A Phase II Study to Assess the Safety, Tolerability and Efficacy of Xanamem™ in Subjects With Mild Dementia Due to AD (XanADu)

This is a Phase II, randomised, multi-centre, double-blind, placebo-controlled
proof-of-concept study to assess the safety, tolerability and efficacy of oral Xanamem™ once
daily in adult subjects with mild dementia due to AD.

Based on Xanamem™'s mode of action on hippocampal function, amnestic symptoms may respond
best, thus favouring the inclusion of mild dementia due to AD, with given evidence of disease
progression. Subjects will be treated in a double-blind fashion, where both the investigators
and subjects will be unaware of the treatment assignments, to minimise any subjective or
unrecognised bias carried by the investigators and subjects. Placebo will be used as the
comparator in this study. In this study, Xanamem™ will be administered in conjunction with
current standard therapy.

It is planned to randomise approximately 174 subjects at approximately 25 study sites in
three countries (Australia, United Kingdom, and United States), with the aim to enrol 7 to 10
subjects at each study site. Subject enrolment will be competitive but a cap of 20 subjects
per study site is to be established to avoid any site effects. In case the sample composition
at one study site is creating concerns, an enrolment stop can also occur at fewer than 20
subjects.

The data safety monitoring board (DSMB) will periodically meet for the review of accumulating
safety study data and will also be involved in the interim analysis.

At the Baseline visit (Week 0), eligible subjects will be randomised on a 1:1 ratio to
receive either Xanamem™ administered orally QD (treatment group) or matching placebo (placebo
group). Subjects will return to the study site for visits at Week 4 and Week 8, End of
Treatment (Week 12) and Follow-up (4 weeks post last dose of study drug) visits, at which
study assessments will be performed.

Ad hoc telephone contact may also occur at any other time-point throughout the study, if
deemed necessary by the investigator/study nurse, or if the subject wishes to report an AE.

Subjects will be interviewed and examined at the study site at each visit, and will complete
a variety of questionnaires and routine safety evaluations.

Optional PD sampling will be performed at specific visits. Subjects who do not provide
consent for this optional sub-study will still be eligible for the main study.

The overall study duration for an individual subject will be 17 to 20 weeks, including a
screening period of one to 4 weeks, a double-blind treatment period of 12 weeks, and a
follow-up period of 4 weeks. The total duration of the study is expected to be 2 years.

Inclusion Criteria:

1. Males and females aged 50 years or older at the time of informed consent.

2. Female Subjects:

1. Post menopausal women, defined as no menses for 12 months without an alternative
medical cause. If there is any concern about the menopausal status of a
prospective female subject, a follicle stimulating hormone test (FSH) should be
requested to confirm post-menopausal status. Post menopausal women confirmed by
FSH level > 40 mIU/mL, will be confirmed by central laboratory.

2. Women of childbearing potential (WOCBP) must have a negative pregnancy test at
Screening and Baseline, and be willing to use highly effective methods of
contraception from the Screening visit until 3 months after last dose of study
drug. If re-test is required, a local urine pregnancy test will be performed at
Baseline to determine if the subject can continue to randomisation.

3. Are permanently sterile or have had a hysterectomy, bilateral salpingectomy or
bilateral oophorectomy.

4. Women must not be breastfeeding.

3. Male Subjects:

1. Who are sexually active, fertile men must use highly effective methods of
contraception from Day 1 until 3 months after last dose of study drug if their
partners are WOBC.

2. Who are permanently sterile or have had bilateral orchiectomy.

4. Diagnosis of mild dementia due to Alzheimer's disease (AD) with increased level of
certainty (provided by evidence of clinical deterioration within the 6 months
preceding Screening, as assessed by the investigator) as determined by the National
Institute of Ageing (NIA) and the Alzheimer's Association (AA) workgroup.

5. Mild dementia due to probable AD with MMSE 20 to 26 (inclusive).

6. Clinical Dementia Rating Scale (CDR) Global Score of 0.5 to 1.0.

7. A brain magnetic resonance imaging (MRI) or computed tomography (CT) scan in the 12
months preceding Screening that in the investigator's opinion is consistent with AD as
the principle aetiology of the dementia with no other clinically significant
abnormality, e.g. another principle underlying aetiology of the subject's dementia, or
a lesion which could affect cognition e.g. a brain tumour or large stroke.

8. On stable dose of acetylcholinesterase (AChEI) and/or memantine (at least 3 months
prior to Screening) OR treatment-naïve. Initiating AChEIs or memantine during the
study will not be permitted.

9. Apart from a clinical diagnosis of mild dementia due to AD, the subject must be in
good health as determined by the investigator, based on medical history and screening
assessments.

10. Has a consenting study partner who, in the investigator's judgement, has frequent and
sufficient contact with the subject to be able to provide accurate information as to
the subject's cognitive and functional abilities. The study partner must be available
to provide information to the investigator and study site staff about the subject and
agrees to attend all study site visits in person for scale completion. A study partner
should be available for the duration of the study. The measure of adequate
availability will be at the investigator's discretion.

11. Must be willing and able to comply with the requirements of the protocol and must be
available to complete the study.

12. Must satisfy a medical examiner about their fitness to participate in the study.

13. Must provide written informed consent to participate in the study.

Exclusion Criteria:

1. Clinically significant abnormalities in vital signs (blood pressure, heart rate,
respiration rate and oral temperature), as determined by the investigator.

2. Clinically significant abnormal haematology, biochemistry and urine examination
values, specifically abnormal liver and renal function and Vitamin B12 levels below
lower threshold since these parameters may impact cognitive function, as determined by
the investigator.

3. Has had a significant systematic illness or infection within the past 4 weeks prior to
randomisation, as determined by the investigator.

4. Clinically significant neurological disease other than AD, such as (but not limited
to) Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure
hydrocephalus, brain tumour, progressive supranuclear palsy, seizure disorder,
subdural haematoma, multiple sclerosis or a history of significant head trauma
followed by persistent neurologic defaults or known structural brain abnormalities.

5. Subjects with clinical evidence of peripheral neuropathy or historical evidence of
clinically significant nerve conduction abnormalities.

6. Has had a stroke within the year prior to randomisation, as determined by the
investigator.

7. Has a lifetime diagnosis of a major psychiatric disorder (other than dementia), based
on the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria.
This includes but is not limited to schizophrenia, schizoaffective disorder, bipolar
affective disorder, alcohol dependence syndrome or major depressive disorder.

8. Has a history of disease directly related to the hypothalamus, the pituitary and/or
the adrenal glands which affect the hypothalamic-pituitary-adrenal axis function.

9. Has uncontrolled clinical conditions relating to glucose and lipid metabolism.

10. Clinically significant electrocardiogram (ECG) abnormalities, including QTc interval >
450 ms, following ECG tracings at Screening.

11. Use of any prohibited medication as detailed in the study protocol.

12. Participation in another clinical study of an investigational drug or device whereby
the last investigational drug/device administration is within 60 days of Screening.

13. Inability to communicate well with the investigator (i.e. language problem, non-fluent
English [as scales will be provided in English only], poor mental development or
impaired cerebral function).

14. Subject will undergo the tests, ADAS-Cog v14, CDR-SOB, MMSE, NTB (executive domain)
and RAVLT at the indicated time-points to avoid uncontrolled learning effects.
Subjects who need to perform these tests externally to and in parallel with this study
will be excluded.

15. Subject has ingested any food or drink containing grapefruit, Seville oranges, star
fruit or derived products (e.g. fruit juice), for at least 3 days prior to the first
administration of study drug.