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.
