Sequential Therapy for the Treatment of Severe Bipolar Depression.

NeuroRx is developing NRX-101, a fixed-dose combination oral capsule composed of D-cycloserine (DCS) and lurasidone for the maintenance of remission from Severe Bipolar Depression with Acute Suicidal Ideation or Behavior (ASIB) in adults with Bipolar Depression following initial stabilization with ketamine. In recent years, intravenous and intranasal ketamine have demonstrated rapid and potent effects in achieving remission from both depression and suicidal ideation in both bipolar depression and major depressive disorder. However ketamine is will understood to induce hallucination and other dissociative side effects, to be addictive and have high abuse potential, and to have potential neurotoxic effects. Moreover, ketamine can only be administered in a monitored hospital or clinic setting. NRX-101 was developed with the objective of seeking a safe, non-hallucinogenic, non-addictive, oral medication that might maintain the effects of ketamine in patients with severe depression and acute suicidal ideation and which might be considered as initial therapy for patients with depression and non-acute suicidal ideation. The D-cycloserine component of NRX-101 is believed to act by inhibiting the brain's NMDA receptor and raising levels of glutamate/glutamine (Glx) in the anterior cingulate cortex. Increased Glx, as measured by magnetic resonance spectroscopy, has been associated with clinical improvement following electroconvulsive therapy (ECT) and following administration of IV ketamine.

The proposed oral combination product is intended to be administered as part of a sequential therapy consisting of the following 2 components:

1. an initial, one-time intravenous (iv) infusion of ketamine (0.5 mg/kg administered over 40 min), followed one day later by
2. twice daily oral capsules of NRX 101 (DCS + lurasidone), dosing of which is initiated 1 day after ketamine administration, titrated over 5 days to a maintenance dose and continued for up to 6 weeks. Each NRX-101 oral capsule contains DCS (237.5 or 175.0 mg) and lurasidone (8.25, 16.5, or 33.0 mg). It is anticipated that subjects entering the study will be receiving concurrent disorder-directed treatment with other approved medications. This treatment regime will be maintained upon entry into the study. However, any use of lurasidone, quetiapine, or olanzapine will be stopped at study entry, so as to avoid either duplication with study drug (groups 1 and 2) or undermining of the control group.

The clinical efficacy goal is to provide extended relief from symptoms associated with Severed Bipolar Depression and ASIB in adults with Bipolar Disorder, after initial stabilization with iv ketamine in a clinic, emergency department, or inpatient setting.

The proposed NRX-101 product takes advantage of a unique synergistic confluence of combining two active pharmaceutical ingredients (DCS and lurasidone) that respectively inhibit the NMDA and the D2/5-HT2A receptors in the brain. NMDA receptor antagonists, most notably ketamine, have been shown in many studies to rapidly reduce depressive and suicidal ideation. However, numerous studies have demonstrated the potential of NMDA antagonists to cause hallucination and other dissociative side effects. Similarly, D2/5HT2A receptor antagonists, such as lurasidone have demonstrated antidepressant effects in bipolar depression, but have demonstrated a propensity to cause akathisia in some patients. The goals of combining these drugs into a single course of treatment is to maximize the beneficial effects of the specific subcomponents while overcoming potential treatment-limiting side effects associated with those subcomponents.

Beneficial effects of the proposed dosage regimen include 1) well-documented pharmacodynamic effects of ketamine in treating both persistent depressive symptoms and suicidal ideation in bipolar disorder (McCloud, 2015; Naughton, 2014; Newport, 2015; Price, 2014), 2) well-documented pharmacodynamic effects of oral DCS against persistent symptoms of depression (Heresco-Levy, 2013) and 3) the FDA-approved efficacy of lurasidone in treatment-resistant depression (Sunovion Pharmaceuticals, 2013). Due to the synergistic effects, the proposed NRX-101 combination capsule is also expected to avoid or minimize the significant undesired adverse effects associated with the usage of these drugs as single agents (eg, negative consequences of repeated use of ketamine (JHP Pharmaceuticals, 2012), potential psychotomimetic effects of long-term treatment with DCS alone (Kantrowitz, 2010) and potential akathisia and susceptibility for increased suicidality associated with lurasidone alone (Sunovion Pharmaceuticals, 2013).

The risk of ASIB is higher in bipolar depression than other psychiatric disorder and the majority of currently available antidepressants are contraindicated for patients with bipolar depression. NeuroRx believes that the proposed NRX-101 treatment regimen (ketamine administration followed by NRX-101) will demonstrate superiority over ketamine followed by lurasidone in maintaining remission from depression and in delaying the time to documented relapse from depression and suicidality in bipolar disorder, providing a new treatment option for patients with Severe Bipolar Depression and ASIB.

There is currently no FDA-approved product for the treatment of ASIB. NeuroRx proposes that NRX-101 will fulfill an urgent medical need for safe and effective treatment for ASIB.

Patients with Severe Bipolar Depression and ASIB will be recruited in inpatient settings and, following informed consent, will be given an intravenous infusion of either ketamine 0.5mg/kg over 40 minutes or normal saline (placebo). Those who exhibit a satisfactory clinical response to ketamine will be randomly allocated to NRX-101 or to lurasidone along (the comparator group). The primary outcome variable for this phase 2 study will be blood level (pharmacokinetic) exposure of NRX-101 and its D-cycloserine component with remission from depression, as measured on the MADRS scale and relapse as secondary endpoints. Relapse is defined as return of either depression or suicidality OR the need to alter therapy, which might include re-hospitalization, additional antidepressant medication, or electroconvulsive therapy (ECT).