[Updated, 12/3/15, see below] A second patient on an experimental treatment from Boston-based Zafgen has died from a pulmonary embolism, casting even more doubt on the future of the drug.
Zafgen (NASDAQ: ZFGN) said in a statement Wednesday morning that it learned on Tuesday that a patient with Prader-Willi Syndrome taking its drug, beloranib had died after suffering a pulmonary embolism—a blood clot that gets lodged in an artery in the lungs. The patient was participating in an open-label (unblinded) extension of a Phase 3 trial whose protocol was modified at the behest of the FDA in mid October, after a first trial participant died of an embolism.
“Our thoughts are with the patient and their family at this time,” CEO Tom Hughes said in a statement.
[Updated with details on FDA hold] In the announcement, Hughes had said Zafgen was in talks with the FDA to “determine the next steps of the beloranib program.” Just hours later, Zafgen revealed in a second statement that the FDA placed a so-called complete clinical hold on the drug, suspending the Phase 3 extension study altogether, and barring Zafgen from continuing any other trials of beloranib until the hold is lifted.
“Together with [Prader-Willi] and thrombosis experts, we are developing a comprehensive approach to better understand the incidence and mechanisms underlying thromboembolic disease in the setting of [Prader-Willi],” Hughes said in the second announcement. “We remain committed to advancing beloranib as a potential new therapy for this underserved patient population.”
[Updated with share price movement] Shares of Zafgen plummeted more than 60 percent on Wednesday (Dec. 2), and were down another 10 percent, to about $5.64 apiece, in pre-market trading on Thursday.
The patient’s death is terrible news for Zafgen and patients with Prader-Willi, a rare genetic disorder that causes insatiable hunger. Prader-Willi can cause severe obesity if not managed properly and, in some cases, even death. The only approved treatment for Prader-Willi is human growth hormone, and it doesn’t impact patients’ never-ending impulse to eat. Zafgen’s drug had shown signs of doing so in an earlier trial, and it’s the closest thing patients have to a treatment. As Janalee Heinemann, the research director of the Prader-Willi Syndrome Association told Xconomy recently, beloranib “is the most exciting potential drug [for Prader-Willi] to come along.”
But new drugs are approved based on how the risk of taking a treatment balances against the benefit it provides. And today’s news is more evidence of risk associated with beloranib.
When Zafgen last revealed data on beloranib a few weeks ago during an earnings call, seven out of about 400 patients dosed with the drug had had blood clots, and none out of about 150 on placebo.
In October, Zafgen announced that a patient taking beloranib in the Phase 3 trial died from respiratory failure following a pulmonary embolism. The FDA came in and placed a so-called partial clinical hold on studies of the drug. Under its terms, Zafgen could continue the Phase 3 Prader-Willi study—but it had to screen each patient for possible blood clots first.
Hughes told Xconomy recently Prader-Willi patients may be predisposed to clots and embolisms, so these incidences might be tied to their underlying condition, rather than the drug. In its recent earnings call, the company 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. 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. Zafgen has asked Loker to talk to the FDA to help its case.
“This is by no means an unusual situation, nor is it one that would keep us from having a commercially viable product. It’s just something that requires some discussion,” Hughes told Xconomy recently.
Yet today’s news makes that case tougher to make. Patients who took part in Zafgen’s open-label extension had to be screened for clots, be deemed not at risk for one, and sign a consent form before going back on the drug. Yet even so, a patient taking Zafgen’s drug died. Will the FDA step in and halt all trials of beloranib? Does the drug still have a future? How much risk is acceptable for patients desperate for a treatment? That remains to be seen, and the benefit of beloranib isn’t really known yet. Data from the trial are expected early next year.
Zafgen couldn’t immediately be reached for further comment this morning. For more on Zafgen, Prader-Willi, and the Loker study, check out this piece from last week.