Pipeline for New Antidepressants Flowing Slowly

When vilazodone was approved by the Food and Drug Administration (FDA) in January 2011, the field of antidepressants seemed to be on the verge of being flooded with new drugs over the next few years. Particularly exciting was the development of several molecules with new mechanisms of action, promising advantages to current depression treatments after selective serotonin and serotonin/norepinephrine reuptake inhibitors (SSRIs and SNRIs) have dominated for decades.

A year later, however, the pharmaceutical pipeline for antidepressants has shrunk to a trickle. Despite tantalizing data in early development, some of the most intriguing molecules have not lived up to expectations in large-scale phase 3 clinical trials.

One of the recent disappointments is agomelatine, a melatonin receptor modulator that was expected to have few side effects and significantly improve sleep quality, a major symptom in depressive patients. Developed by the French company Savier, agomelatine was approved for marketing by the European regulatory authority in 2009 and subsequently acquired by Novartis for phase 3 development in the United States.

In October 2011, however, Novartis announced the demise of the U.S. agomelatine development after disappointing results from phase 3 trials and concerns about its adverse effect on liver enzyme levels. Shortly after, Novartis declared that it would shut down its neuroscience research unit in Switzerland and drastically scale down neuropsychiatric drug development.

In December 2011, more bad news came out of phase 3 trials of another highly anticipated molecule, TC-5214, which was developed by Targacept and picked up by AstraZeneca. TC-5214 is a neuronal nicotinic channel modulator, and many hoped that the alternative biochemical pathway would complement the serotonin pathway and enhance the effectiveness of depression treatment.

Hopes Dashed Anew

But in two phase 3 trials, TC-5214 failed to beat placebo when it was given as an add-on treatment for eight weeks to patients who had had incomplete response to an SSRI or SNRI. The results of three other phase 3 trials, expected in the first half of 2012, will determine the fate of TC-5214.

These setbacks echo that of another promising antidepressant. Two years ago, Sanofi-Aventis’ saredutant, a neurokinin 2 receptor antagonist, also fell by the wayside in phase 3 clinical trials.

The failure of these molecules is disappointing not only for the pharmaceutical companies and their shareholders, but also for researchers who are trying to better understand the pathology of neuropsychiatric disorders. SSRIs and SNRIs have not been able to “cure” major depressive disorder in all patients and continue to carry substantial safety and tolerability problems. New drugs that attack other neurological pathways of depression may complement or replace current antidepressants in patients who have had unsatisfactory response, as well as reveal more about the why and how of the illness.

Although tinkering with the nicotinic, melatonin, and neurokinin receptors looked promising in the laboratory and in small-scale human studies, so far they have not offered real hope for making a clinical impact. Therefore, the failures of these new molecules suggest that thorough understanding and, in turn, a reliable and ubiquitous treatment for depression remain far out of reach.

A Year of Disappointments

Last year was not a good year for psychiatric drug research and development in general, with vilazodone being the only FDA-approved new molecular entity for any psychiatric indication.

Pharmaceutical research is notoriously risky, but drug development in neuropsychiatric disorders seems to be even riskier than in other diseases at the moment. The fact that so many molecules have flunked late-stage trials makes these failures especially costly and makes the industry nervous. Several major pharmaceutical companies, including GlaxoSmithKline and AstraZeneca, have announced that they would reduce or terminate neuropsychiatric drug development programs.

Not surprisingly, the antidepressant molecules that are more successful in clinical trials rely heavily on the tried-and-true serotonin and norepinephrine pathways.

Lundbeck’s molecule Lu AA21004, whose phase 3 development is cofunded by Takeda, binds to a number of serotonin receptor subtypes and inhibits serotonin reuptake. Two of its phase 3 trials have yielded positive efficacy results, the companies announced at APA’s annual meeting in May 2011. Although two other phase 3 trials of Lu AA21004 in major depressive disorder failed to meet their primary efficacy endpoints, the drug remains very much alive, as the FDA requires only two positive-efficacy pivotal trials to gain marketing approval.

Another antidepressant moving forward in late-stage development is levomilnacipran, an enatiomer of milnacipran, a serotonin and norepinephrine reuptake inhibitor that has been approved for treating fibromyalgia. During 2011, Forest Laboratories and the French company Pierre Fabre announced that levomilnacipran beat placebo in efficacy endpoints in two phase 3 clinical trials, and two additional trials are expected to produce results in early 2012.

A few more antidepressants are being studied in phase 3 trials, but none has a completely novel mechanism of action. OPC-34712, codeveloped by Lundbeck and Otsuka, is a dopamine D2 receptor partial agonist with affinity for serotonin receptors. It is pharmacologically similar to aripiprazole and is also being tested for treatment of schizophrenia.

Lundbeck has another serotonin and norepinephrine reuptake inhibitor, Lu AA24530, under investigation. In addition, Eli Lilly’s phase 3 trials of edivoxetine, a norepinephrine reuptake inhibitor, are expected to produce results in the next few years.