It’s been a turbulent year for Zafgen, to say the least. Two patients died in a Phase 3 clinical trial of its leading drug candidate and, in December, the FDA halted all studies of the drug. Zafgen’s stock tumbled, and shareholders filed lawsuits against the company. The future of the company’s drug, a potential treatment for patients with the rare genetic disorder, Prader-Willi syndrome, fell into deep uncertainty.
But finally some good news: Zafgen (NASDAQ: ZFGN) is revealing today that the drug, beloranib, met both its main goals in the Phase 3 trial. The drug bested a placebo at reducing patients’ weight, and importantly, behaviors related to what’s known as hyperphagia—an insatiable hunger that can lead to severe obesity and even death in Prader-Willi patients. Both results were statistically significant, meaning they weren’t likely to be due to chance.
Shares of Zafgen climbed about 60 percent, to $8.96 apiece, in pre-market trading on Wednesday morning.
The 107 patients who participated in the study were randomly assigned to receive a high (2.4 mg) or low (1.8 mg) dose of beloranib or a placebo twice a week for six months. Patients in the high dose group on average lost 5.3 percent of their initial body weight. Those in the low dose group lost 4.05 percent, while those on placebo gained 4.15 percent.
Zafgen also tallied a score meant to measure patients’ hyperphagia-related behaviors—things like stealing food or being upset when denied food—by having their caregivers fill out a nine-question questionnaire. The higher the score, which ranges from 0 to 36, the worse the patient’s hyperphagia. Patients started with an average score of 16.9 at the start of the trial, and those on the high and low dose of beloranib saw those numbers fall by an average of 7.0 and 6.3, respectively.
How meaningful is a six to seven point drop on that scale? “That’s a remarkable decrease,” says study investigator Merlin Butler, a psychiatry and pediatrics professor at the University of Kansas Medical Center who has been treating Prader-Willi patients for years. “The results look very promising.”
Zafgen CEO Tom Hughes says the data “meet or exceed” the company’s expectations and, at minimum, are the “first crucial step” to getting beloranib approved.
“The data actually give us the opportunity to move forward,” he says.
That’s a subdued response for a company that just hit its goal in a Phase 3 trial. But that’s because Zafgen still has a long way to go. First, it has to figure out what other data are needed before it can file for approval of beloranib. Then it has to convince the FDA to release the clinical hold on the drug, so it can run the studies necessary to accrue that data. And then it has to determine, when beloranib is tested in more Prader-Willi patients, what, if any, correlation exists between the drug and potentially dangerous blood clots like the ones that were responsible for the two trial volunteers’ deaths.
Hughes won’t disclose any specifics about Zafgen’s path forward, other than to say that the FDA had previously asked the company to come back once it had the Phase 3 data to determine the next steps. Zafgen’s “base case” before the FDA stepped in last year, according to Hughes, was to run a second Phase 3 trial of beloranib in Prader-Willi.
“We’ll be back to you with more information about [that] as we learn that from the FDA,” he says.
Those talks will be a welcome occurrence for Zafgen, which has seen its share price fall more than 80 percent since early October, when it first disclosed that a patient in its Phase 3 trial on beloranib died from a pulmonary embolism—a blood clot that gets stuck in an artery in the lungs.
After Zafgen disclosed the death, the FDA stepped in and halted the trial when, as Hughes told me previously, the study was “essentially two thirds” done. At that point the agency allowed Zafgen to conduct an extension study in which volunteers who had already participated in the original trial could get back on the drug, but only if they were screened for possible blood clots first and deemed not at risk for one. Nonetheless, one of the patients who participated in the extension study died of a pulmonary embolism as well.
Zafgen shared the news in December, and the FDA placed a complete clinical hold on beloranib, suspending the extension study and barring Zafgen from continuing any other trials of the drug. In total, seven of over 400 patients treated with beloranib have suffered blood clots, compared to none out of over 150 on a placebo.
Zafgen has tried to make the case that Prader-Willi patients may be predisposed to clots and embolisms, so these incidents might be tied to their underlying condition, rather than the drug. It noted a study by pediatric cardiologist James Loker, who has been analyzing the causes of death for patients with Prader-Willi using data collected by the nonprofit Prader-Willi Syndrome Association since 1973. Zafgen has asked Loker, whose daughter has Prader-Willi, to talk to the FDA to help its case. (I wrote in November about the complex interplay between Zafgen, the FDA, researchers, and the Prader-Willi community.)
The connection between Prader-Willi and pulmonary embolisms isn’t totally understood, nor is what role, if any, Zafgen’s drug may be playing in potentially exacerbating the problem. The only way to find out is with more data. Hughes says the company will have to understand “what the correct questions are” to ask about safety, and develop a strategy to help mitigate risk going forward.
“There is a need for more research, more time, more subjects, and more validation to see what holds up in the long term,” Butler says.
Janalee Heinemann, the Prader-Willi Syndrome Association’s research director, wrote in December in an e-mail to Xconomy after the second patient died, the safety question “needs to be answered before any of our children and adults with Prader-Willi are further considered for use of this drug.”
“It appears that it has remarkable effects on weight loss and hyperphagia,” she wrote. “But due to the two deaths from pulmonary embolism and the fact that we are just learning through our study of deaths in Prader-Willi that [patients] are more at risk for pulmonary embolisms—with or without the drug—the benefits versus risk must be carefully weighed.”
That’s exactly what Zafgen and the FDA will be doing in the coming months.