An effective treatment for Prader-Willi Syndrome would mean more to Kate Kane than just being free of the insatiable hunger the disease causes. It could mean being able to do something as normal as hold a job—like her dream of being a veterinary technician.
That dream has been already stamped out once. One of the jobs Kate (pictured), 34, has held and lost over the years was at a veterinarian’s office. She worked there for only a week before her Prader-Willi symptoms overtook her when a cake was brought in for a colleague’s birthday.
“Let’s just say it didn’t work out very well,” said Kate’s father, James Kane. “If there’s something that can take the edge off that appetite, she might not need to live in a group home. If we could get that loosened a little bit, her life could change dramatically.”
Unfortunately, there is only one drug approved for Prader-Willi, human growth hormone, and it doesn’t stifle that hunger, known as hyperphagia. Worse, one experimental treatment that looked like it might actually impact hyperphagia, a drug called beloranib from Boston-based Zafgen (NASDAQ: ZFGN), was shelved last week due to safety problems. But could an emerging drug from Boston’s Rhythm Pharmaceuticals offer new hope?
It’s early, to be sure, but Rhythm’s drug, setmelanotide, is showing small signs that it might have a chance to fill the void left by beloranib. Rhythm published data from an ongoing Phase 2 trial of the drug in the New England Journal of Medicine last week. The report details data from just two patients with an ultra-rare disorder called pro-opiomelanocortin (POMC) deficiency obesity. While a study with such a small sample size normally wouldn’t merit much attention, the magnitude of the effects researchers saw on weight loss made it worthy of publication in the NEJM. And the drug’s impact on hunger, in particular, makes its progress worth watching for Prader-Willi.
Rhythm has a Phase 2 study underway for Prader-Willi that could produce results later this year. If the data show potential for the company’s drug to help Prader-Willi patients not just lose weight, but also control their hunger, it would be a timely development. Just last week, Zafgen said it would no longer seek FDA approval for beloranib. Two Prader-Willi patients on beloranib died in Zafgen’s Phase 3 trial, which doomed the drug despite encouraging effects on patients’ weight loss and hunger. Zafgen doesn’t currently plan to develop its second-generation obesity drug, ZGN-1061, for Prader-Willi either.
“It’s very devastating for all of us to have to turn away from them right now, that’s the hard part,” Zafgen CEO Tom Hughes told Xconomy last week, referring to the community of Prader-Willi patients and caregivers.
It’s yet to be seen whether Rhythm’s drug can take beloranib’s place. But the data reported in NEJM suggest that it has a chance: One POMC patient who took Rhythm’s setmelanotide lost 112.7 pounds, or 32 percent of their body weight, after 42 weeks of treatment. The other lost 45.2 pounds, or 13 percent, after 12 weeks. And both patients reported having essentially no hunger by the end of the trial period, compared to extreme hunger at the start of the study.
The only side effects seen so far are some darkening of hair and skin color, Rhythm says.
POMC deficiency causes obesity and incessant hunger much like Prader-Willi does. Rhythm’s setmelanotide is a peptide drug that targets a protein called melanocortin 4 receptor, or MC4, which plays a key role in weight and appetite regulation in the brain and doesn’t function properly in people with POMC deficiency or Prader-Willi. Setmelanotide is meant to boost the activity of MC4, which in turn might reinvigorate the brain’s ability to regulate weight and hunger.
“That [drug] clearly has application to [Prader-Willi], and we’re hopeful that continues and something happens,” said James Kane, adding that his “extreme hope” for Zafgen’s treatment was dashed once news came out about the patient deaths. “I gotta believe that, in our lifetime, we have to be able to solve this problem.”
Some important answers regarding Rhythm’s drug will come soon. While the company’s data in POMC deficiency comes from a very small (10 person), open-label trial, Rhythm’s drug faces a much stiffer test in the Phase 2 Prader-Willi study, a double-blind, placebo controlled trial enrolling 36 patients, according to clinicaltrials.gov.
Additionally, Rhythm is so encouraged by the POMC deficiency results that it now plans to move setmelanotide into a late-stage trial for the disease, though two of its executives, CEO Keith Gottesdiener and President Bart Henderson, wouldn’t specify when that might happen.
POMC affects fewer than 500 patients worldwide, according to Rhythm. Though Prader-Willi is also rare, it’s much more common by comparison, affecting about one in every 12,000 to 15,000 newborns, according to the Prader-Willi Syndrome Association.
Patients with POMC deficiency are typically born at a normal weight, but because of their hyperphagia, they’re often obese by the age of 1. They can also suffer low blood-sugar levels leading to seizures, among other problems, according to the NIH.
People with Prader-Willi have low muscle tone, a slow metabolism, and an insatiable hunger. If left alone, they might raid the cabinets, fridge, or trash to steal food, and it isn’t unheard of for them to eat so fast they choke to death, or rupture their esophagus or stomach.
Appetite suppressants and gastric bypass don’t work for people with Prader-Willi. While most of us might know what it’s like to feel full, these patients frequently feel what would be the worst feeling of hunger an average person has ever had, according to Gottesdiener.
Take Kate Kane, who lives in a home in Wisconsin for people suffering from Prader-Willi. To regulate her weight, she is restricted to eating 1,200 calories of food a day and must be monitored to ensure she doesn’t over-indulge. That includes during travel. Kate is currently visiting her family in Baltimore, but Jim flew to Wisconsin to pick her up. The autonomy of flying alone ended after a previous incident in which she convinced a flight attended she was in need of numerous bags of cookies because of low blood sugar from diabetes (it wasn’t true). The Kanes have to lock up their food when Kate visits to protect her.
“It totally controls and impacts her life,” Jim Kane said.
Beloranib’s fall puts more of a focus on setmelanotide and other experimental drugs in clinical testing for Prader-Willi. So far Rhythm hasn’t seen any significant safety problems in its own Prader-Willi program. Small molecule drugs that boost the activity of MC4 haven’t made it to market before in part because of an association with heart problems—namely high blood pressure, according to Rhythm. It’s worth watching whether those type of problems pop up with more patients and longer-term use of setmelanotide.
“We’re hopeful that [the drug’s progress] continues and something happens,” Jim Kane said. “If somebody can solve this—wow.”