A Phase 2a, Proof-of-Concept, Open-Label Study to Evaluate the Pharmacodynamics, Pharmacokinetics, and Safety of Obicetrapib in Patients with Early Alzheimer*s Disease (Hetero/Homozygote APOE4 Carriers)

1. Age range: 50-75 years of age at the Screening Visit.
2. Males, or females who are post-menopausal or otherwise not of child-bearing
potential.
a. Women are not considered to be of childbearing potential if they meet 1 of
the following criteria as documented by the Investigator:
i. They have had a hysterectomy or tubal ligation at a minimum of 1 cycle prior
to signing the ICF; or
ii. They are postmenopausal, defined as *1 year since their last menstrual
period for women *55 years of age or *1 year since their last menstrual period
and have a follicle stimulating hormone (FSH) level in the postmenopausal range
for women <55 years of age
b. Men whose partners are of childbearing potential must agree to use an
effective method of avoiding pregnancy from screening to 90 days after the last
visit. Effective methods of avoiding pregnancy are contraceptive methods with a
Pearl index of <1 used consistently and correctly (including implantable
contraceptives, injectable contraceptives, oral contraceptives, transdermal
contraceptives, intrauterine devices, diaphragm with spermicide, male or female
condoms with spermicide, or cervical cap) or a sterile sexual partner;
3. Diagnosis of AD based on the NIA-AA Research Framework criteria:
Biomarker classification A+T+N+ or A+T+N- based upon:
a. CSF profile consistent with AD (an Aβ42 concentration of <1000 pg/mL AND
phosphorylated tau (p-Tau) >19 pg/mL, or a ratio of p-Tau/Aβ42 of >=0.020 taken
during the Screening period prior to the day of the first dose of study
medication or,
b. Documented evidence of a CSF profile consistent with AD obtained within the
previous 12 months, or
c. Documented amyloid positron emission tomography (PET) scan evidence acquired
within the previous 12 months.
4. AD Clinical Stage 3 or 4 based on the NIA-AA Research Framework criteria
a. Have a mini-mental state examination (MMSE) score at Screening and baseline
>=20.
b. Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) global score >=0.5 and
<=1 with memory box score >=1.0.
5. Able to speak, read and write the local language fluently.
6. Have an APOE genotype of E4/E4 or E3/E4.
7. Patients should either be:
a. Not treated with any approved treatments for AD with a reasonable
expectation that, based on the course of illness, need for treatment is not
imminent and the patient should not be initiated on treatment for the length of
the study, or
b. Stabilized on an approved medication(s) for the treatment of AD for at least
3 months prior to baseline. The dose of the AD treatment should remain the same
after entering the study.
8. Patient and study partner are willing to consent to all study procedures.

1. Other than AD, neurologic or medical disorder which may impair cognition
including: head trauma, seizure disorder, neurodegenerative disease,
hydrocephalus, cerebral/spinal hematoma, inflammatory disease, central nervous
system infection (eg, encephalitis or meningitis), neoplasm, toxic exposure,
metabolic disorder (including hypoxic or hypoglycemic episodes), or endocrine
disorder, or any significant medical conditions that, in the opinion of the
Investigator, would prohibit their participation in the study.
2. Any contra-indication to undergo magnetic resonance imaging (MRI), as judged
by Investigator or radiologist.
3. MRI of the brain indicative of significant abnormality, including, but not
limited to, prior hemorrhage or infarct >1 cm3, >3 lacunar infarcts, deep white
matter lesions corresponding to a Fazekas score of 3, cerebral contusion,
encephalomalacia, aneurysm, vascular malformation, subdural hematoma,
hydrocephalus, space-occupying lesion (eg, abscess or brain tumor such as
meningioma). Small incidental meningiomas may be allowed if discussed and
approved by the Principal Investigator (PI).
