most importantly, we have begun to laugh again and enjoy time together as a family,” she wrote. “We can begin to see a future that is not paved with heartache. Thank you for giving us our son back.”