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).

Inclusion Criteria:A subject will be eligible for inclusion in this study only if all of
the following criteria apply:

1. Male or female, 18 to 65 years of age, inclusive, at screening.

2. Able to read, understand, and provide written, dated informed consent prior to
screening. Participants will be deemed likely to comply with study protocol and
communicate with study personnel about AEs and other clinically important information.

3. Diagnosed with Bipolar Disorder (BD) according to the criteria defined in the DSM-5.
The diagnosis of BD will be made by a site psychiatrist and supported by the MINI
7.0.2. The diagnosis will be confirmed by remote, independent raters, via
teleconference between the screen visit and the baseline visit.

4. Suicidal ideation or behavior of sufficient severity to meet the requirements for a
score of 4, or 5 on the C-SSRS (suicide attempt, interrupted attempt, aborted attempt,
preparatory actions toward imminent suicidal behaviors, active method, intent +/-
plan).

5. A score equal to or greater than 20 on the MADRS items of the BISS.

6. In good general health, in the opinion of the investigator, as ascertained by medical
history, physical examination (PE) (including measurement of seated vital signs),
clinical laboratory evaluations, and electrocardiogram (ECG).

7. If female, a status of non-childbearing potential or use of an acceptable form of
birth control per the following specific criteria:

a. Non-childbearing potential (e.g., physiologically incapable of becoming pregnant,
i.e., permanently sterilized [status post hysterectomy, bilateral tubal ligation], or
is post-menopausal with her last menses at least one year prior to screening); or

- Childbearing potential, and meets the following criteria:

- Childbearing potential, including women using any form of hormonal birth
control, on hormone replacement therapy started prior to 12 months of
amenorrhea, using an intrauterine device (IUD), having a monogamous
relationship with a partner who has had a vasectomy, or is sexually
abstinent.

- Negative urinary pregnancy test at screening, confirmed by a negative
urinary pregnancy test at randomization prior to receiving study treatment.

- Willing and able to continuously use one of the following methods of birth
control during the course of the study, defined as those which result in a
low failure rate (i.e., less than 1% per year) when used consistently and
correctly: implants, injectable or patch hormonal contraception, oral
contraceptives, IUD, double-barrier contraception, sexual abstinence. The
form of birth control will be documented at screening and baseline.

8. Body mass index between 18-35 kg/m2.

9. Concurrent psychotherapy will be allowed if the type (e.g., supportive, cognitive
behavioral, insight-oriented) and frequency (e.g., weekly or monthly) of the therapy
has been stable for at least three months prior to screening and if the type and
frequency of the therapy is expected to remain stable during the course of the
subject's participation in the study.

10. Concurrent hypnotic therapy (e.g., with zolpidem, zaleplon, melatonin, benzodiazepines
or trazodone) will be allowed if the therapy has been stable for at least 4 weeks
prior to screening and if it is expected to remain stable during the course of the
subject's participation in the study. Subjects can also continue treatment with
benzodiazepines used for sleep or anxiety if therapy has been stable for at least 4
weeks prior to screening and if it is expected to remain stable during the course of
the subject's participation in the study.

Exclusion Criteria:

A subject will not be eligible for inclusion in this study if any of the following criteria
apply:

1. Female of childbearing potential who is not willing to use one of the specified forms
of birth control during the study.

2. Female that is pregnant or breastfeeding.

3. Female with a positive pregnancy test at screening or baseline.

4. Current diagnosis of a substance use disorder (abuse or dependence, as defined by
DSM-5, with the exception of nicotine dependence), at screening or within 6 months
prior to screening.

5. Current Axis I disorder, diagnosed at screening with the use of the MINI 7.0.2, that
is the primary focus of treatment and BD the secondary focus of treatment for the past
6 months or more.

6. History of schizophrenia or schizoaffective disorders, or any history of psychotic
symptoms.

7. History of anorexia nervosa, bulimia nervosa, or eating disorder not otherwise
specified, within 5 years of screening.

8. Any Axis I or Axis II Disorder, which at screening is clinically predominant to their
BD or has been predominant to their BD at any time within 6 months prior to screening.

9. Has dementia, delirium, amnestic, or any other cognitive disorder.

10. Has a clinically significant abnormality on the screening physical examination that
might affect safety, study participation, or confound interpretation of study results
according to the study clinician.

11. Participation in any clinical trial with an investigational drug or device within the
past month or concurrent to study participation.

12. Current episode of:

- Hypertension, Stage 1 as defined by a systolic blood pressure ≥140 mmHg or
diastolic blood pressure ≥90 mmHg at screening on two of three measurements at
least 15 minutes apart.

- Hypertension, Stage 1 as defined by a systolic blood pressure ≥155 mmHg or
diastolic blood pressure ≥99 mmHg at the Baseline Visit (Visit 1) within 1.5
hours prior to ketamine infusion on two of three measurements at least 15 minutes
apart.

- Recent myocardial infarction (within one year) or a history of myocardial
infarction.

- Syncopal event within the past year.

- Congestive heart failure (CHF) New York Heart Association Criteria >Stage 2

- Angina pectoris.

- Heart rate <50 or >105 beats per minute at screening or randomization (Baseline
Visit).

- QTcF (Fridericia-corrected) ≥450 msec at screening or randomization (Baseline
Visit).

13. Current history of hypertension, or on antihypertensives for the purpose of lowering
blood pressure, with either an increase in antihypertensive dose or increase in the
number of antihypertensive drugs used to treat hypertension over the last 2 months.

14. Chronic lung disease excluding asthma.

15. Lifetime history of surgical procedures involving the brain or meninges, encephalitis,
meningitis, degenerative central nervous system (CNS) disorder (e.g., Alzheimer's or
Parkinson's Disease), epilepsy, mental retardation, or any other
disease/procedure/accident/intervention which, according to the screening clinician,
is deemed associated with significant injury to or malfunction of the CNS, or history
of significant head trauma within the past 2 years.

16. Presents with any of the following lab abnormalities:

- Subjects with diabetes mellitus fulfilling any of the following criteria:

- Unstable diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >8.5%
at screening.

- Admitted to hospital for treatment of diabetes mellitus or diabetes
mellitus-related illness in the past 12 weeks.

- Not under physician care for diabetes mellitus.

- Has not been on the same dose of oral hypoglycemic drug(s) and/or diet for
the 4 weeks prior to screening. For thiazolidinediones (glitazones) this
period should not be less than 8 weeks.

- Any other clinically significant abnormal laboratory result (determined as such
by the investigator and medical monitor) at the time of the screening.

17. Any current or past history of any physical condition which in the investigator's
opinion might put the subject at risk or interfere with study results interpretation.

18. Positive screening urine test for drugs of abuse at screening: cocaine, amphetamines,
barbiturates, opiates.

19. Subjects with exclusionary laboratory values, or requiring treatment with exclusionary
concomitant medications as defined in the study manual

20. Subjects on exclusionary concomitant psychotropic medications.

21. Subjects with a lifetime history of illicit PCP/ketamine drug use or previous failed
use of ketamine for depression.

22. Liver Function Tests higher than 2.5 times upper limit of normal as defined in the
study manual.

23. Known allergies to Lurasidone or Latuda, Cycloserine or Seromycin, Mannitol,
Croscarmellose Sodium, Magnesium Stearate, Silicon Dioxide, and/or HPMC
(hydroxypropylmethylcellulose)