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

A Phase 1b, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study of the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of PMN310 in Patients With Early Alzheimer's Disease

This Phase 1b study aims to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of multiple IV infusions of PMN310 in patients with early Alzheimer's disease.

This study is a Phase 1b, randomized, double-blind, placebo controlled, multi-ascending dose study of repeat doses of PMN310 to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of multiple intravenous infusions of PMN310 in patients with early Alzheimer's disease. This study will evaluate 3 dose levels (350 mg, 700 mg, and 1400 mg are planned). Patients will be randomly assigned 3:1, PMN310: placebo.

Each patient will receive PMN310 or placebo once every 28 days for a total of 12 infusions.

Inclusion Criteria:

1. Patient and caregiver provide written informed consent.

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

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

   1. National Institute on Aging-Alzheimer's Association criteria for MCI due to AD or mild AD dementia (Stage 3 and 4)
   2. Global Clinical Dementia Rating (CDR) of 0.5 or 1.0 and memory box score ≥ 0.5 at Screening and Baseline
   3. MMSE score between ≥ 20 and 30 inclusive at Screening, and
   4. Either a positive amyloid PET scan within 12 months of Screening consistent with AD, or a positive amyloid PET during Screening.

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

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

   1. Male and female patients with reproductive potential must be willing to use an approved double barrier contraceptive method (e.g., condom plus intrauterine device, condom plus hormonal contraception, or double barrier device) during and for 120 days after the last dose of study drug
   2. Females of childbearing potential must have a negative serum pregnancy test during Screening, a negative urine pregnancy test prior to each dose, and not currently be breastfeeding.

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

   1. Post-menopausal female (i.e., 12 consecutive months of spontaneous amenorrhea, age > 51 years).
   2. Surgically sterile (i.e., bilateral oophorectomy or hysterectomy).

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

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

9. Patients taking Food and Drug Administration-approved acetylcholinesterase inhibitors 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 a stable dose for at least 6 weeks prior to baseline.

10. Gradual and progressive memory impairment for >12 months as reported by the patient or informant.

11. A positive result on the Lumipulse G p-tau217/β-Amyloid 1-42 Plasma Ratio test during Screening (when available). If results are indeterminate or unavailable, a patient 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 in outpatient living at home or in an assisted living facility are eligible for the study.

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

3. Laboratory and electrocardiogram (ECG) abnormalities:

   1. QT (QTcF) interval > 450 msec (males) or > 470 msec (females) during Screening
   2. Alanine aminotransferase ≥ 2 × upper limit of normal (ULN); aspartate aminotransferase ≥ 2 × ULN; total bilirubin ≥1.5 × ULN during Screening
   3. Creatinine clearance < 30mL/min during Screening.

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

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

   1. History of unstable angina, myocardial infarction, chronic heart failure, or clinically significant conduction abnormalities within 1 year prior to Screening
   2. Indication of clinically significant impairment of renal or liver function, including hepatitis B surface antigen, or hepatitis C virus antibody at Screening
   3. Poorly managed hypertension (systolic > 160 mmHg and/or diastolic > 95 mmHg) or hypotension (systolic < 90 mmHg and/or diastolic < 60 mmHg). Two repeated assessments during Screening are allowed
   4. Known uncontrolled diabetes defined by hemoglobin A1c > 7.5 or insulin dependent diabetes.

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

7. Seizure in the 3 years prior to Screening.

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

9. History of prior malignancy (except adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix).

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

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

12. Contraindication to PET or brain MRI.

13. Negative PET scan with any amyloid-targeting ligand within 12 months of Screening or during Screening.

14. Pregnant or breastfeeding.

15. History of alcohol abuse and/or other substance abuse within 12 months prior to dosing with study drug.

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

17. Documented history of human immunodeficiency virus antibody.

18. Coronavirus disease 2019 (COVID-19) infection within 2 weeks of Screening or ongoing symptoms of COVID-19 at Screening.

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

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

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

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

23. Known history of severe allergic reaction or hypersensitivity to any components of the PMN310 infusion.