Major depressive disorder (MDD) is a significant health problem that is expected to be the leading cause of global disease burden by 2030. Antidepressants are the most popular treatment for MDD, but are plagued by a lack of efficacy, a slow onset of clinical effects, high placebo response rates in trials and a high frequency of adverse events.
Despite a large patient population and the inadequacy of current treatments, antidepressant pipelines are relatively sparse, with few promising candidates in development. Large pharmaceutical companies including Merck, Pfizer and Sanofi are scaling back neuroscience research efforts in response to perceived risks.
Up to half of patients treated with antidepressants fail to respond, and mean placebo response rates in antidepressant trials hover around 35 per cent, meaning that demonstrating efficacy in trials is difficult. Additionally, most major antidepressants are available as generics, which control a large share of the market. This lack of development is worrying, as it is likely to create a gap in the market of many years before much needed new therapies are available.
The five most prescribed antidepressants in the US are all selective reuptake inhibitors (including selective serotonin reuptake inhibitors [SSRIs] and selective norepinephrine reuptake inhibitors [SNRIs]), which are compounds that increase extracellular levels of neurotransmitters by inhibiting their reuptake into presynaptic cells. In order for a new antidepressant to be successful, it must show significantly greater efficacy, a more rapid onset of clinical effects, or a more favourable side effect profile than is seen with currently available SSRIs and SNRIs. Novel compounds with traditional reuptake inhibition mechanisms are unlikely to be successful amongst the generic competition, leading many companies to focus on therapies that combine multiple mechanisms of action for a multimodal approach.
Vortioxetine
Vortioxetine (Brintellix, Lundbeck and Takeda), a small molecule compound already approved in the US and awaiting approval in the EU and Canada, has shown significant promise in a range of pivotal trials. This orally administered agent combines serotonin uptake inhibition with receptor activity modulation, and has been shown to be a serotonin 3 (5-HT3) and 5-HT7 receptor antagonist, a 5-HT1A receptor agonist, and a 5-HT1B receptor partial agonist. Preclinical studies have shown that vortioxetine increases the levels of serotonin, norepinephrine, dopamine, acetylcholine and histamine in specific areas of the brain. It is hoped that the multimodal mechanism of action of vortioxetine will result in distinct clinical effects in patients with MDD.
Vortioxetine has demonstrated statistically significant efficacy in eight of 10 placebo-controlled trials, including six of eight short-term trials, a notable achievement given the difficulties inherent in placebo-controlled MDD trials. Results from the REVIVE trial showed vortioxetine to be significantly superior to agomelatine (Valdoxan, Servier) by 2.2 points on the Montgomery-Asberg Depression Rating Scale (MADRS), in patients who showed an inadequate response to SSRIs or SNRIs. Vortioxetine also demonstrated greater tolerability, compared with agomelatine. This trial was noteworthy for being one of few randomised, double-blind trials in patients unresponsive to first-line antidepressant treatment, arguably the patient population most in need of novel effective therapies. Statistically significant efficacy has also been demonstrated in two duloxetine-referenced trials.
Despite a large, but poorly served, patient population there are few promising late-stage candidates
Fixed-dose combinations
Fixed-dose combinations offer another way of combining multiple mechanisms of action. A combination of low-dose pipamperone (a dopamine D4 and serotonin 2A receptor antagonist) and citalopram (an SSRI and dopamine D2 receptor antagonist) is in phase III development with PharmaNeuroBoost. Pipamperone has been shown to accelerate the antidepressant effects of citalopram, and preliminary clinical data has shown that citalopram/pipamperone has a higher response rate and faster onset of action than existing treatments.
ALKS 5461 (Alkermes) is a fixed combination of buprenorphine and samidorphan being developed as a therapy for treatment-resistant MDD. Buprenorphine is a mu opioid receptor partial agonist, while samidorphan is an antagonist of mu opioid receptors. The combination of these mechanisms may result in attenuation of the mu agonist effects of buprenorphine, potentially making this a non-addictive therapy. ALKS 5461 is being developed as a once-daily therapy administered as a sublingual tablet. In two phase II trials in patients with MDD who had an inadequate response to an SSRI or SNRI, ALKS 5461 significantly reduced depressive symptoms (measured by the Hamilton Depression Rating Scale). Additionally, the agent was well tolerated and treatment effects were evident after one week of dosing. Based on these results, Alkermes is meeting the US FDA to advance ALKS 5461 into pivotal phase III trials.
