A Phase 1, Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ISM8969

Prior treatment

• History of significant cardiovascular or cerebrovascular disease within 6 months before screening, including but not limited to defined in the protocol.
• Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days (or 5 half-lives, whichever is longer) prior to the first dosing, administration of a biological product in the context of a clinical research study within 90 days (or 5 half-lives, whichever is longer) prior to the first dosing, or concomitant participation in an investigational study involving no drug or device administration.

Other illness

• Positive serology test results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antigen and antibody, treponema pallidum antibody or QuantiFERON®-TB test at screening.
• History of any central nervous system (CNS) disorder or history of seizure of any cause.
• History of an active or untreated malignancy or are in remission from a clinically significant malignancy (other than basal- or squamous-cell skin cancer, or in situ carcinomas of the cervix) for less than 5 years; or there is a potential malignancy during screening.

Lab values

• Clinically significant 12-lead ECG, physical examination, vital signs or laboratory abnormalities at screening, including but not limited to defined in the protocol.

Other

• Participants for whom any of the following applies will be excluded from the study:
• Columbia suicide severity rating scale (C-SSRS) score above Type 1 ideation.
• Positive pregnancy test or lactating female participant.
• Presence of contraindication to lumbar puncture or lumbar catheter as judged by Investigator.

• Participants must meet all the following criteria to be included in the study:
• Male or female participants, including adult participants (≥18 and \<65 years of age) for the SAD cohorts 1-6 and MAD cohorts 1-3, and elderly participants (≥65 and ≤80 years of age) for MAD cohort 4.
• Body mass index (BMI) \>18.5 and \<30.0 kg/m2 and body weight ≥50.0 kg for males and ≥45.0 kg for females.
• Non-smokers (no use of tobacco or nicotine products within 1 month prior to screening).
• Healthy as defined the current protocol.
• Male or female, ≥18 and ≤65 years of age.
• 30.0 kg/m2 ≤ BMI \< 42.0 kg/m2.
• No change in body weight or self-reported change of less than 5.0% within 3 months before screening.
• Presence of 1 or more risk factors for cardiovascular disease such as hypertension, hyperlipidemia. If present, must be controlled with stable medication dose/therapy (defined as a stable medication dose/therapy for 3 months or longer).
• hsCRP ≥3 mg/L.