Born Again

October 1, 2006

Pharmaceutical Executive

Volume 0, Issue 0

Most people have never heard of psychotic depression, but they are familiar with the case of Andrea Yates, who tragically murdered her children during an episode of the disease.

MIFEPRISTONE, BETTER KNOWN AS RU486, IS ONE OF THE MOST CONTROVERSIAL AND politically charged drugs ever approved. To abortion opponents, it does the unthinkable: It stops the creation of a human being. But researchers at Corcept, a small pharmaceutical company based in Menlo Park, California, believe the drug represents much more. To them, mifepristone is potentially

  • the first therapy specifically targeted at psychotic major depression (PMD), a disease that affects more patients than either schizophrenia or manic depression, and leads to suicide in approximately 15 percent of patients;
  • the first psychiatric treatment intended for acute, episodic use in a therapeutic area where patients often rely on perpetual, daily medication—often throughout their entire lives;
  • a major step forward in drugs based on the concept of regulating cortisol, the "stress hormone"—which could lead to treatments in conditions as diverse as Alzheimer's disease and weight gain associated with the use of antipsychotic drugs.

Corcept CEO and co-founder Joseph Belanoff

Corcept has a long way to go to prove to FDA that Corlux, its mifepristone product, works. The early-stage trials were promising, but the first of its three Phase III studies produced disappointing results. Corcept is soldiering on with its two remaining trials, as well as with a separate study, funded by Eli Lilly, involving weight gain. Even if studies of Corlux fail to meet critical endpoints, the tests might still provide clues to improving the current arsenal of treatments for psychosis.

The field of drug development is rife with examples of old drugs being used for new purposes. But Corlux is the exact same drug at the exact same dose as Danco Laboratories' Mifeprex, one of the two pills used to induce a medical abortion. If it successfully completes Phase III trials, the drug could face more than the usual regulatory challenges, and Corcept's management team will need to respond to concerns about access and distribution.

They say they're ready. They say that the drug's controversial past is actually an opening for company executives to spotlight what's truly unique and innovative—not just sensational—about their product.

ACUTE-CARE DEPRESSION

PMD is a disease in which severe depression is laced with episodes of delusions, hallucinations, anxiety, and insomnia. Though it affects approximately three million people—about 20 percent of those who suffer major depression—and can lead to strikingly bad outcomes (patients with PMD are 70 times more likely than the general population to kill themselves), it is not well known.

CFO Fred Kurland believe that mifepristone, or RU486, might one day treat psychotic major depression.

"Most people have never heard of [PMD]," says Fred Kurland, Corcept's chief financial officer. "But most people in this country have heard of the case of Andrea Yates, the woman in Texas who, while suffering from an episode of this disease, unfortunately drowned her five children. It was not only a bad ending for her and her family, but it just displayed yet again the inadequacy that psychiatry has in dealing with this disease."

Psychiatrists often try a combination of antidepressants and antipsychotics to address the disease symptomatically. When those options fail, their next best hope is several treatments with electroconvulsive therapy (ECT), which is administered under general anesthesia and carries significant risk.

Still, while psychosis is the hallmark of the disease, patients experience only a median of three to five episodes over the course of a lifetime. And that profile makes treating PMD akin to treating an infection, Kurland notes.

"PMD is not a chronic disease like, say, schizophrenia; it's an episodic disease," he says. "Now, the episodes are very severe; they last anywhere from six to 18 months. And they are the primary cause of all suicides and homicides that occur. But, interestingly, if you get through an episode...you could be well."

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.

Normal cortisol levels resemble a sine curve: high in the morning, low in the afternoon, and rising at night. Cortisol levels also spike up during a stressful event. "But in healthy people, after the event comes and goes, the cortisol level goes back down to normal," Kurland says. "In patients with PMD, the cortisol level is high and stays high. It is what they call unrelentingly high."

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.

If the product is approved, Corcept will handle sales, marketing, and distribution in the United States, hiring about 35 sales reps to focus on the 300 or so hospitals that offer ECT. It also plans to work with FDA to closely monitor how the drug is dispensed.

Giving psychiatric patients mifepristone isn't controversial in and of itself. Neither men nor women experienced any reproductive side effects in a study of 250 patients, Kurland notes. One of Corlux's trials even included a nun, he adds. "People get it—you don't ban scalpels because they can be used to kill people." But like Mifeprex, Corlux would be administered under observed dosing guidelines, and women would be required to fail a pregnancy test before receiving it. As Kurland points out: "We don't want to be—even inadvertently—in the abortion business."

Yet controlled distribution could prove to be an advantage to Corcept, because it discourages generic competition, notes Sanchez.

Even if Corlux's trials do not meet their necessary endpoints, Kurland notes that the company was built around the study of the GR2 receptor and its antagonists, not mifepristone, which is off patent. Corcept's own patents, some of which are licensed from Stanford, cover the use of GR2 antagonists to treat disorders such as early dementia, stress disorders, mild cognitive impairment, psychosis associated with cocaine addiction, and weight gain associated with antipsychotic medication. The next evolution of the company's research would involve finding a compound that can block GR2 without blocking progesterone—with the hopes of one day treating disorders ranging from post-traumatic stress disorder to post-surgical delirium.

NEXT GENERATION DRUGS

Cortisol, moreover, doesn't just play a role in stress. It also acts as an insulin sensitizer. In animal studies, rats that were given Corlux in combination with the antipsychotic drug Zyprexa (olanzapine) were able to avoid the weight gain that is a common side effect of that product. They also lost weight that they had put on after taking a course of standalone Zyprexa.

Eli Lilly, Zyprexa's manufacturer, is now partnering with Corcept to fund a proof-of-concept study that would test whether it's possible to develop an antipsychotic that avoids severe weight gain. Patients on antipsychotics gain an average of two pounds a week—worrisome enough for FDA to require a black-box warning about diabetes on package labels. Corcept also counts five additional companies that market antipsychotics containing the same warning.

Eli Lilly has no intention of marketing Corlux as a concomitant therapy to Zyprexa. Rather, the study will help the company understand whether GR2 antagonists can mitigate weight gain, which might not even be caused by the drug itself, notes Carole Puls, a spokeswoman at Eli Lilly. "There's been no research that draws any conclusion in that regard," she says. "We just want to understand the how and why, and how we can lessen this [side effect] in the future. You want to make sure you're treating the patient holistically."

The results could also show that there is life for Corcept beyond Corlux's Phase III results. The financial future of a still-productless company is always uncertain—but, confident, Corcept will seek funding to continue trials in 2007. And the company's researchers plan to pursue additional proof-of-concept studies, to move forward the next generation of pre-clinical compounds.

Sanchez wants to see more evidence beyond rat studies—but is cautiously optimistic about Corcept's future prospects. "You shouldn't assign too many expectations until there's more clinical data," he says. "But if it's positive, it's huge."