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Four months after going public on the strength of its GR-II receptor antagonists, Corcept Therapeutics Inc. reached agreement on a special protocol assessment for pivotal Phase III trials to test its lead product Corlux (mifepristone) against the psychotic features of major depression.

The company's stock (NASDAQ:CORT) rose $1.16 Monday, or 15.6 percent, to close at $8.60.

Corlux gained fast-track status from the FDA, since there is no approved drug for psychotic major depression (PMD), which afflicts about 3 million people in the U.S., and the compound is expected to enter the first Phase III trial under the SPA right away, with the second to start in the fourth quarter.

Corcept aims to have initial results from both studies in the first half of 2006.

The primary endpoint for the two randomized, double-blind, placebo-controlled trials is the proportion of patients with at least a 50 percent improvement in the subset of the Brief Psychiatric Rating Scale (BPRS) known as the Positive Symptom Subscale (PSS) at both day seven and day 56, otherwise known as a categorical improvement. In an earlier trial called Corcept 03, responses in one-third of the patients were measured from days seven through 56 and showed a statistically significant difference between Corlux and placebo at 56. Hence the longer endpoint in the new trials.

"We have good data on that [already]," noted Fred Kurland, chief financial officer for Menlo Park, Calif.-based Corcept.

The BPRS is an 18-item rating instrument used to assess psychopathology, and the PSS includes the four items in the BPRS that specifically measure psychosis. Patients must have at least mild psychotic symptoms (that is, BPRS PSS greater than or equal to 12) to enter the studies and will be hospitalized if clinically necessary. Score measures also will be made at days 14, 28 and 42.

The first of the pivotal trials, called Corcept 07, is similar in design to the Corcept 03 trial, and will enroll up to 280 patients at about 20 sites in the U.S., with a randomized one-to-one distribution into either a treatment or a placebo arm.

Patients in the treatment arm will receive 600 mg of oral Corlux once daily for seven days. (All patients must be off any antidepressant and antipsychotic medication for at least one week before beginning the treatment period.) After the seven days of Corlux, all patients will get antidepressant therapy through day 56, although antipsychotic medications or electroconvulsive therapy (ECT) will not be allowed at any time during the study.

The second Phase III trial, named Corcept 06, will enroll about 440 patients at about 30 sites in the U.S. Those patients will be evenly distributed among three active-dose groups (300 mg, 600 mg and 1,200 mg) or a placebo group, with patients getting once-daily dosing for seven days.

Those three dosing levels fulfill the FDA's request to supplement data on a range of potential doses beyond that provided by the 33-patient dose-ranging study finished in 2001. All patients in the study must be off antidepressant and antipsychotic medication for at least one week before the seven-day treatment period and will get antidepressant therapy from day one through day 56. As with Corcept 07, no treatment with antipsychotic medications or ECT will be allowed.

PMD is characterized by severe depression accompanied by delusions, hallucinations or both. People with the disorder are about 70 times more likely to commit suicide than the general population.

Psychiatrists typically use either a drug "cocktail" of antidepressants and antipsychotics or ECT to treat PMD.

"The one that appears to be most effective is electroshock therapy, which everybody knows from seeing movies in the mid-1970s," Kurland said. "It hasn't changed all that much since then. It's very tough on the system, and even setting aside the effects of having 200 volts put through your brain, the costs are staggering."

Corcept found the average cost for an ECT patient is $70,000, with $20,000 to $30,000 of that being the actual shock therapy, and the rest being hospital expenses. At least 100,000 patients get ECT each year in the U.S., requiring six to 12 procedures over a period of three to five weeks.

As for the drugs used in the cocktail, "they have a fairly good track record," Kurland told BioWorld Today. "Maybe as many as 60 percent of patients do get a response, but only after many weeks of therapy" - often in the expensive hospital setting.

"Probably the more important issue is the side effect profile of these cocktails," he said. "This is particularly true of the antipsychotic drugs, which have been in the news lately and not necessarily in a positive way."

Corlux, licensed by Corcept from Stanford University, has patent protection for the PMD indication through 2018, Kurland said. Stanford researchers uncovered the role of "abnormally high and unrelenting levels" of the hormone cortisol in PMD.

This spring, Corcept priced its initial public offering, raising $54 million by selling 4.5 million shares of stock at $12 each, down from the hoped-for amount of $80 million. (See BioWorld Today, Feb. 12, 2004, and April 16, 2004.)

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