THE CORTISOL CONNECTION

Corcept's approach to PMD grew out of research done by two of its founders, Alan Schatzberg, MD, chairman of the company's scientific advisory board, and CEO Joseph Belanoff, MD. (Both are also professors in the Department of Psychiatry and Behavioral Sciences at Stanford University.) Schatzberg's early research, which he conducted at Harvard's McLean Hospital in the 1970s and 1980s, focused on the biochemical differences between PMD, schizophrenia, and clinical depression. He eventually identified a link between PMD and cortisol, and began to look for a way to regulate cortisol levels.

Cortisol plays a role in regulating metabolism and emotional stability; it also has anti-inflammatory effects. But exposure to too much of it can cause high blood pressure, insensitivity to glucose, and concentration and memory problems.

In 1991, Schatzberg became chairman of the psychiatry department at Stanford, where he and Belanoff continued to look for a way to reduce excess cortisol levels in PMD patients without disrupting the hormone's daily rhythm. Several years later, they found mifepristone.

When used to induce an abortion, mifepristone works by blocking the receptor for the pregnancy hormone progesterone. But it also blocks glucocorticoid receptor two (GR2), a low-affinity receptor that takes up the excess cortisol that is produced in response to stress, without blocking GR1, the high-affinity receptor that maintains the diurnal sine curve. Mifepristone has been studied for a host of conditions ranging from Cushing's syndrome, a condition caused by excessive production of corticosteroids, to Alzheimer's disease.

Two Phase II studies, published in the past year in Neuropsychopharmacology and the Journal of Clinical Psychiatry, found that mifepristone significantly reduced the symptoms of psychotic depression. And both studies found no side effects associated with a daily 600-mg dose (which is the same dose as Mifeprex) over a course of eight and six days, respectively.

But in the first Phase III trial of Corlux, for reasons that are not entirely clear, a weeklong course of the drug failed to show greater efficacy than a placebo.

Part of the problem seems to stem from an unusually high placebo effect. At day 56, for instance, 80 percent of patients in both the placebo and mifepristone arms of the study reached the target amount of improvement—a finding made more unusual since PMD patients typically demonstrate low rates of placebo response. "This really is an unprecedented high placebo rate," Belanoff said after the release of the data. "Obviously we're very disappointed with the results. We're certainly going to look into the details."

Two more Phase III trials are in the works: a trial in Europe that was to be wrapped up last month and another in the United States that is expected to yield results at the end of the year. "The studies do have minor differences," Belanoff says, "but basically the protocol is quite similar."

CONTROLLING DISTRIBUTION

If Corlux is approved, psychiatrists could be attracted to its relative inexpensiveness, weeklong dosing regimen, and comparative safety profile, notes Juan Sanchez, MD, an analyst at Punk, Ziegel & Co. In other words, physicians would try Corlux simply because there is no reason not to. "You have nothing to lose," he says.

But Sanchez is concerned about whether a company of Corcept's size will be able to conduct enough well designed clinical trials to see a positive effect. Corcept needs two positive trials for its FDA application, which was given Fast Track status by the agency; both of its remaining Phase III studies, therefore, will need to show better results than the first. If they don't, the company might not have the funds to redesign trials.