Receptor modulators
Antipsychotics, such as brexpiprazole (Otsuka) and cariprazine (Gedeon Richter), often have additional antidepressant effects. Brexpiprazole is a dopamine D2 partial agonist being developed as an oral adjunctive therapy. The agent will act as a successor to the atypical antipsychotic aripiprazole, which is due to lose patent exclusivity in the US in April 2015. Four phase III trials of brexpiprazole are underway in the US and Europe. In phase II trials, a 1.5mg dose of brexpiprazole was well tolerated and associated with statistically significant improvements in MADRS score, compared with placebo. The trial enrolled patients who were receiving a US FDA-approved antidepressant treatment, and assessed brexpiprazole as an adjunctive therapy. Cariprazine is an oral dopamine D2 and D3 receptor antagonist awaiting approval in the US for the treatment of schizophrenia and bipolar disorder. Phase III studies of the antipsychotic drug as an adjunctive therapy for MDD are underway, despite a lack of efficacy in phase II placebo-controlled trials.
GLYX 13 is a glycine-site functional partial agonist (GFPA) of the N-methyl-D-aspartate (NMDA) receptor originally discovered at Northwestern University, which is now in development with Naurex. The tetrapeptide compound is derived from an amino acid sequence obtained from a monoclonal antibody with NMDA receptor-modulating properties, and is administered by intravenous injection. It is believed that GFPAs of the NMDA receptor may have a therapeutic effect without the side effects commonly observed with NMDA receptor modulators, such as dissociation and sedation. Phase II results have shown that GLYX 13 treatment reduces depression scores in patients with treatment-resistant MDD, while being generally well tolerated and free of the psychotomimetic side effects associated with other NMDA receptor modulators. Importantly, the therapeutic effect of GLYX 13 treatment was evident within 24 hours of dosing.
Reuptake inhibitors
Amitifadine (Euthymics Bioscience) is an example of a triple reuptake inhibitor, disrupting the reuptake of serotonin, dopamine and norepinephrine. Like many other therapies in clinical development, amitifadine is being positioned as a second-line treatment after first-line generic antidepressants have failed. In the phase IIb/IIIa TRIADE trial, amitifadine did not meet its primary end point of a significant difference in MADRS score, compared with placebo. However, Euthymics believes the lack of side effects seen with the 100mg dose and signs of efficacy in post-hoc analyses suggest that MDD patients may benefit from higher doses. Liafensine (Bristol-Myers Squibb) is another triple reuptake inhibitor that completed two phase II trials in treatment-resistant depression earlier in 2013.
Of the handful of promising candidates in clinical development, edivoxetine (Eli Lilly) is one of the few traditional reuptake inhibitors. This SNRI compound has shown promise as both a monotherapy and an adjunct therapy to SSRIs. Five phase III trials are underway to support registration of edivoxetine in the US. In a randomised, double-blind study, edivoxetine-treated patients showed a significant improvement in MADRS scores, compared with placebo, as well as a significantly higher probability of achieving response and remission. However, the agent was associated with significant increases in pulse, systolic and diastolic blood pressure, compared with placebo, and a significantly higher rate of discontinuation due to adverse events or death. These results show the difficulty in developing a traditional antidepressant that is free of the traditional problems plaguing current therapies.
Despite a large patient population and the poor efficacy and tolerability of current treatments, there are few promising antidepressant therapies in late-stage clinical development. Companies are scaling back or ceasing their neuroscience research efforts in response to strong generic competition and difficulties in demonstrating efficacy. However, with up to half of MDD patients showing an inadequate response to first-line treatment, there is a great need for antidepressants that demonstrate greater efficacy or lower rates of adverse events than those currently available. A handful of candidates have shown promising results in placebo-controlled trials, but few have achieved the holy grail of demonstrating efficacy against an antidepressant comparator. Those with the greatest promise combine multiple mechanisms of action, with the belief that these will translate into distinct clinical effects and offer a more robust treatment. With generic SSRIs and SNRIs continuing to control a large share of the market, this multimodal approach seems to be the best shot at success for companies struggling to develop antidepressants that stand out among the generic crowd.