[Update: Zafgen announced on Dec. 2 that a second patient in its clinical trial has died, see more details here.] Whether or not a new drug is approved boils down to one basic question: How does the risk of taking the treatment balance against the benefit it provides? And the weight that regulators give to each of those elements can be different for different diseases—for a rare one with no approved treatments, the bar for a drug’s safety and effectiveness might be lower than for, say, yet another drug that reduces blood pressure or soothes aches and pains.
That calibration is going to play a big part in determining the future of a Cambridge, MA-based biotech called Zafgen (NASDAQ: [[ticker:ZFGN]]). Zafgen delivered some bad news a month ago when a 23-year-old patient taking its lead drug in a clinical trial died after suffering a pulmonary embolism—a blood clot that breaks loose from a leg or other part of the body and gets lodged in an artery in the lungs.
A death of a young volunteer in a clinical trial of a “me too” drug for a relatively minor condition might be enough to kill the drug and perhaps even sink the company, but Zafgen’s drug, beloranib, isn’t for blood pressure or tennis elbow. It’s for severe, life-threatening forms of obesity—including a rare genetic condition called Prader-Willi Syndrome that causes insatiable hunger that, if not managed properly, can lead to extreme obesity and in some cases, death. The only approved treatment for Prader-Willi is human growth hormone, and while it helps with some of the complex condition’s myriad symptoms, it doesn’t do anything about one of the disease’s core problems, the never-ending drive to eat.
The possibility of addressing that problem and changing the lives of patients who have virtually no other treatment options represents a powerful potential counterweight to the safety questions raised by the trial volunteer’s death—and gives Zafgen a fighting chance to still get its drug to market. Data from the trial, to be revealed early next year, will show how well the drug lives up that promise, and will largely determine whether the scales tip toward risk or benefit for beloranib.
The story of how Zafgen and its drug got to this point and what might be in store next is a fascinating example of the complicated interplay between drug companies, researchers, patients, and regulators, and of the lengths patients and their families are willing to go in pursuit of new treatments for rare conditions. And it illustrates one of the reasons—alongside premium pricing power and market exclusivity—why biotech companies often target rare diseases before tackling common ones.
Zafgen’s Prader-Willi trial was nearly complete when the company found out about the patient’s death—sometime in early October, according to CEO Tom Hughes—and based on subsequent discussions with the FDA, it expects the agency to still view the study as pivotal (ie, substantial enough to base a drug-approval decision on), the company has said in a statement.
Still, the whole episode has been a mess for Zafgen. Reports on October 12 from Bloomberg and TheStreet.com that it had cancelled a few investor meetings led to speculation that bad news about beloranib was coming, and Zafgen shares went into freefall as the company stayed radio silent. Zafgen finally broke that silence on Oct. 14, revealing that someone in the study had died, but not what the cause of death was or whether the patient had been taking beloranib or placebo. Then, two days later, the company announced that patient had indeed been taking beloranib, and that the FDA had stepped in with a so-called partial clinical hold. Under its terms, Zafgen could continue the trial, but it must screen each patient for possible blood clots. Six days after that, on Oct. 22, Zafgen revealed that the patient’s cause of death was respiratory failure from a pulmonary embolism.
Investors, meanwhile, were clearly livid. Zafgen has already been named in several class action suits that allege it withheld some old data potentially tying beloranib to blood clots, and that the company revealed the information only after its share price was decimated and the FDA hold began.
And questions about beloranib’s safety don’t just jeopardize the drug’s future as a treatment for Prader-Willi. Zafgen hopes to eventually get it approved to treat a more common type of severe obesity as well. When a drug is potentially meant to be taken over the long term by a large group of patients, safety concerns become particularly critical. “Overall, I think you have to lower the probability of [the drug’s] success and the market penetration it might have,” says RBC Capital Markets analyst Simos Simeonidis.
But before Zafgen can reach even the first small market segment that it’s targeting it will need, among other things, to address the question of whether beloranib causes clots and embolisms of the sort that killed the patient in the Prader-Willi trial. There’s not a lot of data to go on: So far, seven out of about 400 patients dosed with the drug have had serious blood clots (including the patient who died), compared to none out of 150 on placebo, according to Zafgen. Simeonidis says he thinks there is a correlation between the drug and the clots, but “you can’t really say that with certainty” given the data so far.
Zafgen’s Hughes, on the other hand, says that patients with Prader-Willi may be predisposed to clots and embolisms, and so the fact that a patient taking beloranib suffered one is not necessarily an indictment of the drug’s safety.
“It’s a very sad thing, and we’re very touched by it, and we feel horrible for the family who had to experience this as well as for the investigator involved, but this is not an uncommon form of death or cause of death in this population,” Hughes says. “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.”
Involved in that discussion are the FDA and the company, of course, but also patient groups, researchers, and the families of Prader-Willi patients. Jim Loker, a pediatric cardiologist at Bronson Hospital in Kalamazoo, MI, belongs to
