NRX-101: First Antidepressant to Lower Suicidality in Bipolar Depression

Andrew Nierenberg, MD

Credit: Dauten Family Center, Massachusetts General Hospital

NRX-101, granted an investigational breakthrough therapy designation in 2018 by the US Food and Drug Administration (FDA), could become the first antidepressant to reduce suicidality in bipolar depression if approved.^1,2

NRx Pharmaceuticals announced the phase 2b/3 trial comparing NRX-101 with Lurasidone for adults with bipolar depression and subacute suicidal ideation or behavior will be presented on Wednesday, May 29, 2024, 11:15 am, at the American Society of Clinical Psychopharmacology (ASCP) in Miami Beach, Florida.¹

“Presentation of these data at this highly respected conference is another important step toward bringing a life-saving product to patients in tremendous need," said Jonathan Javitt, MD, MPH, Chairman and Chief Scientist of NRx, in the press release.

Led by Andrew Nierenberg, MD, director of Dauten Family Center for Bipolar Treatment Innovation at Massachusetts General Hospital and professor of Psychiatry at Harvard Medical School, the randomized, double-blind phase 2b/3 trial showed NRX-101, a formulation of d-cycloserine and lurasidone, had a similar effect as lurasidone, the Standard of Care drug. Both antidepressants had a > 50% response for treating depression and no difference on the primary efficacy endpoint.

However, NRX-101 performed better on both primary and secondary endpoints. This antidepressant was linked to a 58% relative time reduction to reach sustained suicidality remission, measured by the Columbia Suicide Severity Rating Scale (C-SSRS) when stratified by sex, mood stabilizer use, antipsychotic use, and lifetime suicide event (P = .05).

Additionally, NRX-101 was associated with a relative 76% reduction in akathisia symptoms compared to lurasidone sustained over 42 days (Effect Size, 0.37; P = .03) on the Barnes Akathisia Rating Scale. Investigators observed akathisia in 2% of patients treated with NRX-101 and 11% treated with lurasidone. Ultimately, NRX-101 exhibited superiority to lurasidone in akathisia beginning on day 6 and continuing through day 42.

Investigators observed no treatment-related serious adverse events for patients on NRX-101 or lurasidone. The only safety issue was MedDRA general disorders for patients on NRX-101 (18.2%) but not lurasidone (0%) (P = .002).

“Based on these findings, together with the earlier STABIL-B trial, the Company believes that NRX-101 has the potential to become a standard of care drug for treating bipolar depression, an addressable population of 7 million patients in the US and many times that around the world,” NRx Pharmaceuticals wrote in their press release.

Supported by several trials, NRX-101 was demonstrated to be the first antidepressant for bipolar depression to bring meaningful reductions in suicidality and akathisia. All antidepressants currently on the market have black box warnings on their labels informing people the medication may increase suicide risk.

“I think it’s becoming increasingly apparent that 50 years of serotonergic drugs have benefitted, at most, half of the people that need them,” Javitt told HCPLive at the 2018 American Psychiatric Association annual meeting in New York City.³ “Every 1 of those drugs has a warning on the label that says it may cause suicide—and there’s a good reason for that. Everything you do to raise serotonin in the brain has the potential to cause an [adverse effect] called akathisia. People with bipolar depression, tragically, are even more susceptible.”

In NRx Pharmaceuticals’ trial, patients randomized to lurasidone faced a substantial increase in akathisia, and patients randomized to NRX-101 experienced the opposite: a significant reduction.¹ Akathisia, occurring in 10 – 15% of patients who take lurasidone, is associated with suicide.

Not only may NRX-101 reduce suicidality, bipolar depression symptoms, and akathisia, but the antidepressant also has the potential to act as a non-opioid treatment for chronic pain and a cure for complicated UTI.

“We believe that NRX-101 may offer a paradigm-changing approach to treatment of bipolar depression, with a product highly effective in both treating depression and reducing suicidality and associated side effects,” Javitt said. “We will continue working to bring hope to life with life-saving medications."

References

1. ^{NRx Pharmaceuticals (Nasdaq:NRXP) Presents Landmark Trial of NRX-101 in Suicidal Bipolar Depression At the American Society of Clinical Psychopharmacology Annual Meeting: NRX-101 is the First Oral Antidepressant Demonstrated to Reduce Suicidality in Bipolar Depression. PR Newswire. May 28, 2024. https://www.prnewswire.com/news-releases/nrx-pharmaceuticals-nasdaqnrxp-presents-landmark-trial-of-nrx-101-in-suicidal-bipolar-depression-at-the-american-society-of-clinical-psychopharmacology-annual-meeting-nrx-101-is-the-first-oral-antidepressant-demonstrated-to-re-302156419.html. Accessed May 28, 2024.}
2. ^{NeuroRx Receives FDA Breakthrough Therapy Designation for NRX-101, First Oral Drug Targeting Suicidal Bipolar Depression. BioSpace. November 13, 2018. https://www.biospace.com/article/releases/neurorx-receives-fda-breakthrough-therapy-designation-for-nrx-101-first-oral-drug-targeting-suicidal-bipolar-depression/. Accessed May 28, 2024.}
3. ^{Hoffman, M. FDA Awards SPA Letter to NeuroRx for Pivotal Studies of NRX-101. HCPLive. May 7, 2018. https://www.hcplive.com/view/fda-awards-spa-letter-to-neurorx-for-pivotal-studies-of-nrx101. Accessed May 28, 2024.}