Phase 3, Double-blind, Randomized, Placebo-controlled Trial to Evaluate the Efficacy and Safety of AR1001 in Participants With Early Alzheimer's Disease (Polaris-AD)

A Phase 3 Double-blind, Randomized, Placebo-controlled, Multi-center Trial to Evaluate the Efficacy and Safety of AR1001 Over 52 Weeks in Participants With Early Alzheimer's Disease (Polaris-AD)

This AR1001-ADP3-US01 protocol is a double-blind, randomized, placebo-controlled, multi- center, parallel-group comparison pivotal Phase 3 study to evaluate the efficacy and safety of AR1001 for the treatment of participants with early AD.

The purpose of this Study is to evaluate the efficacy and safety of AR1001 in participants with Early Alzheimer's Disease (AD).

AR1001 is a small molecule that has demonstrated its potential as a therapeutic agent for AD via its polypharmacological characteristics with multiple mechanisms to ameliorate AD pathology.

Inclusion Criteria:

1. Male or female participants aged 55 to 90 years of age inclusive at the time of signing the informed consent form

2. Mild cognitive impairment or mild dementia consistent with AD defined by stages 3 to 4 according to the National Institute on Aging and Alzheimer's Association (NIA-AA) at Screening

3. Participants with a history of subjective cognitive and memory decline with onset within 5 years before Screening, confirmed by study partner.

4. Participants who have a MMSE score greater than or equal to 20

5. Participants with a CDR global rating of 0.5 or 1

6. Participants with a RBANS score based on the Delayed Memory Index (DMI) score less than or equal to 85

7. If an historic magnetic resonance imaging (MRI) is available, findings must exclude other causes of dementia.

8. Positive biomarker for brain amyloid pathology as indicated by assessment of at least one of the following:

   1. Current or historical CSF assessment with FDA-cleared assays, including Lumipulse® beta-amyloid ratio [1-42/1-40] ≤ 0.072, Elecsys® pTau 181/Aβ[1-42] greater than 0.023, Elecsys® tTau /Aβ[1-42] greater than 0.28, or other assays or cut-offs as they become FDA-cleared.
   2. Historical amyloid positron emission tomography (PET) assessment confirmed by the Sponsor or Designee.

9. Participants (or participant's legally authorized representative) and caregiver (s) who can sign an informed consent to participate in the study.

10. Participants who have one (or more) identified adult study partners (s) who, in the opinion of the Investigator, has sufficient contact with and knowledge about the participant as to be able to report knowledgably about the participant's cognition, function, behavior, and safety, and compliance with the protocol. The informant/care partner must be available by phone to provide information to the Investigator and study staff about the participant as well as agree to attend in-person clinic visits that require partner input for scale completion. The informant/care partner must be literate and provide informed consent and should be available for the duration of the study. The same informant/care partner is required to be consistent across all study visits except under rare, unavoidable circumstances (e.g., unexpected informant health crisis) that are approved by the Investigator and Sponsor.

Exclusion Criteria:

1. Participants who are female and are either pregnant, nursing, or of childbearing potential and not practicing effective contraception

2. Participants who have signs of significant delirium which, in the opinion of the Investigator, would interfere with this study

3. Participants who have any diagnosis of dementia or cognitive decline other than that related to AD, including, but not limited to concomitant history of significant head trauma, alcohol abuse, frontotemporal dementia, Huntington Disease, Parkinsonism (e.g., Parkinson's disease, Dementia with Lewy Bodies, etc.), significant cerebrovascular disease, and/or significant seizure disorder

4. Participants with any current psychiatric diagnosis if, in the judgment of the Investigator, the psychiatric disorder (e.g., schizophrenia) or symptom is likely to confound interpretation of drug effect, affect cognitive assessments, or affect the participant's ability to complete the study

5. Participants with a history of vascular dementia

6. Participants with evidence of other neurological conditions thought to interfere with the evaluations in this study

7. Participants with a history of myocardial infarction, unstable angina, coronary artery disease, and/or New York Heart Association (NYHA) class III or IV heart failure within the last 12 months

8. Participants with uncontrolled hypertension (systolic blood pressure (BP) >160 mmHg or diastolic BP > 95 mmHg) or hypotension (systolic BP <90 mmHg or diastolic BP <50 mmHg). Participants may undergo repeated testing to ensure that accurate BP readings are obtained

9. Participants with a body mass index (BMI) > 35 kg/m2

10. Participants with any of the following:

    1. elevation (>2.5x upper limit of normal [ULN]) of AST (aspartate aminotransferase, ALT (alanine transaminase, or total bilirubin (unless known prior history of Gilbert's syndrome)
    2. deficiency (< lower limit of normal [LLN]) of Vitamin B12
    3. known history of HIV (human immunodeficiency virus) positivity or positive test for HIV 1/2 at screening
    4. known history of Hepatitis C virus (HCV) or positive test for HCV antibody (HCVAb) at screening (unless negative on confirmatory PCR test)'
    5. positive test for Hepatitis B surface antigen (HBsAg)
    6. known history of neurosyphilis or positive test for RPR at screening

11. Participants who have history of cancer or malignant tumor within 5 years prior to screening with the exception of:

    1. Basal or squamous cell carcinoma of the skin or cervical dysplasia, which has been adequately treated
    2. In situ Grade 1 cervical cancer, fully treated at least 2 years prior to screening, and without recurrence.
    3. Prostate cancer, confined to the prostate gland, which has been adequately treated (e.g., surgery and/or radiation or watchful waiting) with normal or low and stable prostate-specific antigen (PSA) levels for 2 years prior to Screening
    4. Adequately treated non-metastatic breast cancer

12. Participants who in the opinion of the Investigator have an inadequately treated thyroid disorder

13. Participants with inherited degenerative retinal disease

14. Participants who have an undiagnosed or uncontrolled seizure disorder (and/or an epileptic syndrome), which has or could lead to cognitive impairment either from repeated seizures or the medications used to control the seizure disorder

15. Participants who are being treated, or likely to require treatment during the study, with any medications prohibited by the study protocol

16. Participants who have participated in any investigational drug or device trial within the previous 30 days or five half-lives of an investigational drug at Screening, whichever is longer

17. Participants taking an oral cholinesterase inhibitor and/or memantine not on a stable dose for at least 3 months prior to screening. Treatment and dosing should remain stable, with no changes throughout the trial.

18. Participants who have been and/or are currently being treated with anti-amyloid, anti-tau, or any other investigational therapies for AD

19. Participants who currently take any other PDE-5 Inhibitors (e.g., sildenafil)

20. Participants who are currently receiving (or unable to stop use for at least 14 days [2 weeks] prior to receiving the first dose of the AR1001 and throughout the study) prescription or nonprescription medications or other products known to be potent inhibitors of cytochrome P450 isozyme 3A4 (CYP3A4)

21. Alcohol or substance use disorder within the past 5 years according to Diagnostic and Statistical Manual of Mental Disorders (DSM-5)

22. Participants who have previously participated in a clinical trial with AR1001

23. Participants, in the opinion of the Investigator, who are unsuitable to participate in the trial

24. Participants who in the opinion of the Investigator are at significant risk of suicide.

25. GDS-15 score greater than equal to 8 at Screening

26. Participants, in the opinion of the Investigator, who have any who have any contraindications to undergoing LP. Participants receiving ongoing anticoagulant therapy or antiplatelet therapy (other than aspirin and non-steroidal anti-inflammatory drugs [NSAIDs]) should also be excluded if it is considered unsafe to temporarily discontinue the therapy