A partial clinical hold placed by the FDA on two Zafgen Inc. trials following a participant’s death continued to hold company shares (NASDAQ:ZFGN) near an all-time low Friday, pushing them $10.66 lower, or 50.7 percent, to close at $10.36.
The cause of the death is still unknown. But Zafgen now plans to better screen Prader-Willi syndrome (PWS) patients enrolled in the phase III study of beloranib for existing thrombotic disease – the hypothesized culprit – and expects to resume dosing for most study patients within about two weeks.
“The death, we know, was not due to something that would be easily explained. Otherwise, we wouldn’t be in this situation,” said Tom Hughes, Zafgen’s CEO, during an investor conference call to discuss the hold. “If we knew what had gone on, we would be far better informed as to how to carry out our next steps and to integrate the finding.” (See BioWorld Today, Oct. 15, 2015.)
The hold affects two phase III studies in PWS, both the ongoing ZAF-311 trial in which the death occurred and the planned ZAF-312 trial, which the Boston-based company expects to start after ZAF-311 is completed and a full assessment of the safety and efficacy of beloranib by the FDA is complete. Patients will also be re-consented for the trials.
Zafgen has proposed to the FDA screening patients in its ongoing phase IIb study, ZAF-203, a study of beloranib in patients with severe obesity complicated by type 2 diabetes that’s being conducted in Australia.
Without knowing exactly where to start, Zafgen and the FDA have decided to look at “what’s the most potentially dangerous thing that we’ve observed in any of the studies, whether or not it’s attributed to the drug, and [work to] get our arms around that to make sure that we’re not ignoring a potential risk that should be managed,” said Hughes. The biggest threat to patients on beloranib in the PWS studies so far has been thrombotic events. Six have been reported to date, including one in ZAF-311, one in severe obesity trial ZAF-203 and four events in an earlier general obesity trial designated ZAF-201.
The focus now is on the risk of thromboembolic events in the context of PWS, a rare genetic syndrome with a high rate of mortality – about 3 percent annually across the population, the company said – with an average life expectancy of about 30 years. Mortality in the condition is often linked to obesity and related co-morbidities.
While there’s really no signal that Zafgen has been able to flag in the trials, Hughes said that “what we can’t exclude – and this is the point of this screening and monitoring that we’re doing – is there may be some potential interaction between the drug treatment that would unmask some latent predisposition for thrombosis.”
Zafgen’s chief medical officer, Dennis Kim, told investors he believes the new screening measures can be implemented rapidly, allowing dosing in the ZAF-311 study to resume “in short order, on a patient-by-patient basis, with minimal impact to trial integrity and timelines.” In fact, said Kim, the ‘311 study is nearly complete, with about 75 percent of patients having already reached the full six-month endpoint of the blinded randomized phase of the trial, progress that will allow the company to stick with plans to report top-line data in early 2016. Once Zafgen has those data in hand, it will work with the FDA to get a better picture of the risk-benefit proposition of the study.
Cowen and Co. analyst Phil Nadeau said he found the “emerging association troubling. It is fair of ZFGN to note that just one or two events in placebo patients would eliminate the imbalance and therefore the strength of beloranib’s association is difficult to judge given the relatively small patient numbers. Nonetheless, in the data available as of today it does appear that an association is emerging.” Based on that concern, Cowen lowered its price target on Zafgen shares to $20, from a former $60.