After Patient Death in Zafgen's Phase III Obesity Study, FDA Places Partial Hold on Trial

After Patient Death in Zafgen's Phase III Obesity Study, FDA Places Partial Hold on Trial
October 16, 2015
By Mark Terry, BioSpace.com Breaking News Staff

After a week of concerns over company stock, canceled investor meetings and a death in a clinical trial, Boston-based Zafgen announced today that late yesterday the U.S. Food and Drug Administration (FDA) gave the company verbal notice that a partial hold had been placed on its clinical trial of beloranib.

Zafgen is working on a drug to treat obesity. Its experimental compound, beloranib, a methionine aminopeptidase 2 (MetAP2) inhibitor, is believed to re-establish the body’s ability to metabolize fat. It is currently undergoing a Phase III clinical trial in patients with a rare genetic disorder, Prader-Willi Syndrome (PW), which, among other symptoms, causes uncontrolled eating. The drug is also being investigated in Phase II trials in patients with hypothalamic injury-associated obesity and severe and complicated obesity.

On Monday, the company canceled an investor meeting originally scheduled for Tuesday, Oct. 13 organized by RBC Capital, then canceled a Wednesday investor dinner hosted by the Maxim Group. Analysts and investors speculated that something was amiss, and the company responded accordingly, dropping from Oct. 9’s price of $34.40 to $22.15 on Monday Oct. 12. Shares are currently trading at $13.67.

Later in the day on Wednesday, Zafgen released a statement that a patient had died during the course of the Phase III study in patients with Prader-Willi Syndrome. At that time, the cause of death had not been determined. That is apparently still true, although it has been determined that the patient who died had been receiving beloranib, which is why the study is being halted.

“Patient safety is our top priority,” said Thomas Hughes, chief executive officer of Zafgen, in a statement today, “and we will work closely with the FDA to implement these measures to support the further development of beloranib.”

Patients in the study will be screened for existing thrombotic disease before continuing the study, and will also be regularly monitored. The study is almost completed and Zafgen indicates it expects to report top-line results in the first quarter of 2016. It is also considering screening and monitoring in the company’s other studies of the drug.

A second late-stage study is planned, but won’t begin now until the FDA assesses the first study. The Phase III clinical trial began in October 2014 and has been confirmed as safe in earlier trials.

Prader-Willi Syndrome is caused by a chromosomal deletion in chromosome 15. Although its most prominent symptom is insatiable appetite that leads to excessive eating and obesity, it also includes cognitive disabilities, behavioral problems, short stature, low muscle tone, and incomplete sexual development. As stated by The Prader-Willi Syndrome Association, “Those who have PWS need intervention and strict external controls, sometimes including padlocking access to food, to maintain normal weight and to help save their lives.”

The genetics of Prader-Willi Syndrome is very complex, and is typically noted in comparison to another genetic syndrome, Angelman Syndrome, as the first primary example of genetic imprinting. Both Prader-Willi Syndrome and Angelman Syndrome involve deletions of the same genes on chromosome 15. However, certain genes are switched on or off in a process called imprinting. If the missing genes originated from the father’s chromosomes, PWS is the results. If the missing genes originate from the mother’s chromosomes, Angelman Syndrome is the results. Angelman Syndrome is characterized by learning and speech difficulties, a very happy disposition, and very idiosyncratic jerky movements.

Patients with PWS have an approximately death rate of 3 percent per year compared to 1 percent per year for the general population.

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