PMN310 in Patients With Early Alzheimer's Disease (PRECISE-AD)

Inclusion Criteria:

1. Patient and caregiver provide written informed consent.

2. Ambulatory male or female ≥ 50 years of age with adequate visual and auditoryabilities to perform the cognitive and functional assessments in the opinion of theInvestigator.

3. Meets all of the following clinical criteria for mild cognitive impairment (MCI) dueto AD or mild AD dementia at Screening:

4. National Institute on Aging-Alzheimer's Association criteria for MCI due to ADor mild AD dementia (Stage 3 and 4)

5. Global Clinical Dementia Rating (CDR) of 0.5 or 1.0 and memory box score ≥ 0.5at Screening and Baseline

6. MMSE score between ≥ 20 and 30 inclusive at Screening, and

7. Either a positive amyloid PET scan within 12 months of Screening consistentwith AD, or a positive amyloid PET during Screening.

8. Body mass index between 18 and 36 kg/m2 inclusive.

9. Patients of childbearing potential must meet the following criteria:

10. Male and female patients with reproductive potential must be willing to use anapproved double barrier contraceptive method (e.g., condom plus intrauterinedevice, condom plus hormonal contraception, or double barrier device) duringand for 120 days after the last dose of study drug

11. Females of childbearing potential must have a negative serum pregnancy testduring Screening, a negative urine pregnancy test prior to each dose, and notcurrently be breastfeeding.

12. Patients of non-childbearing potential must meet 1 of the following:

13. Post-menopausal female (i.e., 12 consecutive months of spontaneous amenorrhea,age > 51 years).

14. Surgically sterile (i.e., bilateral oophorectomy or hysterectomy).

15. Has a reliable caregiver who agrees to accompany the patient at study visits,accurately report patient's status, provide feedback on functional and safetyassessments, and ensure compliance to study requirements.

16. Confirmed to have acceptable venous access for blood collections and IVadministration of study drug (i.e., PMN310 or placebo).

17. Patients taking Food and Drug Administration-approved acetylcholinesteraseinhibitors or memantine are allowed as long as the dose has been stable for at least 3 months prior to Screening. Patients taking low-dose (5mg) donepezil only require astable dose for at least 6 weeks prior to baseline.

18. Gradual and progressive memory impairment for >12 months as reported by the patientor informant.

19. A positive result on the Lumipulse G p-tau217/β-Amyloid 1-42 Plasma Ratio testduring Screening (when available). If results are indeterminate or unavailable, apatient with a plasma p-tau-217 result of ≥0.50 ng/L will be considered eligible.

Exclusion Criteria:

1. Living in a continuous care or long-term care nursing facility. Patients inoutpatient living at home or in an assisted living facility are eligible for thestudy.

2. Medical or neurological condition (other than AD; i.e., Parkinson's disease,Huntington's disease, frontal temporal dementia, dementia with Lewy bodies) judgedto be contributing to the patient's cognitive impairment.

3. Laboratory and electrocardiogram (ECG) abnormalities:

4. QT (QTcF) interval > 450 msec (males) or > 470 msec (females) during Screening

5. Alanine aminotransferase ≥ 2 × upper limit of normal (ULN); aspartateaminotransferase ≥ 2 × ULN; total bilirubin ≥1.5 × ULN during Screening

6. Creatinine clearance < 30mL/min during Screening.

7. In the opinion of the Investigator, any clinically significant current or relevanthistory of physical or psychiatric illness (including suicidal risk, ideation,behavior, or suicide attempts), any medical disorder that may require treatment ormake the patient unlikely to fully complete the study, or any condition thatpresents undue risk from the investigational product or procedures.

8. Clinically significant recurrent disease or unstable disease that could affect theaction, absorption, or disposition of the investigational product, or could affectclinical or laboratory assessments, such as (but not limited to) the following:

9. History of unstable angina, myocardial infarction, chronic heart failure, orclinically significant conduction abnormalities within 1 year prior toScreening

10. Indication of clinically significant impairment of renal or liver function,including hepatitis B surface antigen, or hepatitis C virus antibody atScreening

11. Poorly managed hypertension (systolic > 160 mmHg and/or diastolic > 95 mmHg) orhypotension (systolic < 90 mmHg and/or diastolic < 60 mmHg). Two repeatedassessments during Screening are allowed

12. Known uncontrolled diabetes defined by hemoglobin A1c > 7.5 or insulindependent diabetes.

13. Experienced a significant systemic illness, as judged by the Investigator, within 30days of the first dose of study drug.

14. Seizure in the 3 years prior to Screening.

15. History of a clinically significant medical condition that would interfere with thepatient's ability to comply with study instructions, would place the patient atincreased risk, or might confound the interpretation of the study results.

16. History of prior malignancy (except adequately treated non-melanoma skin cancer orcarcinoma in situ of the cervix).

17. Brain MRI with evidence of any of the following findings at Screening: >4microhemorrhages; > 1 lobar microhemorrhage, area of superficial siderosis;subarachnoid hemorrhage; any other hemorrhage > 10 mm; > 2 lacunar infarcts orcortical infarct; subjects with severe perivascular spaces or with white matterhyperintensities in a multisort pattern will require PI review prior to inclusion.

18. History of stroke or transient ischemic attack within 12 months prior to Screening.

19. Contraindication to PET or brain MRI.

20. Negative PET scan with any amyloid-targeting ligand within 12 months of Screening orduring Screening.

21. Pregnant or breastfeeding.

22. History of alcohol abuse and/or other substance abuse within 12 months prior todosing with study drug.

23. Positive test for illicit drugs of abuse at Screening.

24. Documented history of human immunodeficiency virus antibody.

25. Coronavirus disease 2019 (COVID-19) infection within 2 weeks of Screening or ongoingsymptoms of COVID-19 at Screening.

26. Currently receiving an anti-amyloid treatment, either marketed (lecanemab,donanemab) or investigational or has received anti amyloid therapy within 9 monthsprior to Screening. In the case of investigational treatment, those known to havereceived placebo will not be excluded.

27. Contraindication to undergoing lumbar puncture (LP) including: sensitivity to localanesthetic, international normalized ratio (INR) > 1.4 or other coagulopathy,platelet cell count of < 120,000/µL, infection at the desired LP site, current useof anti-coagulant medication except for low dose aspirin, degenerative arthritis,spinal scoliosis, back surgery, suspected increased intracranial pressure on historyor neurologic exam, non-communicating hydrocephalus or intracranial mass, or priorhistory of spinal mass or trauma and/or other known clinically significant spinalabnormalities.

28. Donated blood or blood products (e.g., plasma, platelets) within 56 days prior tofirst dose of study drug.

29. Received an investigational active agent (e.g., not placebo) within the last 30 daysor 5 half-lives, whichever is longer (if known).

30. Known history of severe allergic reaction or hypersensitivity to any components ofthe PMN310 infusion.