Corcept Therapeutics Inc. still has hopes of building a portfolio based on cortisol blocking drug mifepristone, but it looks like psychotic major depression (PMD) is off the table after the monitoring committee reported that an ongoing phase III trial was unlikely to hit its primary endpoint, defined as a rapid and sustained reduction in psychotic symptoms.

Shares of the Menlo Park, Calif.-based company (NASDAQ:CORT) fell $2.03, or 50.5 percent, to close Wednesday at $1.99.

The latest miss marks the fourth pivotal failure for mifepristone in PMD, a disorder characterized by severe depression accompanied by delusions, hallucinations or both that has no currently FDA-approved treatments and, according to Cortellis Clinical Trials Intelligence, there are no other candidates making their way through the clinical pipeline in PMD.

Corcept's Studies 07 and 09, which read out in 2006, both missed their endpoints. The studies were designed to assess the proportion of patients with at least a 50 percent improvement in the Brief Psychiatric Rating Scale Positive Symptom Subscale at both day seven and day 56, and Corcept execs attributed both misses to higher-than-expected responses in the placebo arms. (See BioWorld Today, Aug. 28, 2006, and Oct. 2, 2006.)

A third phase III study, Study 06, missed in 2007, though the company latched onto a statistically significant correlation between plasma levels and clinical outcome. Corcept then designed 450-patient Study 14 to incorporate those lessons, opting to use the higher 1,200-mg dose once daily for seven days and again comparing the number of patients in the treatment group who meet response criteria at both days seven and 56 vs. either placebo or antidepressant control.

Yet, that trial, too, fell short. An interim analysis of data from the first 226 patients enrolled failed to reach the primary endpoint, and the monitoring committee advised that continuing on to full enrollment would unlikely result in statistically significant data.

"Mifepristone beat placebo," CEO Joseph K. Belanoff clarified during the earnings call, "but not with statistical significance." Quantitative data will be available at a later date. Belanoff, whose work on the drug dates back a number of years and who personally treated the first five patients in the PMD program, called the miss "disappointing," and said it also highlights the difficulty in designing a trial that will yield data in a consistent manner. "it's a problem for a lot of CNS diseases," he added.

At this point, "we've maxed out what we can do to make these studies run the best that we can," Belanoff noted. Should further information come to light, Corcept could consider revisiting the PMD indication with mifepristone.

But even if Study 14 had hit its endpoint and garnered Corcept an approval, it's unclear how successful mifepristone would have been commercially in PMD. Corcept licensed the glucocorticoid receptor II antagonist – perhaps more infamously known as abortion pill RU-486 – from Stanford University and the method-of-use patent for PMD expires in 2018.

Regardless, the company is moving on, opting to redeploy resources to move mifepristone in other indications.

SHIFTING TO ONCOLOGY

So far, Cushing's disease has been the only win, though the firm has been slow to reap the rewards. Corcept gained approval of mifepristone, branded Korlym for Cushing's in February 2012. Despite the unmet medical need, the drug's orphan status and the lack of competition, Korlym's launch was disappointing, posting sales of only $1.1 million in the third quarter of 2012, its first full quarter on the market.

And Korlym was not to have the Cushing's space all to itself for long. Novartis AG's Signifor (pasireotide) gained approval in late 2012.

Belanoff attributed the slow sales start to the fact that Korlym represented a new mechanism of action for treating Cushing's disease with which a lot of endocrinologists weren't familiar. "So there's really an opportunity for growth."

In its first quarter earnings, reported Wednesday, Corcept reported net product sales of $4.4 million for Korlym, falling just under consensus estimates of $5 million. But the company reported increasing prescriptions for the drug in Cushing's, prompting it to raise its guidance, previously, $24 million to $28 million, up to $25 million to $29 million.

Korlym also is under review in Europe. Belanoff said the firm has received the EMA's 180 day list of questions and is in the process of submitting a response.

Going forward, the aim is to take mifepristone further into cancer. Preclinical data, largely conducted by researchers at the University of Chicago, have shown that cortisol, a glucocorticoid stress hormone, and its receptors play a significant role in chemotherapy resistance in cancer, particularly in relapsed, metastatic triple-negative breast cancer.

Corcept filed an investigational new drug application late last year for a phase I trial in that patient population, with initial efficacy data expected in the first half of 2015.

Money from the PMD program will be shifted to the firm's "broader goals, particularly our oncology program," Belanoff said.

Additional mifepristone studies are under way at academic institutions, including a phase I/II trial testing the drug in combination with Xtandi (enzalutamide, Medivation Inc. and Astellas Pharma Inc.) in prostate cancer and studies evaluating mifepristone in combination with several existing agents in breast cancer.

Earlier in the pipeline are next-generation compounds, two of which are set to start clinical testing this year, though the firm has not yet disclosed specific indications. Triple-negative breast cancer, Cushing's, metabolic disorders and psychiatric disorders are all possibilities.

Corcept reported a first quarter net loss of $13.9 million, or 14 cents per share, wider than the net loss of 9 cents per share predicted by analysts. The company said its first quarter figures include $3.3 million in performance bonuses for accomplishments during 2013.

As of March 31, the firm had about $43.6 million on its balance sheet.

Corcept said it expects to reach cash flow-positive status without having to raise additional funds.