A Study of Bryostatin in Moderately Severe to Severe Alzheimer's Disease Subjects Not On Memantine

Eligible subjects will be stratified based on Mini Mental State Exam (MMSE-2) scores 4-9 vs.
10-15 and will be randomized 1:1 to one of two treatment arms: 20µg bryostatin or placebo for
twelve weeks. The first two doses of study drug will be a loading dose 20% higher (i.e.,
24µg) than the assigned dose and will be administered one week apart. Thereafter, the
assigned dose of 20µg will commence with the third dose and be administered every other week.
Drug is administered IV by continuous infusion over 45(±5) minutes. Subjects are scheduled to
receive seven doses over 12 weeks.

Inclusion Criteria:

1. Written informed consent from caregiver and subject (if possible) or legally
acceptable representative if different from caregiver

2. Male and female subjects 55-85 years of age inclusive

3. Cognitive deficit present for at least 2 years that meet the diagnostic criteria for
probable Alzheimer's dementia. The diagnosis must be confirmed at the time of the
screening visit

4. MMSE-2 score of 4-15 inclusive (applies to Screening Visit only)

5. Patients must be able to perform at least one item on the SIB and may not have a SIB
score >93 at screening

6. Neuroimaging computerized tomography (CT) or Magnetic Resonance Imaging (MRI) within
the last 24 months consistent with a diagnosis of probable AD without any other
clinically significant co-morbid pathologies. If there has been a significant change
in the subject's clinical status since the last imaging study that is not consistent
with progression of the subject's AD, an imaging study should be performed to confirm
eligibility

7. Reliable caregiver(s) or informant(s) who attends the subject at least an average of 3
hours or more per day for 3 or more days per week and who will agree to accompany the
subject to the clinic visits and reliably complete the caregiver questions

8. Adequate vision and motor function to comply with testing

9. If taking an approved cholinesterase inhibitor for treatment of Alzheimer's disease,
must be on a stable dose for at least 3 months prior to entry into study and the dose
must not change during the study unless a change is required due to an adverse effect
of the prescribed medication or a clinically significant change in the patient's
status

10. Subjects who are memantine naïve or have been off memantine for at least 30 days prior
to initial treatment with study drug

11. Subjects on neuroleptic medications must be on a stable dose for ≥4 weeks (dose
adjustments will be permitted)

12. Females participating in the study must meet one the following criteria:

1. Surgically sterilized (e.g., hysterectomy, bilateral oophorectomy or tubal
ligation) for at least 6 months or postmenopausal (postmenopausal females must
have no menstrual bleeding for at least 1 year) or

2. If not postmenopausal, agree to use a double method of contraception, one of
which is a barrier method (e.g., intrauterine device plus condom, spermicidal gel
plus condom) 30 days prior to dosing until 30 days after last dose and have
negative human chorionic gonadotropin (β-hCG) test for pregnancy at screening

13. Males who have not had a vasectomy must use appropriate contraception methods (barrier
or abstinence) from 30 days prior to dosing until 30 days after last dose

14. In the opinion of the PI subjects should be in reasonably good health over the last 6
months and any chronic disease should be stable -

Exclusion Criteria:

1. Dementia due to any condition other than AD, including vascular dementia
(Rosen-Modified Hachinski Ischemic score ≥ 5)

2. Evidence of significant central nervous system (CNS) vascular disease on previous
neuroimaging including but not limited to: cortical stroke, multiple infarcts,
localized single infarcts in the thalamus, angular gyrus, multiple lacunar infarcts or
extensive white matter injury

3. Clinically significant neurologic disease or condition other than AD, such as cerebral
tumor, chronic subdural fluid collections, Huntington's Disease, Parkinson's Disease,
normal pressure hydrocephalus, or any other diagnosis that could interfere with
assessment of safety and efficacy

4. Evidence of clinically significant unstable cardiovascular, pulmonary, renal, hepatic,
gastrointestinal, neurologic, or metabolic disease within the 6 months prior to
enrollment. . If there is a history of cancer the subject should be clear of cancer
for at least 2 years prior to screening. More recent history of basal cell or squamous
cell carcinoma and melanoma in situ (Stage 0) may be acceptable after review by the
Medical Monitor.

5. Creatinine clearance (CL) of <45ml/min

6. Poorly controlled diabetes, at the discretion of the Principal Investigator

7. Concomitant treatment with NMDA receptor antagonists such as but not limited to
memantine or drug combinations containing memantine, dextromethorphan (a cough
suppressant), ketamine, phencyclidine (PCP), methoxetamine (MXE), nitrous oxide (N2O)
and the following synthetic opioids: penthidine, levorphanol, methadone,
dextropropoxyphene, tramadol, and ketobemidone.

8. Use of vitamin E > 400 International Units (IU) per day within 14 days prior to
screening

9. Use of valproic acid within 14 days prior to screening

10. Use of an active Alzheimer's vaccine within 2 years prior to screening

11. Use of a monoclonal antibody for treatment of AD within 1 year prior to screening

12. Any medical or psychiatric condition that is likely to require initiation of
additional medication or surgical intervention during the course of the study

13. Any screening laboratory values outside the reference ranges that are deemed
clinically significant by the PI

14. Use of an investigational drug within 30 days prior to screening

15. Suicidality defined as active suicidal thoughts during the 6 months prior to screening
or at Baseline [Type 4 or 5 on C-SSRS], or history of suicide attempt in previous 2
years, or at serious suicide risk in PI's judgment

16. Major psychiatric illness such as current major depression according to Diagnostic and
Statistical Manual of Mental Disorders, 5th Edition , current or past diagnosis of
bipolar disorder, schizophrenia, or any other psychiatric disorder that might
interfere with the assessments of safety or efficacy at the discretion of the PI

17. Diagnosis of alcohol or drug abuse within the last 2 years

18. Abnormal laboratory tests that suggest an alternate etiology for dementia. If the
patient has prior history of serum B12 abnormality, anemia with hemoglobin ≤10g /dl,
thyroid function abnormality, electrolyte abnormality, or positive syphilis serology
the patient should be revaluated to determine if these potential causes of dementia
have been addressed. Only if these causes have been ruled out as the cause of the
dementia can the patient be enrolled.

19. History of prolonged QT or prolonged QT on screening ECG (QTcB or QTcF >499 per
central reader)

20. Acute or poorly controlled medical illness: blood pressure > 180 mmHg systolic or 100
mmHg diastolic; myocardial infarction within 6 months; uncompensated congestive heart
failure [New York Heart Association (NYHA) Class III or IV]

21. Known to be seropositive for human immunodeficiency virus (HIV)

22. Known to be seropositive for Hepatitis B or C, unless successful curative treatment
for Hepatitis C (e.g., Harvoni) has been received and there is documentation that
there is no Hep B/C virus detected 3 months after completion of treatment

23. AST or ALT >3x upper limit of normal (ULN) and total bilirubin >2x ULN or
International Normalized Ratio (INR) >1.5

24. Prior exposure to bryostatin, or known sensitivity to bryostatin or any ingredient in
the study drug

25. Any other concurrent medical condition, which in the opinion of the PI makes the
subject unsuitable for the clinical study