A novel approach to depression?

Rapastinel may sidestep cognitive deficits seen with ketamine

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DUBLIN, Ireland—Allergan plc, a leading global pharmaceutical company, has presented new data on the investigational medication rapastinel (GLYX-13) and its lack of impairment on cognitive function in the peer-reviewed journal Behavioural Brain Research.
“This work demonstrates that rapastinel, unlike ketamine, did not induce transient or persistent cognitive deficits in normal mice. Further, rapastinel, but not ketamine, as administered here, demonstrated pro-cognitive benefits in a well-studied animal model of cognitive impairment. This difference merits further study in patients who are candidates for rapidly acting antidepressant treatment,” said Dr. Herbert Y. Meltzer, professor of psychiatry at the Northwestern University Feinberg School of Medicine.
The goal of this study was to compare the effects on cognition of rapastinel and ketamine in novel object recognition (NOR) in mice. The NOR task is a validated animal model of human declarative memory (memory of facts and events) that has been widely used to identify differences across compounds. Deficits in learning and memory are often comorbid conditions in patients suffering from a number of mental illnesses including major depressive disorder (MDD), bipolar disorder and schizophrenia.
“Allergan is committed to advancing potential new treatment options for mental health. We are encouraged by these promising study findings and what they could mean in clinical practice and plan to begin pivotal Phase 3 trials of rapastinel later this year,” said David Nicholson, executive vice president and president of Global R&D brands at Allergan.
“There is a high unmet need for novel therapies for depression,” Nicholson tells DDNews. “Rapastinal has the potential to be a fast-acting therapy without ketamines’s negative affect on cognition.” Ketamine, he adds, is also an abused drug (sometimes called Special K) due to non-competitive blocking of N-methyl-d-aspartate (NMDA). Both ketamine and phencyclidine (PCP) induce hallucinations by blocking ion exchange through NMDA.
The study found that unlike ketamine and PCP, rapastinel (a functional NMDA receptor modulator) did not cause deficits in NOR in mice. This study also demonstrated rapastinel’s ability to reverse NOR deficits produced by a single exposure to ketamine or multiple doses of PCP or ketamine. In addition, rapastinel, like ketamine, has fast-onset antidepressant effects. The data from this study demonstrate that rapastinel does not share some of the less-desirable pharmacological properties of ketamine.
Rapastinel (formerly known as GLYX-13) is an investigational intravenous formulation of a novel NMDA receptor partial agonist, which is being evaluated for adjunctive treatment of MDD, and has shown a rapid onset of antidepressant efficacy one day after a single dose in a Phase 2 clinical trial of patients with MDD who had an inadequate response to one or more antidepressants. No psychotomimetic or hallucinogenic side effects were observed with rapastinel. A series of Phase 3 registration trials are planned to begin in 2016.
NRX-1074 is an investigational orally available derivative of rapastinel that is entering Phase 2 as a monotherapy treatment for adults with MDD. An intravenous formulation of NRX-1074 has previously shown a rapid antidepressant efficacy in an initial single-dose Phase 2 study in patients with MDD. Proof-of-concept studies of NRX-1074 are planned for 2016.
Approximately 16 million Americans are living with MDD. There remains a significant unmet need in treating MDD. Upwards of 70 percent of patients with MDD are partial or non-responders to first-line therapies which include SSRIs and SNRIs. Additionally, the STAR*D trial reported that only 33 percent of patients reported remission of their MDD symptoms after monotherapy with an SSRI. In patients that do respond to an SSRI, numerous clinical trials have shown that it can take anywhere from two to six weeks for a patient to perceive and report that their depressive symptoms are improving. During these first two to six weeks of traditional monoamine-based therapy, patients may continue to experience significant depressive symptoms, which can include suicidal ideation in patients with severe, recurrent or chronic depression.

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