FDA Grants Breakthrough Therapy Designation to First Oral Drug for Suicidal Bipolar Depression

November 13, 2018
  • Bipolar disorder affects 5.7 million people in the US alone
  • NRX-101 was previously granted fast track status


NeuroRx, announced on 11/13/18 that it has been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for development of NRX-101. The designation is for treatment of Severe Bipolar Depression with Acute Suicidal Ideation & Behavior (ASIB) after initial stabilization with ketamine or other effective therapy. In April, the FDA also issued a Special Protocol Agreement (SPA) for the design of the upcoming pivotal Phase 2b/3 clinical trial. The company recently reported encouraging top- line data from its STABIL-B study, which demonstrated that the drug was well- tolerated with no serious adverse events or discontinuations for side effects.

NRX-101 is a patented, oral, fixed-dose combination of D-cycloserine (DCS), an NMDA antagonist, and lurasidone, which has 5-HT2a receptor antagonist activity. In contrast with all currently approved antidepressant drugs, which primarily raise serotonin levels in the brain, DCS is shown to raise levels of two neurotransmitters: glutamate and glutamine (Glx). As such, NRX-101 may represent a new class of antidepressants with the potential to decrease suicidal thoughts, whereas serotonin-based antidepressants are associated with an increase in risk of suicide in certain vulnerable patient populations.

“The FDA grant of Breakthrough Therapy Designation to NRX-101 recognizes the extraordinary unmet medical need that confronts patients with Severe Bipolar Depression," said Jonathan Javitt, M.D., M.P.H., CEO of NeuroRx. “These patients have previously been excluded from clinical trials of nearly all currently marketed antidepressants. We aspire to change that reality for more than 150,000 Americans each year who present for emergency care and more than 25,000 each year who lose their lives to this lethal condition.”

The FDA decision to award Breakthrough Designation to NRX-101 was based in part on clinical data obtained in a multicenter STABIL-B feasibility study designed to evaluate the clinical effect of NRX-101 compared to a lurasidone control group. These data will be presented next month at the annual meeting of the American College of Neuropsychopharmacology.

Patients with bipolar depression are at uniquely high risk for suicide, with more than 50% attempting suicide at some point and up to 20% succumbing to suicide. Currently the only FDA-approved treatment for suicidal bipolar depression is electroconvulsive therapy (ECT), which is shown to increase levels of Glx in the brain. Despite its effectiveness, ECT has a myriad of well-known adverse side effects, including confusion and memory loss. In April 2018, NeuroRx received a biomarker letter of support from the FDA, documenting that the company had shared evidence of increased Glx levels associated with oral administration of D-cycloserine, a phenomenon not seen with serotonin-targeted (SSRI) antidepressants.

NeuroRx is initiating a pivotal Phase 2b/3 clinical trial under the SPA comparing daily oral NRX-101 to standard therapy (lurasidone) in patients with Severe Bipolar Depression and Acute Suicidal Ideation following initial stabilization with ketamine. The FDA previously granted FAST TRACK designation for this protocol in 2017.

Bipolar disorder affects 5.7 million people in the US alone. It is characterized by significant changes in mood, from mania or hypomania to depression, often quite severe. The depressive phase, which is called “bipolar depression,” can trigger suicidal thoughts and behaviors. Standard of care consists of hospitalized observation and electroconvulsive therapy (ECT). Unfortunately, most commonly-used antidepressants bear an FDA- mandated warning label identifying the potential to increase the risk of suicide.


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