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In 2002, the Food and Drug Administration rejected an antidepressant known as gepirone. In 2004, it gave the drug the thumbs-down again. Ditto in 2007.

And yet, an FDA advisory committee will be considering the drug once more on Tuesday, marking just the latest act in the decades-long drama of gepirone.


Gepirone’s repeated appearances before the FDA represent how companies press ahead in spite of rejection, haggling with regulators over study details in hopes that persistence will carry the day. At a time when potential blockbuster drugs and accelerated approvals grab headlines, grinding it out can occasionally pay off. Last year, for example, the FDA gave the greenlight to three drugs on their fourth or fifth review.

The development saga of gepirone stretches back to at least 1984, with more than a dozen clinical trials conducted over the span of 20 years. The drug bounced among different companies like a therapeutic hot potato, with Fabre-Kramer Pharmaceuticals, a private company based in Houston, holding the rights today.

The FDA rejected gepirone the first two times, when it was licensed to Organon, because it found only one relevant study showed positive results. In 2007, when GlaxoSmithKline had partnered with Fabre-Kramer on the drug, the FDA determined that the sponsors had the two positive trials needed to meet standards for approval for psychiatric medicines but said concerns from a host of negative or failed trials outweighed those studies.


In 2012, Fabre-Kramer appealed the decision to the director of the FDA’s Office of New Drugs, which asked an advisory committee to re-review gepirone.

Which brings us to Tuesday’s hearing.

At the heart of the dispute: the FDA and the company remain at odds over how many studies outside the two positive trials the FDA should consider when determining whether to approve gepirone.

In documents, Fabre-Kramer (which is no longer partnered with GSK on the drug) argues that several of the gepirone studies should be considered “uninterpretable” and not factored into the regulatory decision, either because they were stopped early or had the wrong patient population. It asserts that performing an analysis of what it considers to be valid studies show “statistically significant benefits” of the drug.

But the FDA has accounted for a larger selection of the studies, finding that the trials that don’t demonstrate benefit outnumber the two trials that did. “The large number of negative/failed trials has led to a conclusion that the two positive trials could have occurred by chance and that substantial evidence of effectiveness has not been provided,” agency officials wrote in an Oct. 13 memo to the advisory committee of outside experts.

“What I find at stake here is not just gepirone.”

Dr. Stephen Stahl

Fabre-Kramer, for its part, also contends that gepirone has a significant advantage over existing depression medicines when it comes to side effects. Prozac, Zoloft, and many other antidepressants block the absorption of serotonin at a number of receptors in the brain, but gepirone modulates serotonin by targeting just one receptor. This difference, Fabre-Kramer claims, explains why gepirone does not impair sexual function — a common side effect of the other drugs.

But homing in on only one receptor might not do the trick to combat depression. “I don’t know if that’s enough to the push the system in the direction that makes it work,” said Dr. Adam Kaplin, a Johns Hopkins psychiatrist who does not have ties to Fabre-Kramer. But, Kaplin added, the long-term effects of focusing on one receptor are not known.

When the FDA last considered gepirone, analysts predicted that sales of the drug could reach up to $1.6 billion each year if it was approved, according to a 2007 Reuters story. The company has not speculated on sales recently, but some analyses have predicted a shrinking market for anxiety and depression treatments overall.

Dr. Michael Thase, a consultant for Fabre-Kramer who will be presenting before the FDA Tuesday, said new antidepressants like gepirone are needed because many patients do not respond to available drugs or cannot tolerate the side effects. “I have my patients tell me this every day,” said Thase, a psychiatrist at the University of Pennsylvania Perelman School of Medicine.

Another Fabre-Kramer consultant, Dr. Stephen Stahl, worries that if the FDA does not approve gepirone, it would discourage companies from trying to create new psychiatric drugs, which many companies already avoid because of the high failure rate. “The last thing we need to do is nail the coffin shut,” said Stahl, founder of the Neuroscience Education Institute. “What I find at stake here is not just gepirone.”

But the need for new treatments should not push regulators to ignore evidence about a drug’s effectiveness, said Dr. Dost Öngür, chief of the psychotic disorders division at McLean Hospital. Öngür, who is not affiliated with Fabre-Kramer, said any one study could be explained away, and that’s why the committee should consider the totality of the trials.

“It certainly raises those unusual concern of, were those positive studies just happening by chance?” he said.