[Updated, 9:45 am ET] Alkermes (NASDAQ: ALKS) has released all the details from a mid-stage clinical trial on a drug that attacks depression in a whole new way, giving the company a shot to add a potentially big moneymaker to its portfolio should the results hold up in a bigger study.
The Dublin, Ireland and Waltham, MA-based company today revealed that its once-daily pill for major depressive disorder, ALKS 5461, significantly improved patients’ scores on two standardized, clinically validated tests measuring their symptoms of depression over a two-month span—the primary goal of the 142-patient study. Alkermes CEO Richard Pops says the company will begin discussions with the FDA on a pivotal trial “probably in the late summer,” and aims to start the study at the end of the year or in the beginning of 2014. Alkermes told investors that the trial was a success in April, but the more detailed results of the study haven’t been presented until today at the New Clinical Drug Evaluation Unit (NCDEU) meeting in Hollywood, FL.
Though Alkermes must first successfully reproduce those data in a larger late-stage clinical trial, the results at the very least put Alkermes in the game to make an impact on a large market. About 16.1 million people in the U.S. suffer from major depressive disorder, according to data published in the Archives of General Psychiatry. Many of them don’t respond to initial treatment—typically selective serotonin reuptake inhibitors, or SSRIs. As many SSRIs are generic and thus easy to pay for, Alkermes hopes to treat the group that doesn’t respond to them, giving those people another option before settling on more invasive forms of treatment such as deep brain stimulation, or old techniques like electroshock therapy.
“There’s about 4 million people a year in the U.S. who have failed two SSRIs and move onto a third drug, about 3 million people need a fourth drug,” Pops says. “The need for an alternative pathway is really important.”
SSRIs combat depression by changing the balance of serotonin, a neurotransmitter, in the brain. Alkermes’ drug, by comparison, is designed to work by creating a balance among the opioid receptors in the brain. Opioids, Pops says, have long been known to positively affect mood and depression, but have never been clinically useful because of their addictive properties. ALKS 5461, however, is a combination of both an opioid stimulator (buprenorphine) and an inhibitor (which Alkermes calls ALKS 33) that Pops says is supposed to allow the drug to maintain its antidepressant punch while blocking the addictive potential of an opioid.
Here’s how Alkermes tested that hypothesis. It enrolled 142 patients with major depressive disorder who already didn’t respond well to at least two previous treatments with either an SSRI or a serotonin-norepinephrine reuptake inhibitor (SNRIs). It then utilized a sequential parallel comparison design, a clinical trial paradigm created by Dr. Maurizio Fava and Dr. David Schoenfeld of Massachusetts General Hospital in 2003, as a way for Alkermes to weed out the placebo effect that can easily muck up the data in a depression trial (Fava is the lead investigator in Alkermes’ study).
What this means is, Alkermes broke down the study into two four-week periods, one after the other. During the first four-week period, patients were randomly assigned either a low dose (2 milligrams of buprenorphine and 2 mg of ALKS 33) or a high dose (8 mg of each) of Alkermes’ drug once a day, for four weeks. Once that ended, the trial investigators switched things up. Patients who had been on Alkermes’ drug for the first month got a placebo for the second month. Those that got the placebo the first month were broken into two groups: the ones that responded to the placebo the first month were kept on it the second month; and patients who didn’t respond to the placebo the first month were given Alkermes’ drug the second month. All patients continued taking their SSRIs or SNRIs while on the study.
“The trick is to signal for noise,” Pops says. “You’re able to compare in the second phase what the placebo effect is and then what the drug effect is in the patients who have demonstrated that they don’t respond to placebos.”
Alkermes’ goal for the study, then, was to compare patients’ scores at the beginning and end of the second month on two standardized diagnostic tests administered by mental health specialists: the Hamilton Depression Rating Scale (HAM-D17), which is a 17-question exam gauging the severity of depression symptoms such as anxiety, insomnia, paranoia, sexual function, and weight loss; and the Montgomery-Asberg Depression Rating Scale (MADRS), a similar 10-question test. Each question has its own range of severity, along with a numerical score. The higher the total score, the more depressed the person is. Scores on the HAM-D17 range from normal (0 to 7) to very severe (greater than 23); the MADRS has a range of 0 to 60, with a score of 35 to 60 judged as severe depression.
Pops says the minimum score for patients entering Alkermes’ trial on the HAM-D17 was 16 or 17; the median score was 22.
Alkermes reported that those taking the low dose of its drug saw their scores reduced by an average of 5.3 points on the Hamilton scale, compared with 1.2 points for the placebo group. Those taking ALKS 5461 also saw their scores on the Montgomery-Asberg scale drop 8.7 points over a one-month span, compared to a 1.8 point reduction over the same time frame for the group on the placebo.
While it’s tough to characterize what a 5 point or 8 point difference on either scale truly means for a patient—Pops says, for example, that the points could be spread out over several questions on different depression symptoms or heavily weighted towards one symptom—but both studies are often used to clinically validate approved drugs. Forest Laboratories’ (NYSE: FRX) vilazodone (Viibryd), for example, won FDA approval in 2011 after improving patients’ scores on HAM-D17 and MADRS by 3.2 and 2.5 points, respectively, over eight weeks.
“Drugs get approved for very subtle changes to these scores,” Pops says. “This is a very significant treatment effect in Phase 2.”
[Updated with comments from analyst.] Corey Kasimov, an analyst with JP Morgan, is bullish on the results, though he cautioned that Alkermes hasn’t yet revealed all the details regarding ALKS-5461’s side effects. Alkermes said in its statement that the most common side effects patients experienced were nausea, dizziness, and headaches.
“We continue to believe that [ALKS-5461] could be an important value driver for [Alkermes] as it is an oral, 1x/day drug that has a novel mechanism of action treating [major depressive disorder],” he wrote in a note to investors. “[Alkermes] was clearly excited ahead of the oral presentation, and the data from the press release appear to justify the enthusiasm.”
Alkermes’ next trial will be similar structurally to this one. Its primary mark to hit in a pivotal study will probably be a baseline differentiation on the MADRS scale, according to Pops. One key difference is that the next study will require more long-term follow-up of patients, Pops says.