A Phase 2a, dose-finding, randomized, double-blinded, placebo-controlled study to Evaluate the Pharmacodynamics, Pharmacokinetics, and Safety of Efavirenz in Patients with Early Alzheimer’s Disease

Prior treatment

• 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 PI.
• 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.

Other illness

• 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.
• History of drug (including cannabis) or alcohol abuse within the last 5 years.
• 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.
• 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.

Lab values

• 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 or 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
• 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
• 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 h. CYP3A4 inhibitors i. terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, or ergot alkaloids (for example, ergotamine, dihydroergotamine, ergonovine, and methylergonovine)

Other

• Regular use of cannabis or cannabis products, including non-prescription products containing cannabidiol.
• Any contra-indication to undergo magnetic resonance imaging (MRI), as judged by Investigator or radiologist.
• Presence of contraindication to lumbar puncture as judged by local PI.

• Age range: 50-75 years of age at the Screening Visit.
• Males, or females who are post-menopausal or otherwise not of child-bearing potential.
• 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.
• 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. CDR global score 0.5 up to 1.0
• Able to speak, read and write the local language fluently.
• 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.
• Patient and care partner are willing to consent to all study procedures.