Despite trial miss, NRx pushes antidepressant forward with blockbuster hopes in bipolar depression

NRx Pharmaceuticals’ investigational antidepressant has failed to reach statistical significance in reducing depression severity in a phase 2/3 trial, though the biotech is pressing forward to a registrational study with the belief that the candidate could eventually become a “paradigm-changing blockbuster drug.”

The data, shared right after market open April 30, sent NRx’s stock tumbling 24% to $2.8 per share at the time of publication.

The trial centered on NRX-101, an investigational combination of D-cycloserine and lurasidone, the latter of which is sold under brand name Latuda as a treatment for schizophrenia. The study enrolled 74 participants with bipolar depression and suicidal ideation. The study had no placebo group given the high-risk nature of the patients. Instead, NRX-101 was compared to the standard-of-care lurasidone alone.

NRX-101 failed to hit the trial’s primary endpoint, which evaluates the mean change from baseline on a 10-item clinician-rated scale—dubbed the Montgomery Åsberg Depression Rating Scale or MADRS-10—measuring depression severity at six weeks.   

Both NRX-101 and lurasidone performed similarly among patients who hadn’t received prior ketamine treatment, demonstrating comparable antidepressant effects, each reducing depression on the MADRS by about 50% from baseline, according to NRx’s press release.

The study also missed its secondary endpoint of statistical significance in reducing suicidality in patients with subacute suicidal ideation and behavior, as measured by the Columbia Suicide Severity Rating Scale. NRX-101 “demonstrated a promising, though not yet statistically significant 33% reduction in suicidality,” NRx said.

The investigational antidepressant was also tied to a 70% decrease in symptoms of akathisia—restlessness that is known to be a side effect of antidepressants and can be tied to suicidality—findings that also were not statistically significant.   

Despite the trial flop, NRx plans to power through to a registrational trial that includes 300 patients, apparently with a planned focus on the suicide endpoint. The company cited previous findings that were statistically significant. In that study, a phase 2 trial known as STABIL-B, NRX-101 demonstrated (PDF) superiority to lurasidone in reducing both depression and suicidality after ketamine treatment.

“We originally proposed to test suicidality, rather than depression as the primary endpoint for this trial and took the advice of senior FDA leadership that demonstrating a difference in suicidality might be too challenging,” Philip Lavin, Ph.D., the study's lead methodologist, said in the April 30 release. “Today's findings demonstrate that differences in suicidality and akathisia can be demonstrated compared to best available antidepressant therapy in a properly sized registration trial, and that superiority over placebo on the depression scale may readily be demonstrated in a less acute patient population where it would be safe to do so.”

NRX-101 has snagged an FDA breakthrough therapy tag for suicidal treatment-resistant bipolar depression, and NRx has partnered up with pharma Alvogen for the asset's development and potential marketing.

“We are gratified by these results, which extend the findings of the STABIL-B trial in suggesting that NRX-101 has the potential to be the first oral antidepressant to decrease potential for suicide, whereas all currently approved oral antidepressants are known to increase the risk of suicide,” said NRx Chair and Chief Scientist Jonathan Javitt, M.D. “Should these findings be confirmed in a registrational trial of 300 patients, NRX-101 has the potential to represent a paradigm-changing blockbuster drug.”

The company also believes NRX-101 could become the drug of choice for boosting the effect of ketamine in patients with acute and subacute suicidality. The biotech intends to file a new drug approval with the FDA for IV ketamine from its wholly owned company Hope Therapeutics by July.

NRx also said it plans to explore NRX-101 as a main treatment for patients with bipolar depression who don’t have active suicidality and therefore don’t require prior ketamine treatment.