NRX-101 Expanded Access

Overview

There is no currently-approved pharmacotherapy for patients with Treatment-Resistant Bipolar Depression and Suicidal Ideation or behavior. The purpose of this Expanded Access Treatment Protocol is to make NRX-101 available to patients who have depression and suicidal ideation despite treatment with currently approved medication and to gather information on safety and efficacy in a real-world data environment. Participants will be treated by their own practicing psychiatrist and will agree to periodic psychometric evaluations to assess depression, suicidal ideation, and side effects.

INTRODUCTION 1 Suicidal Ideation and Behavior in Bipolar Disorder Bipolar Disorder (formerly known as manic depressive disorder) is a well-established psychiatric diagnosis, with a prevalence of about 2.6% in the United States (approximately 8.5 million people) (Kessler et al., 2005). The risk of subacute suicidal ideation or behavior (SSIB) is uniquely high in patients during bipolar depressive episodes, compared to those with major depressive disorder (MDD), thought disorders, and personality disorders. Lifetime suicide behavior occurs in 25% to 56% of people with bipolar disorder (Nierenberg et al., 2001). About 40% of the nearly 50,000 annual deaths from suicide in the United States are associated with bipolar disorder (Mahli et al., 2015). The overall rate of death by suicide among patients with bipolar disorder is 164 per 100,000 person-years, compared to about 14 per 100,000 person-years for the general population. Those who have attempted suicide are 2.3 times more likely to die by suicide compared to those without a suicide attempt (Coryell et al., 2016). Thus, bipolar depression with suicidal ideation has uniquely lethal clinical characteristics (Pompili, et al., 2013). 6.2 Current Treatment Options Despite its lethal characteristics, there is no approved pharmacologic treatment for patients with bipolar depression and suicidal ideation. Electroconvulsive therapy (ECT), often combined with inpatient psychiatric care, remains the only Food and Drug Administration (FDA)-approved treatment for patients with acute suicidal ideation in bipolar depression, despite ECT's well-documented side effects that include memory loss and confusion, along with its high cost. However, the toxicity of ECT is such that it is less likely to be used in patients with subacute levels of suicidal ideation and no oral medication has been shown to reduce suicidal ideation in patients with depression in general or bipolar depression in specific. Physicians are increasingly cautious about the use of selective serotonin release inhibitors (SSRIs), particularly in patients with suicidal ideation because of evidence that SSRIs and other antidepressants may actually increase the risk of suicidal ideation, particularly in younger patients (Stone et al., 2009). This evidence has resulted in an FDA warning on the label of current antidepressants. Moreover, it seems clear that antidepressants do not decrease SSIB in proportion to their mitigating effect on symptoms of depression. In recent years, several combined D2/5-HT2A antagonists have shown efficacy in treating bipolar depression (olanzapine/fluoxetine combination, quetiapine, and lurasidone) with treatment guidelines endorsing common use as first-line standard of care treatment in acute bipolar depression. While these medications are effective at reducing overall symptoms of depression, they do not specifically reduce suicidal ideation, as shown in recent clinical trials of lurasidone (Loebel et al., 2014a; Loebel et al., 2014b). Moreover, in these two studies, individuals with active suicidal ideation (Montgomery Asberg Depression Rating Scale \[MADRS\] item 10 ≥ 4) were specifically excluded because of concerns regarding the possibility of exacerbating suicidality with these medications. Similarly, acutely suicidal patients are routinely excluded from clinical trials of other experimental anti-depressive agents. Thus, bipolar depression with suicidal ideation represents a major unmet medical need that must frequently be treated with voluntary or involuntary hospitalization under highly supervised conditions and ECT. 6.3 Preclinical Models of Anxiety and Akathisia Although the mechanisms mediating antidepressant-related increases in suicide remain unclear, leading theories suggest that increases in anxiety/akathisia may play a critical role (Harada et al., 2014; Popovic et al., 2015). Serotonin-related anxiety/akathisia may be modeled in rodents using several well-established assay systems, such as the elevated plus maze, and are known to be sensitive to serotonergic agents (Sachdev and Brune, 2000). In this assay, reduced percent time spent in the open arms of the maze is believed to be associated with increased akathisia and anxiety. In contrast, increased total distance traveled in the maze is thought to be a signal related to psychosis. As shown by Javitt (2014), D-cycloserine (DCS) significantly reduces the anxiogenic effects of lurasidone and