After a Clinical Trial Death, Zafgen Presses On, Families Stay Calm

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fall that much more dramatic. Hughes won’t say the exact date, but towards the beginning of this October the Prader-Willi study was “essentially more than two thirds done,” he says, when Zafgen learned that a participant had died. FDA protocol mandates that this information has to be submitted to the agency within seven days, and Zafgen did so, notified the trial’s safety oversight committee, and began talks with the FDA.

Hughes says when Zafgen got the news, it didn’t have a death certificate or the autopsy results. A scramble ensued over the Columbus Day weekend to get more information so Zafgen could begin to figure out what happened. “As the sponsor of a study, we don’t know who these patients are, we don’t know where they live, they’re blinded to us for patient confidentiality reasons, and so the study center itself is what was really charged with working with the family to get this information, to get consent, and get the documents transferred,” Hughes says. “The family is grieving, there’s a holiday weekend involved, and it was just very, very hard for us to get information that would be very useful.”

From the outside, no one had a clue about any of this until reports surfaced on Columbus Day Monday, October 12 that Zafgen cancelled investor meetings in New York slated for the 13th and 14th. Word spread quickly through social media, and speculation ran rampant that something was up. Zafgen stonewalled requests for comment from reporters (Xconomy included), analysts, and shareholders, and its stock began dropping faster and faster. In two days, without any news, shares lost more than half their value, from $34.76 at the open on the 12th to $15.75 at the close on the 13th.

Zafgen finally made its initial disclosure about the patient’s death on Oct. 14, and its shares temporarily rebounded. Hughes says Zafgen worked with the FDA to get all the information, and unblinded the trial and agreed on the clinical hold the following day. Then, on the morning of Oct. 16, it released another announcement and held a conference call, during which it gave details on both the patient who died and the six other instances of blood clots in beloranib trial participants. Zafgen’s shares plummeted more than 50 percent that day and closed at $10.36 apiece. Lawsuits soon started popping up, with accusations made that Zafgen hadn’t previously disclosed some of the prior instances of blood clots in its trials. Given all that, does Hughes have any regrets? “There’s nothing we would’ve done differently,” he says.

Winning back the trust of investors rattled by the trial participant’s death and Zafgen’s handling of it is one of many challenges that company now faces. But, interestingly, members of the Prader-Willi community itself have reacted with relative calm to the incident. The PWSA’s Heinemann says that there’s been “surprisingly little concern” among PWSA members about the death—a fact that illustrates just how heavily the potential benefit of a new drug can weigh against its potential risks for families coping with serious diseases and few treatment options. “Obviously everybody is sad about a death, everybody gets disturbed about a death,” Heinemann says matter-of-factly. “But this is not the only death they’ve been disturbed about.”

Heinemann plans to have her son, who she says has lost weight and become less obsessed with food on beloranib, participate in a so-called open-label (ie, unblinded) extension of the trial. Zafgen is conducting the study to accumulate more safety data and give patients—at least those who pass the blood-clot screening—continued access to the drug.

“The drug has a lot of potential, and a lot of potential to take away some of the other life threatening issues from Prader-Willi and make his life easier. That has to be taken into consideration,” Heinemann says. “The risk factor needs to be dealt with, but he’s getting the blood tests and the ultrasound and if everything’s ok, I have no problem putting him back on the drug.”

For his part, Hughes took me through each instance of pulmonary embolism or deep vein thrombosis in Zafgen’s trials, and made a case as to why each could’ve simply been part of the patient’s underlying condition. One patient in a Phase 2 study had gout, her leg became inflamed and had to be elevated and immobilized for days, and she developed a blood clot that led to a pulmonary embolism. Another patient had a “major inflammatory dysfunction” in the lungs.

“This is one of the underlying problems of studying an ill population that is at elevated risk of these types of events in the first place,” Hughes says, saying that, in “the absence of any specific knowledge,” all Zafgen can conclude is that beloranib might exacerbate problems these patients already have. If so, as is the case with certain drugs for other diseases, patients taking beloranib might just have to be monitored for particular risks, he says. “In diseases like multiple sclerosis, there’s a screening that has to be done to make sure that the drug doesn’t cause a lethal brain virus to re-emerge,” he says.

In a similar vein, Heinemann points to a past “crisis” with growth hormone, which was eventually linked to potentially severe respiratory problems and even deaths in Prader-Willi patients, and now requires certain safeguards. While people died, the Prader-Willi community learned more about the disease and preventative care from it, she says, and now reaps the benefit of an important drug. “I think that’s what we have to do here,” she says.

And Loker is hoping that the measures Zafgen is now taking will help everyone get a better read on how big a problem blood clots are for Prader-Willi patients, and who is at risk for them. Maybe a trend will be found, and someday as standard procedure, a child with certain characteristics will get an anticoagulant drug that saves his life. That’s beneficial regardless of what happens with beloranib, or Zafgen’s share price.

“Whether it’s this clinical trial or others, we need to know the answer of, is this a risk factor?” Heinemann says. “Because doing nothing and just not doing clinical trials isn’t going to save our kids’ lives.”

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