Phase II Trial to Evaluate Safety and Efficacy of GM-CSF/Sargramostim in Alzheimer's Disease

Inclusion Criteria:

• Males or females between age 60 and 85 years, inclusive, at time of consent.

• Have a dedicated partner/caregiver informant who is in the company of theparticipant at least 12 hours a week, who can accompany them to scheduled visits,and who is able to provide accurate reporting upon the behavioral, cognitive andfunctional abilities of the participant.

• Be physically able to participate with adequate visual acuity and auditorydiscrimination.

• Be willing / able to provide written informed consent or assent.

• Must reside within a proximity of the study site that will not preclude theirregularly-scheduled participation in the trial, as well as a catchment area forlocal lab blood draws (i.e. central contracted laboratory).

• Meet criteria for probable AD dementia according to the National Institute of Aging

• Alzheimer's Association (NIA-AA) 2018 core research criteria, and have thefollowing at screening:

• A diagnosis of mild AD or moderate AD, or

• A provisional research diagnosis consistent with probable mild AD or moderateAD, and

• MoCA score of 4-24 inclusive.

• Have positive biomarker for brain amyloid pathology as shown by:

• Positive plasma assay for Aβ(42)/ Aβ(40) ratio AND

• Either postivie CSF assay for AD assessment or positive amyloid PET, per PIread.

• If receiving anti-dementia treatment (i.e. AChEI), be on stable treatment for atleast 60 days (i.e., cholinesterase inhibitor and/or Memantine) before initialscreening visit.

• Be stable on all other medications for at least 30 days prior to initial screeningvisit.

• Have had a dental exam within 6 months of date of screening.

Exclusion Criteria:

• Individuals with a first degree relative diagnosed with AD before 55 years of age.

• BMI ≥35.

• Is unable to read/write at an appropriate level to reliably participate in clinicaltrial psychometric assessments.

• Is a prisoner.

• Other neurological or psychiatric condition (other than AD) that can impactcognition, as well as atypical presentations of AD and AD related dementias,including logopenic primary progressive aphasia (PPA), or posterior cortical atrophy (PCA); or, CT/MRI evidence of potentially significant intracranial abnormalities notrelated to AD (e.g., evidence of major stroke or lacune in an area critical tocognition, infections, cancer, hydrocephalus, multiple sclerosis, etc.); or abnormalCSF not consistent with AD.

• Presence of current, serious mood or anxiety disorder, and/or a psychotic disorder,and/or a substance-related disorder according to Diagnostic and Statistical Manualof Psychiatric Disorders, Edition IV, text revision (DSM-IV-TR) or DSM-V that, inthe opinion of the Principal Investigator, might impact cognitive assessment, affectparticipants ability to complete the study, or confound interpretation of the studydrug effect; or is considered suicidal or shows suicidal ideation as assessed by thestudy physician

• History of deep vein thrombosis, pulmonary embolism, familial predisposition fordeep vein thrombosis, or pulmonary embolism.

• Active cancer / malignant neoplasm within 5 years of screening other thannon-melanoma skin cancers (e.g. Basal cell or squamous cell). Previous diagnosis ofLeukemia, despite remission state or length of time, is considered exclusionary.

• History of a latex or yeast allergy.

• Presence/history of drug hypersensitivity; or known hypersensitivity tosargramostim, yeast-derived products, any other component of the product, or benzylalcohol (present in bacteriostatic water or saline for injection).

• History of asplenia, hyposplenia, or splenectomy

• History of, or treatment for, an autoimmune disease (e.g. Rheumatoid Arthritis,Multiple Sclerosis, Myasthenia Gravis, etc.).

• Untreated or unstable medical condition that could interfere with the studyassessments in the opinion of the study physician, or may requireimmune-stimulating, immune-suppressive, or immune-modulating treatment(s) during theconduct of the study.

• History of seizures (except infant febrile seizures).

• Pregnant or breastfeeding female, or female of childbearing potential and notprotected by highly effective contraceptive method of birth control (i.e., oral ordepot contraceptives or intrauterine device (IUD) or participant was surgicallysterilized) and/or unwilling or unable to be tested for pregnancy; Male refusing touse condoms, if partner can get pregnant.

• MRI evidence of >4 micro-hemorrhages; participants who may be prone to spontaneousARIA-H and/or may be more susceptible to adverse effects of the ARIA-H.

• Laboratory results that are, in the judgement of the investigator, indicative of anuntreated medical or hematologic condition that could increase risk or interferewith study assessments

• Evidence of:

• Clinically significant pre-existing fluid retention (clinical or radiological);

• respiratory symptoms (e.g., dyspnea), moderate-to-severe lung disease (e.g.COPD, pulmonary infiltrates)

• cardiovascular symptoms or electrocardiographic evidence of cardiac diseasethat warrant therapeutic intervention (e.g., congestive heart failure,supraventricular arrhythmia, heart block, uncontrolled atrial fibrillation,etc.)

• a resting pulse less than 50, as reviewed by the study physician;

• prolonged QTc interval >470 ms in females, 450 ms in males).

• screening blood pressure measurement of greater than 160 systolic and/or 95diastolic

• Known renal dysfunction or serum creatinine >150 μmol/L, or Glomerular FiltrationRate (GFR) less than 55 ml/min

• Known hepatic dysfunction (apart from Gilbert's syndrome) or serum ALT ≥3 times theupper limit of normal (ULN)

• Positive serology for hepatitis B surface antigen (HBs Ag), anti-hepatitis C virus (anti-HCV), anti-human immunodeficiency virus 1 and 2 antibodies (anti-HIV1 andanti-HIV2 Ab) or spirochetal infection (e.g. syphilis)

• Contraindication or inability to complete magnetic resonance imaging (e.g., cardiacpacemaker/defibrillator, ferromagnetic metal implants) or PET scan.

• Sensitivity to fluorodeoxyglucose F 18

• Having past or planned exposure to ionizing radiation that would, together with theradiation resulting from the administrations of the PET tracer(s) used in thisstudy, exceed applicable institutional, local, or national recommendations forannual or lifetime exposure.

• Poor venous access.

• History of chronic or recurrent bacterial infections, at the discretion of the PI ordelegated Sub-I.

• Taking any prohibited medication or therapy

• Be the recipient of an investigational drug within 60 days of screening, or within 5times the elimination half-life of that drug, whichever is the longest.

• Prior treatment with an investigational anti-amyloid or anti-tauopathy therapy, orAD vaccine, unless it can be documented that they were on placebo.

• Participation in the treatment phase of an investigational sargramostim clinicaltrial within 6-months of screening.

• Any interested participant who:

1. Is in the judgement of the Principal Investigator likely to be non-compliantwith study protocol, including, but not limited to, leaving the area of thestudy for any extended period; or separate from the designatedcaregiver/informant, without acceptable replacement, for any of the scheduledassessment visits during the study.

2. Is unable to cooperate because of a language problem or because of adevelopmental disability.

3. Oversees or implements any aspect of the study, or is employed by PartnerTherapeutics or its affiliates or subsidiaries, or is an employee of theUniversity of Colorado Alzheimer's and Cognition Center and is engaged in theconduct of the study, or first degree relative of such.