quetiapine, as measured by time spent in open arms, suggesting that this treatment might reduce medication-induced suicidality, as well as suicidality associated with bipolar depression itself. Preclinical data, using the Rodent Akathisia model, suggests a potential synergistic interaction between DCS and lurasidone. On one hand, as described above, DCS appears to block the anxiogenic effects of lurasidone. On the other hand, lurasidone may reverse the low-level psychotomimetic effects of DCS. Lurasidone mediates its antipsychotic effects at both D2 and 5-HT2A receptors. As opposed to pure serotonergic agents used in the treatment of major depressive disorders (e.g., SSRIs), the additional D2 blockade of lurasidone makes it a clinically effective antipsychotic; thus, it could also be effective in treating the psychotic symptoms that may be induced by an N-methyl-D-aspartate receptor (NMDAR) antagonist. Clearly, the phenomena observed in rodents should not be viewed as isomorphic with drug-induced akathisia and/or restlessness/anxiety syndrome in humans. However, these findings provide a rationale for combining glycine site-binding NMDAR antagonists with 5-HT2A antagonists in phase 2 and 3 studies of otherwise-safe drugs for the treatment of bipolar depression. This is particularly true in situations where akathisia is believed to predispose vulnerable patients to suicide. 6.4 Clinical Experience with DCS Antidepressant effects of high-dose DCS were first noted in the late 1950s when it was introduced as a treatment for tuberculosis (TB). Several clinicians noted a dramatic improvement in patients' depressive symptoms, leading to suggestions of DCS' potential psychotropic effects. These effects were subsequently confirmed in small-scale clinical studies (Crane, 1959 and 1961). The mechanism of action was unknown at the time, and the finding was not pursued. The interaction of DCS with the NMDAR was first demonstrated in 1989 (Hood et al., 1989), leading to some interest in NMDAR blockers as potential antidepressant treatments (Trullas and Skolnick, 1990; Skolnick et al., 1996). For example, both DCS and the related compound aminocyclopropanecarboxylic acid (ACPC) were shown to be active in mice, using the forced swim test for depression (Lopes et al., 1997). To the best of our knowledge, no clinical antidepressant research programs targeting the NMDA receptor were initiated at that time. Interest in the potential clinical use of DCS as an antidepressant agent was renewed following Berman's fortuitous observation of ketamine's rapid antidepressant effect (Berman et al., 2000). An initial study performed with DCS at a dose of 250 mg/day did not show therapeutic effects, but it did demonstrate a relative lack of psychotomimetic side effect when DCS was combined with concurrent antidepressant treatment (Heresco-Levy et al., 2006). Based upon these safety data, a study using a higher dose of 1000 mg/day was initiated, with results reported in 2013 (Heresco-Levy et al., 2013). At the higher dose of 1000 mg/day, significant beneficial effects were observed in 13 subjects vs. placebo control with SSRI-nonresponsive depressive symptoms. The improvements were manifested within 2 weeks and persisted throughout the 6-week treatment period. These data suggest a \>0.9 effect size. In that study, a slow DCS titration was used, with 250 mg/day for 3 days, followed by 500 mg/day for 18 days (i.e., until the end of week 3); followed by 750 mg/day for 1 week (i.e., until the end of week 4), followed by 1000 mg/day (i.e., until the end of study). A statistically significant improvement was observed in the DCS group compared to placebo by the end of week 4, i.e., within 1 week of initiation of a DCS dose \>500 mg/day The phase 2 STABIL-B trial provides evidence of efficacy from a study of NRX-101 versus Lurasidone in patients with severe bipolar depression (MADRS ≥ 30) and Acute Suicidal Ideation or behavior (C-SSRS 4, or 5), after initial stabilization with a single infusion of ketamine. 6.5 Investigational Therapy Following screening and informed consent, participants will be treated with NRX-101 twice daily by mouth. It is anticipated that participants will also be receiving concurrent bipolar disorder-directed treatment with various predefined combinations of medications. This treatment regimen will be maintained upon entry into the study. However, any use of lurasidone, quetiapine, aripiprazole, risperidone, brexpiprazole, olanzapine, cariprazine, or lumateperone, will be discontinued at study entry because NRX-101 contains a therapeutic dose of lurasidone. The treating psychiatrist should ensure that any medications to be discontinued can be done so safely. At entry, at the discretion of the investigators or the delegated treating physician subjects may continue their mood stabilizers which should not change over the course of the trial. In addition, participants receiving the olanzapine/fluoxetine combination will continue to receive the fluoxetine component.

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