Antidepressants Moving in Pipeline

With numerous NMDA receptor antagonists in development, it is no coincidence that the FDA recently released a draft guidance to explain the view of the agency on clinical trials of rapid-acting antidepressants.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 The new draft guidance points out that, while conventional antidepressants typically are evaluated for efficacy at the end of six to eight weeks of continuous treatment, an earlier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.

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.

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. ■