4. History of any of the following neurological, psychiatric or medical
conditions:
a. History of large vessel stroke
b. History of myocardial infarction or unstable angina within the previous 12
months
c. Type 1 diabetes and uncontrolled type 2 diabetes (hemoglobin A1c [HbA1c] >8%)
d. Systemic blood pressure >150/90 mmHg on 3 separate determinations
e. History of hyperaldosteronism
f. Significant renal or hepatic dysfunction
g. Current or previous hepatitis B infection (defined as positive test for
hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody
(anti-HBc). Subjects with immunity to hepatitis B (if due to natural infection
defined as negative HBsAg, positive hepatitis B antibody [anti-HBs] and
positive anti-HBc; if due to vaccination defined as negative HBsAg, negative
anti-HCV and positive anti-HBs) are eligible to participate in the study
h. History or positive test at Screening for hepatitis C virus antibody
(anti-HCV)
i. History or positive test at Screening for human immunodeficiency virus (HIV)
j. Diagnosed with cancer with metastatic potential within the last 5 years
other than carcinoma in situ of the breast or cervix, or basal cell carcinoma
of the skin that has been completely excised
k. Major depressive episode requiring initiation of medication or
hospitalization within the previous 90 days
l. Presence of hallucinations or delusions
m. Surgery within 12 weeks of Screening
5. Any of the following laboratory abnormalities at Screening
a. Clinically significant (as determined by a cardiologist or local PI) 12-lead
ECG abnormalities
b. Any serum chemistry value (eg, aspartate aminotransferase [AST], alanine
aminotransferase [ALT], alkaline phosphatase, creatine kinase [CK], total
bilirubin etc) >2x the upper limit of normal (ULN) on 2 successive
determinations less than 2 weeks apart
c. Serum creatinine above the ULN or estimated glomerular filtration rate
(eGFR) <60 mL/min
d. Platelet count, international normalized ratio (INR), prothrombin time (PT)
or partial thromboplastin time (PTT) not within the normal range or other risk
for increased or uncontrolled bleeding
e. Not carrying an APOE4 allele (eg, E3/E3; E3/E2/ E2/E2).
6. Presence of contraindication to lumbar puncture as judged by local PI.
7. Any other significant medical conditions that, in the opinion of the
Investigator, would prohibit participation in the study, including inability to
tolerate the MRI scan or lumbar puncture procedures.
8. Taking any of the following medications
a. Antipsychotic agents, including pimavanserin
b. Stimulant medications
c. Antidepressant medications whose dose has not been stable for at least 90
days
d. Immunosuppressant medications, including chronic corticosteroids
e. Injected or infused antibody therapies, including but not limited antibodies
directed against tumor necrosis factor (TNF), anti-interleukin(IL)-6,
natalizumab, rituximab and similar agents
f. Anticoagulant or anti-platelet medications including warfarin, heparanoids
and direct coagulation factor inhibitors (eg, apixaban, dagibatran,
rivaroxaban); either aspirin at a dose of <=100 mg/day or clopidogrel at a dose
of 75 mg/day, but not both in combination is permitted.
g. Any lipid-altering therapies
9. Participation in any other interventional clinical trial, or treatment with
any investigational drug or investigational use of an approved therapy within
30 days (or 5 half-lives of such agent) prior to the first Screening visit.
10. Regular use of cannabis or cannabis products, including non-prescription
products containing cannabidiol.
11. History of drug (including cannabis) or alcohol abuse within the last 5
years.
12. Known CETP inhibitor allergy or intolerance.
13. Has an active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
infection
a. Note: A subject being screened for this study who had a documented, positive
polymerase chain reaction (PCR) or serology test for SARS-CoV-2 may be enrolled
provided the subject has:
i. Recovered from COVID-19 ie, all COVID-19 related symptoms and major clinical
findings which could potentially affect the safety of the subject should be
resolved to baseline, and
ii. A negative result from a health authority-authorized nucleic acid
amplification (PCR) test for SARS-CoV-2 taken.