Antidepressants Moving in Pipeline

When ketamine was found to exert a rapid antidepressant effect by researchers at the National Institute of Mental Health (NIMH) more than a decade ago, it sparked hope for a new generation of treatments for depressive disorders. Now, new drug candidates are finally edging toward the finish line.

iStock/bymuratdeniz

Esketamine nasal spray, an isomer of ketamine and antagonist to the N-methyl-D-aspartate (NMDA) receptor, may be the closest to reaching clinics. Just last month, Janssen Pharmaceutical Companies of Johnson & Johnson announced the company had submitted a new drug application (NDA) to the Food and Drug Administration (FDA) seeking approval of esketamine nasal spray for treatment-resistant depression in adults.

According to the press release by Janssen, the NDA is based on five pivotal phase 3 studies of esketamine nasal spray in patients with treatment-resistant depression: three short-term studies, one withdrawal maintenance-of-effect study, and one long-term safety study up to a year.

The results of two phase 3 trials of esketamine were presented at the APA Annual Meeting in May. In one trial, patients who failed to respond to at least two antidepressants during the current episode of depression were randomized to two treatments: esketamine nasal spray (56 mg or 84 mg) plus a new antidepressant or placebo nasal spray plus a new antidepressant. Patients who received esketamine experienced a statistically significantly greater drop on the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28 compared with placebo. In patients 65 years and older with treatment-resistant depression, esketamine missed the primary efficacy endpoint in a phase 3 trial.

In the clinical trials, esketamine treatment was linked to side effects such as dizziness, nausea, increased blood pressure, and dissociation, which are similar to the side effects of ketamine.

Other NMDA receptor antagonists are also making their way through clinical development, including rapastinel (previously known as GLYX-13) and AGN-241741. Both molecules were developed by Naurex Inc. and recently acquired by Allergan. Rapastinel is purported to exert a rapid antidepressant effect, like ketamine, without the dissociative side effects. Several phase 3 trials of rapastinel as an adjunctive treatment and as monotherapy in major depressive disorder are currently ongoing. AGN241741 is being tested in phase 2 trials.

Another NMDA receptor antagonist, dextromethorphan, is combined with bupropion in a product known as AXS-05. In addition to its known effectiveness as an antidepressant, bupropion inhibits the metabolism of dextromethorphan by liver enzymes, so that dextromethorphan may accumulate in the body and reach therapeutic levels. AXS-05 is currently in phase 3 trials for treatment-resistant depression and for agitation associated with Alzheimer disease.

FDA Updates Guidance on Antidepressant Development

With numerous NMDA receptor antagonists in development, it is no coincidence that the FDA recently released a draft guidance to explain the view of the agency on clinical trials of rapid-acting antidepressants. The last FDA guidance on antidepressant development dated from 1977, 10 years before the approval of Prozac. The new draft guidance points out that, while conventional antidepressants typically are evaluated for efficacy at the end of six to eight weeks of continuous treatment, an earlier endpoint (for example, within one week) would be more appropriate for a rapid-acting antidepressant. In addition, the agency recommends that the durability of such rapid effect be measured over time, especially if the drug is intended for repeated use.

Notably, the guidance states that “patients with a history of suicidal ideation and behavior need not be systematically excluded from trials.” As ketamine has been shown to potentially reduce suicidal thoughts, NMDA receptor antagonists may offer an alternative to selective serotonin reuptake inhibitors (SSRIs), which have been linked to the emergence or exacerbation of suicidality and carry a boxed warning in labeling.

As a caution, the FDA guidance cites the potential risk of NMDA receptor antagonists to cause Olney lesions—fluid-filled vesicles in the brain that sometimes precede permanent neuronal injury or death. The agency requires adequate safety evaluation in animals before any NMDA receptor antagonist is tested in humans.

Neurosteroids Crack Postpartum Depression

A type of neurosteroid known as allopregnanolone may be effective in treating a variety of neuropsychiatric diseases, including depression, anxiety disorder, and epilepsy, through their action on the gamma aminobutyric acid (GABA)-A receptors. Several drugs in this class have entered clinical development.

In April, Sage Therapeutics submitted an NDA to the FDA for brexanolone, a GABA-A receptor modulator, for the treatment of postpartum depression. Brexanolone is given through intravenous infusion for 60 hours. Studies show that women with postpartum depression administered the medication experience statistically significant reductions in depression by the end of the infusion. The company is also developing similar molecules, including SAGE-217, an oral drug candidate. SAGE-217 is being tested in phase 3 trials for postpartum depression and for major depressive disorder.

Ganaxolone, another GABA-A receptor modulator, is undergoing phase 2 and 3 trials for postpartum depression and other neurological indications. The manufacturer, Marinus Pharmaceuticals, is developing an oral formulation in addition to the intravenous version.

Opioid Receptor Modulators for Depression?

An NDA for ALK-5461, a combination product of buprenorphine and samidorphan, is currently under FDA review for adjunctive treatment of major depression. The agency initially refused the filing by Alkermes in April but quickly reversed its decision. The product previous failed two phase 3 trials but saw positive results over placebo in a third trial. A decision is expected in January 2019. ■