A Phase 2 Study to Assess the Safety of EI-1071 and the Effects of EI-1071 on Neuroinflammation in Alzheimer's Disease Patients

This is an open-label, phase II, exploratory, proof-of-concept study to assess the safety and tolerability of EI-1071 and the effects of EI-1071 on neuroinflammation in patients with mild, moderate, or sever Alzheimer's disease (AD). The main goals include:

• to validate mechanism-engagement of EI-1071 by tracing the change of activated microglia in selected brain regions in AD patients using TSPO PET/MRI imaging.
• to assess effects of EI-1071 on changes of inflammatory biomarkers associated with AD progression.

Inclusion criteria

• Must meet all the clinical criteria for mild to severe AD (i.e., probable or possible AD dementia by NIA-AA criteria; must have objective evidence of cognitive impairment at Screening
• Clinical Dementia Rating Scale (CDR)≧0.5
• If using drugs to treat symptoms related to AD, doses must be stable for at least 8 weeks prior to screening.
• Adequate hematologic, hepatic, and renal function at the screening visit defined by the following criteria:

• Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
• Hemoglobin [Hgb] > 10 g/dL
• Platelet count ≥ 100 × 10⁹/L
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1 × upper limit of normal (ULN)
• Total bilirubin and direct bilirubin ≤ 1.0 × ULN
• Alkaline phosphatase (ALP) ≤ 1.0 × ULN
• Creatinine clearance (CCr) ≥ 60 mL/min
• Female subject with childbearing potential must have a negative serum pregnancy test at the screening visit (female subjects must be surgically confirmed sterile, i.e., had hysterectomy, bilateral oophorectomy, or tubal ligation procedures), post-menopausal for at least 1 year (documented in the medical history), or must commit to use two contraceptive methods during the study.
• Female subject with childbearing potential must be willing to implement adequate, highly effective contraceptive measure during the study period. Effective birth control includes:

• Intrauterine device plus one barrier method
• Oral, implantable, or injectable contraceptives plus one barrier method; or
• Two barrier methods

• Effective barrier methods are male or female condoms, diaphragms, or spermicides (creams or gels that contain a chemical to kill sperm). Women of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥ 1 year.
• Male subject who agrees to use an adequate method of contraception during the study period [e.g., barrier contraceptives (male condom)].
• Subjects or his/her legal representative or guardian are willing to sign written informed consent and willing to comply with study requirements.

Exclusion criteria

• Body weight ≥ 150 kg or body mass index (BMI) ≥ 35 kg/m² at the screening visit.
• Prior use of pexidartinib (Turalio), other chemical entities, or any biologic treatment targeting colony stimulating factor 1 (CSF-1) or the CSF-1 receptor within 3-month of the first dose with EI-1071; previous uses of oral tyrosine kinase inhibitors are allowed (e.g., imatinib or nilotinib).
• AD patients with low binding affinity for tracer TSPO rs6971 SNP polymorphism at screening
• Pregnant, breast feeding or plan to be pregnant women during the study period
• Active tuberculosis (TB), active or chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) or known active or chronic infection with human immunodeficiency virus (HIV) at screening or in the medical history.
• Any medical or neurological/neurodegenerative condition (including mental deficit, intracranial tumor, glioma or meningioma; head trauma, Lewy body dementia; other disease than AD) that, in the opinion of the Investigator, might be a contributing cause to the participant's cognitive impairment or could lead to discontinuation, lack of compliance, interference with study assessments, or safety concerns
• Clinically significant, unstable psychiatric illness or have contraindications to brain magnetic resonance imaging (MRI) or PET scans
• Have had a stroke or Transient Ischemic Attack (TIA), unexplained loss of consciousness or relevant brain hemorrhage, bleeding disorder and cerebrovascular abnormalities in the past year based on medical history (with MRI imaging results as confirmation in the medical history) at screening. Subjects with clinically relevant cerebrovascular abnormalities in MRI will be excluded per PI's discretion.
• Evidence of clinically significant gastrointestinal, cardiovascular, hepatic, renal, hematological, neoplastic, endocrine (including poor-controlled T2DM), neurological, immunodeficiency, pulmonary, or other disorder or disease at the screening visit (such as neurological or cognitive impairment/decline due to substance abuse, vitamin B12 deficiency, abnormal thyroid function, or other underlying condition might contribute to cognitive, functional or behavioral impairment will be excluded) by investigator's judgment at screening; subjects who have to be fed by enteral tube will be excluded.
• History of or ongoing malignancy or carcinoma (either concurrent or within the last year of starting study treatment) that requires therapy (e.g., surgical, chemotherapy, or radiation therapy), except for adequately treated basal or squamous cell carcinoma of the skin, melanoma in-situ, carcinoma in-situ of the cervix or breast
• Currently participating in any other clinical study or have participated in clinical trial within the last 60 days prior to screening; had donated blood (≥ 250 mL) within 30 days at screening.
• Known allergy to EI-1071 or hypersensitivity to any component of the formulation (e.g., hydroxypropyl methylcellulose acetate succinate) or hypersensitivity to any radiochemical tracer or [¹⁸F]FEPPA radiochemical tracer
• Required to use strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) and is anticipated to use these inhibitors or inducers during the study period