Innovative antidepressant developments depend on unlocking new targets
In February, when Shire decided to halt development of Vyvanse for the treatment of depression, it was perceived as a major setback for the company—and for patients waiting for new treatment options. The drug, which is used for the treatment of ADHD, was in late-stage clinical trials and had progressed well, but the efficacy data was not strong enough to pursue regulatory approval for a depression treatment. The drug had effectively failed.
According to the World Health Organization, 350 million people worldwide have depression. Depression leads to one million suicides per year and is the leading cause of disability in the world. In the US, almost 40 million adults have clinical depression. All told, 20% of adults are taking some type of psychiatric medication.
Public awareness around depression is fairly high, bolstered in part by very strong messaging campaigns created and sponsored by the pharmaceutical industry. Despite the fact that many depressed individuals remain untreated, the main problem is not unwillingness to seek psychiatric support. The real challenge is a lack of innovation in developing drugs to treat depression due to a fundamental lack of understanding of the underlying biology driving depression.
The most effective advertising and educational campaigns focus on the fact that treatments for depression exist. The message: If a person is depressed, taking action means taking medication, and perhaps engaging in talk therapy. However, in actual clinical practice, prescribing tends to be scattershot. If one medication doesn’t work, the prescribing physician simply prescribes another, and so on, until something works. When something has been working and stops working, the next step is to switch medications.
Since imipramine was developed in the 1950’s, there have been fewer than 30 drugs approved for the treatment of depression. And though the current armamentarium of antidepressant drugs provides a range of treatment options, there haven’t been huge shifts in long-term efficacy since the early days of drug treatment for depression—though there has been substantial improvement in safety and tolerability. Available drugs modulate one or more of three molecular targets---serotonin, dopamine, and norepinephrine.
Unlocking other molecular targets
Shire’s molecule wasn’t the first to fail in clinical development for depression. Progress in this therapeutic category has been slow-moving, and efforts to target novel molecules have generated excitement precisely because they offer an innovative approach.
In 2011, Novartis was testing agomelatine, a melatonin receptor modulator, for the treatment of depression, and showing positive results in early clinical trials. However, the company halted development during phase III when the drug proved to be ineffective throughout the duration of the study period. Likewise, AstraZeneca stopped trials of its neuronal nicotinic channel modulator for similar reasons in December 2011. Had one or both of these treatments proven effective, options for targeting different areas of the brain would have expanded the treatment paradigm—and possibly shed new light on the biology of depression.
The approval of Brintellix (votioxetine) in September 2013 was welcome by clinicians. Brintellix, which is co-marketed by Takeda and Lundbeck, is indicated for the treatment of major depressive disorder (MDD) and has shown significant improvement in symptoms, compared with placebo. In phase III trials, patients who took Brintellix had a significantly longer time to recurrence than placebo-treated subjects. The good news is that Brintellix represents another treatment option---but is it truly innovative? The primary mode of action of Brintellix is serotonin reuptake inhibition and modulation, with activity at various receptor sites.
In the final analysis, every drug that makes it to market for the treatment of depression strengthens the therapeutic category even as researchers work behind the scenes to understand the underpinnings of depression, find new molecular targets and confirm once and for all the basis for treating this disease biologically.