all of the latter three groups. The father of a daughter with Prader-Willi, Loker has been analyzing the causes of death for patients with Prader-Willi using data collected by the Prader-Willi Syndrome Association since 1973. The study is meant to help better understand Prader-Willi, the types of problems it causes for patients, and how to prevent the sudden deaths that are sometimes associated with the disease. In a study presented two weeks ago at the annual meeting of the PWSA in Florida, Loker found that of the 310 patients in the PWSA’s database whose cause of death was known, 19 had been killed by a pulmonary embolism. An additional four died of something else but had a pulmonary embolism as well.
Interpreting this number without knowing, for example, how it compares to pulmonary embolism deaths among obese patients without Prader-Willi, is tricky. Still, Zafgen views it as a piece of the beloranib puzzle. The company included Loker’s findings as a slide in its latest earnings call with analysts last week, with Hughes stating that “it’s against this backdrop of severe morbidity and increased mortality that our drug should be evaluated.” Via e-mail, Simeonidis said the findings are “helpful and relevant…definitely helps their case.” No surprise, then, that Zafgen has asked Loker to talk to the FDA to help make its case about beloranib.
Loker had only sporadically heard of beloranib until recently—his 21-year-old daughter doesn’t need it, he says. But he and his wife have been active members of the PWSA for years, and much of that time he’s been on the nonprofit’s “mortality review committee.” After a Prader-Willi patient dies, the agency talks to the family, and collects information about the patient and his or her cause of death.
“The best way to prevent future deaths is to know what’s been causing the deaths that we have,” Loker says.
Indeed, there’s much that’s still not known about Prader-Willi. The disease is rare, currently affecting one in every 12,000 to 15,000 babies born, according to the PWSA. Much of the underlying biology remains a mystery, but two things are certain. First, it’s genetic, caused when certain genes on chromosome 15 don’t work properly. Second, patients with Prader-Willi are essentially born with a malfunctioning hypothalamus, the part of the brain that controls the production of hormones.
As a result, people with Prader-Willi have very low muscle tone, a super 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. Loker says choking and gastrointestinal perforations were responsible for 5 percent and 6 percent, respectively, of the Prader-Willi deaths he’s tracked.
“It’s a wicked combination of everything that could go wrong has gone wrong to create obesity,” says Janalee Heinemann, the research director of the PWSA, whose 42-year-old son Matt (pictured above, left, with Heinemann and her husband) has Prader-Willi, and is in the clinical trial for beloranib.
Appetite suppressants don’t work for people with Prader-Willi, and gastric bypass and other types of surgery are dangerous—they only make the stomach smaller and more likely to be overwhelmed by a food binge. Loker and his wife instituted a strict food regimen to help their daughter, Anna, who was diagnosed with Prader-Willi before the age of two.
“She’d always had the same schedule—we never varied. Always the same thing for breakfast, morning snack, lunch, afternoon snack, and we just fed her what we were eating but a smaller portion at dinner,” he says. “That’s what she got used to, so if she ever said she was getting hungry, we could say, ‘Ok look at the time, this is when you eat.’ And that was enough for her.”
This is an example of the sort of thing that most families and caregivers of Prader-Willi patients have to do to protect their loved ones. It could mean bolting the refrigerator, monitoring exactly what a patient eats and when, and having someone around at all times to make sure they don’t ultimately harm themselves. Most, though not all patients can’t live independently; Loker’s daughter, for instance, is in a group home.
What would make beloranib potentially a game changer here is that, in a 17-patient, four week (the small scale and brevity should be noted), mid-stage trial, it helped patients not only to lose weight, but also to feel less hungry. This was measured via a composite score based on patients’ behaviors (logged by caregivers) such as stealing food, or becoming “unmanageable” because of a preoccupation with food, according to Hughes. The official number was a 52.4 percent reduction in these types of behaviors at the highest dose of beloranib (1.8 mg) over the course of the study.
“To be quite frank, this has been the most exciting potential drug [for Prader-Willi] to come along,” Heinemann says.
Beloranib is an injectable small molecule that inhibits the activity of an enzyme called methionine aminopeptidase 2 which, in turn, is supposed to cause the body to burn more fat. Zafgen’s strategy has been to test beloranib against very severe obesity-related conditions, including Prader-Willi and a type of obesity caused by injury to the hypothalamus. It’s also testing the drug in a more general population of severely obese patients with type 2 diabetes—a larger market opportunity—but moved Prader-Willi to the forefront so it could run smaller, quicker trials and potentially get to market faster. [An earlier version of this story incorrectly referred to beloranib as an antibody.]
In October of last year, the company began enrolling patients in its key test, a 108-patient, placebo-controlled, six-month study of beloranib in Prader-Willi patients. Given the type of rapid and substantial weight loss Zafgen has shown in earlier studies and the apparent lack of severe safety problems—the most common side effects reported were nausea, vomiting, diarrhea, and sleep trouble—expectations have been high. Zafgen priced an initial public offering in June 2014 at $16 per share, the top of its projected range, and shares climbed following the IPO. They were worth as much as $50 apiece in March 2015 and $46 apiece in mid-September, in the heights of the biotech boom. Zafgen raised money through secondary offerings during the good times, and had $204 million in the bank at the end of September.
“We were as surprised as everybody else that our stock rose to the level that it did on the absence of any news,” Hughes says.
Those numbers have only made Zafgen’s subsequent
