Safety and Pharmacokinetics of Single Ascending Doses and Multiple Ascending Doses of CS6253 in Healthy Volunteers

Prior treatment

• The subject has an increased bleeding risk or is treated with anti-coagulation therapies including but not limited to aspirin, coumarin, warfarin and heparin.
• The subject has changed the frequency or dose of chronic medication within the last 8 weeks.
• The subject has received an investigational drug within 30 days of Check-in.

Other illness

• The subject has had a clinically significant illness within 30 days of check-in, as determined by the investigator.
• The subject has a history of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, or metabolic disease.
• The subject has a history of substance abuse or a positive alcohol or urine drug screen at screening or at check-in.
• Have positive test results for, or evidence of active infection with, human immunodeficiency virus type 1 or 2, or hepatitis B, or C.

Lab values

• The subject has any clinically significant deviations from normal in physical examination, ECG, or clinical laboratory tests, as determined by the investigator.
• History of Type 2 diabetes mellitus or hemoglobin A1c (HbA1c) \> 7%.
• Fasting triglycerides \> 400 mg/dL
• Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2 (Cockcroft-Gault formula)
• The subject has a positive serum hepatitis B surface antigen or positive anti-hepatitis C virus test at the Screening Visit.

Other

• Subjects who meet any of the following criteria will not be enrolled:

• Male HVs at least 18 years old.
• a) Cohort 5 only: Male and female HVs at least 50 years old and if female be of non-childbearing potential, i.e. meet at least one of the following criteria: postsurgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or postmenopausal (amenorrheic for at least 2 years and a serum follicle-stimulating hormone (FSH) \> 30 IU/L).
  • If subject is male, must be willing to use acceptable contraception from Day 1 until 30 days after the last dose of study drug.
• The subject has a body mass index (BMI) within 18-32 kg/m² (inclusive).
• The subject is in reasonably good health as determined by medical history and physical examination and clinical laboratory tests.
• The subject is willing and able to speak, read, and understand Spanish and give signed informed consent.
• The subject must agree to comply with a lumbar catheterization and collection of blood and CSF samples (SAD Cohorts 3-5 only and MAD cohorts).
• The subject is willing and able to comply with all testing and requirements defined in the protocol.
• The subject is willing, deemed compliant, and able to remain at the Clinical Research Unit (CRU) for the duration of the confinement period and return for all outpatient visits.
  • Phase 1B MAD
  • The eligibility criteria for the Phase 1B MAD study are the same as described for Phase 1A SAD, with the following exceptions:
• At least 50 years old and female need to be of non-childbearing potential
• Known to have at least 1 APOE4 allele (homozygous or heterozygous). Note: this criterion applies to on average for the MAD at least 4 APOE4 subjects per cohort.