Open label extension study for patients with early Alzheimer's Disease (AD) enrolled in study ANAVEX2-73-AD-004

Cognitive deficits in patients Alzheimer's disease (AD) often involve
dysregulation of neuronal signaling. This neuronal signaling imbalance may be
countered by enhancing neuronal homeostatic mechanisms. Considering the high
unmet medical treatment need for neurodegenerative diseases, novel therapeutic
strategies, such as those targeting neuronal homeostatic mechanisms, could lead
not only to improving acquisition or slowing
progression of cognition but also of other neurologic functions.

ANAVEX2-73 is an investigational oral sigma-1 receptor (*1R) agonist whose
mechanism of action is to activate the *1R, which in turn enhances cellular
homeostasis by targeting mitochondrial dysfunction, including oxidative stress;
protein misfolding; autophagy, neuroinflammation; and other cellular stress
responses, known to be implicated in neurodegenerative disorders. ANAVEX2-73
has been shown pharmacologically to be an effective neuroprotective,
anticonvulsive, and anti-depressant therapeutic agent.
ANAVEX2-73 has shown to significantly improve cognitive functions in various
experimental pre-clinical models.

Because of its targeted upstream mechanism of action, ANAVEX2-73 is assumed to
be potentially disease modifying for Alzheimer's Disease and potentially
possessing a better safety profile than currently approved drugs.

ANAVEX2-73 has been studied in animal models as well as normal volunteers and
patients with mild to moderate AD. In general, ANAVEX2-73 has a favorable
safety profile, with the majority of TEAEs associated with daily oral doses of
50 mg or greater. Furthermore, these studies support ANAVEX2-73*s long-term
efficacy and the possibility of using precision medicine approaches for the
treatment of AD and other neurodegenerative and neurodevelopmental disorders.
Of interest was the observation from the Phase 2a in AD study showing
beneficial effects of ANAVEX2-73 on insomnia, agitation and anxiety at 31 weeks
identified by the HAM-D item scores, which might suggest an additional
important role of ANAVEX2-73 for the amelioration of behavioral and
psychological symptoms of dementia (BPSD). Accordingly, sleep continuity and
sleep disorders symptomatology will be assessed on a periodic basis for the
duration of the proposed trial using self-report instruments.

Given the current lack of approved treatment options with acceptable side
effect profiles for AD, the development of ANAVEX2-73 could meet this critical
unmet medical need for AD patients.

Primary objective:
To continue assessing the safety and tolerability of ANAVEX2-73.
Safety and Tolerability Measures:
* Physical examination
* Vital signs (heart rate, respiratory rate, systolic blood pressure [SBP],
diastolic blood pressure [DBP], pulse oximetry, and oral body temperature)
* Graded AEs according to common Terminology Criteria for Adverse Events
(CTCAE) V4.0.3
* 12-lead ECG
* Columbia-Suicide Severity Rating Scale (C-SSRS)
* Clinical laboratory tests (hematology including coagulation, clinical
chemistry including lipid panel, and urinalysis)
* Concomitant medication log

Secondary objective:
* Observation of P-tau blood level concentration
* To determine whether ANAVEX2-73 modifies cognition, behavior, or QoL,
according to the following standardized measures commonly used in AD:
- Change from baseline to week 96 in ADAS-Cog
- Change from baseline to week 96 in ADCS-ADL
- Change from baseline to week 96 in MMSE
- Change from baseline to week 96 in NPI-Q
- Change from baseline to week 96 in ZBI
- Change from baseline to week 96 in QoL-AD

This is a Phase 2b/3 open-label extension study to evaluate the effects of
ANAVEX2-73 on safety and efficacy (cognition) after 96 weeks of daily
treatment. Additional outcome measures include measures of function and
behavioral symptoms typically observed in AD during treatment with ANAVEX2-73.

The study is limited to subjects who completed the ANAVEX2-73-AD-004
double-blind clinical study who consent to enroll in the open label study. The
dosing schedule is as follows:
• Up-Titration over 10 weeks and then maintenance at either 50 mg daily or best
tolerated dose.
• All patients regardless of their prior dose during the ANAVEX2-73-AD-004
clinical trial will undergo the following titration schedule: Treatment will
begin at 10 mg/day ANAVEX2-73 for the first two weeks (Week 0 and Week 1),
increasing by 10 mg every two weeks over a 10-week period to a maximum
maintenance daily dose of either 50 mg or best tolerated dose*.
• Maintenance (Weeks 11-96): Subjects will take 50 mg ANAVEX2-73 per day or
best tolerated dose*.
* Best tolerated dose will be determined during the titration period based on
the basis of tolerability. Dosing adjustments (such as a dose decrease) may
occur at any time under the supervision of the investigator. Patients should be
maintained on the best tolerated ANAVEX2-73 daily dose between 20 mg - 50 mg.
Should the patient continue to experience adverse events (AE) at the 20 mg/day
dose, a dose of 10 mg/day (or temporary drug holiday) will be allowed under the
guidance of the investigator.

Safety and tolerability will be assessed throughout the study, starting from
the first dose of study medication. Participants who experience any dose
interruption >= 10 consecutive days must be withdrawn from the study.

If the roll-over visit into this study occurs in clinic on the same day as the
AD-004 doubleblind study End of Treatment Visit, the final double-blind dose
should be taken in clinic on this day and the first dose of the open-label
extension study should then be taken at home the following day.

The research medication is ANAVEX2-73.

Treatment will begin at 10 mg/day ANAVEX2-73 for the first two weeks (Week 0
and Week 1), increasing by 10 mg every two weeks over a 10-week period to a
maximum maintenance daily dose of either 50 mg or best tolerated dose.

The study medication will be taken once daily.

Currently there are no well-developed treatment methods for people who are
diagnosed with Alzheimer*s Disease. The development of ANAVEX2-73 could meet
critical unmet medical need for AD patients.

ANAVEX2073 will be delivered as capsules for oral intake.

Side effects of ANAVEX2-73 are: Dizziness, Headache, Disorientation, Fatigue,
Drowsiness, Gastrointestinal (stomach) disorders, like nausea, vomiting,
diarrhoea and constipation, Hallucinations, Anxiety, Agitation, Delirium.

Risk associated to study assessments:
ECG: redness and itching caused by the sticky pads.
Blood draws: discomfort, bruising, minor infection or bleeding.

The following procedures are performed:
- Measurement of vital signs - all visits;
- Physical and neurological examination - all visits;
- ECG - all visits;
- Blood draws for safety and P-tau blood level concentration - all visits;
- Urinalysis and urine drug screen - all visits;
- Questionnaires ADAS-Cog and ADCS-ADL - at baseline and week 48;
- Questionnaires MMSE, ZBI, NPI-Q, QoL-AD and C-SSRS - all visits.