Intervention: Bryostatin 1
Trial phase: Phase 2
SMILES: CCCC=CC=CC(=O)OC1C(=CC(=O)OC)CC2CC(C(C)O)OC(=O)CC(O)CC3CC(OC(C)=O)C(C)(C)C(O)(CC4CC(=CC(=O)OC)CC(C=CC(C)(C)C1(O)O2)O4)O3
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 53
Group description: 20µg Bryostatin administered IV over 45 minutes every other week after 2 initial loading doses of 24 micrograms administered weekly. A total of 7 doses administered over 12 weeks.

Bryostatin: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.
Eligibility criteria:
Inclusion Criteria:

Written informed consent from caregiver and subject (if possible) or legally acceptable representative if different from caregiver
Male and female subjects 55-85 years of age inclusive
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
MMSE-2 score of 4-15 inclusive (applies to Screening Visit only)
Patients must be able to perform at least one item on the SIB and may not have a SIB score >93 at screening
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
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
Adequate vision and motor function to comply with testing
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
Subjects who are memantine naïve or have been off memantine for at least 30 days prior to initial treatment with study drug
Subjects on neuroleptic medications must be on a stable dose for ≥4 weeks (dose adjustments will be permitted)

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

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
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
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
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:

Dementia due to any condition other than AD, including vascular dementia (Rosen-Modified Hachinski Ischemic score ≥ 5)
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
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
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.
Creatinine clearance (CL) of <45ml/min
Poorly controlled diabetes, at the discretion of the Principal Investigator
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.
Use of vitamin E > 400 International Units (IU) per day within 14 days prior to screening
Use of valproic acid within 14 days prior to screening
Use of an active Alzheimer's vaccine within 2 years prior to screening
Use of a monoclonal antibody for treatment of AD within 1 year prior to screening
Any medical or psychiatric condition that is likely to require initiation of additional medication or surgical intervention during the course of the study
Any screening laboratory values outside the reference ranges that are deemed clinically significant by the PI
Use of an investigational drug within 30 days prior to screening
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
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
Diagnosis of alcohol or drug abuse within the last 2 years
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.
History of prolonged QT or prolonged QT on screening ECG (QTcB or QTcF >499 per central reader)
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]
Known to be seropositive for human immunodeficiency virus (HIV)
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
AST or ALT >3x upper limit of normal (ULN) and total bilirubin >2x ULN or International Normalized Ratio (INR) >1.5
Prior exposure to bryostatin, or known sensitivity to bryostatin or any ingredient in the study drug
Any other concurrent medical condition, which in the opinion of the PI makes the subject unsuitable for the clinical study