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

Study Overview
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Brief Summary
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Phase 1A SAD: Five or more cohorts of 8 healthy volunteers (HVs) will receive a single IV bolus injection of study drug or placebo. The first 4 cohorts will be male only. The last cohort will be repeated with the max safe dose of the previous cohorts in healthy elderly subjects (male and female of non childbearing potential, > 50years) Phase 1B MAD: Two or more cohorts of 8 male and female HVs will receive multiple (4) IV bolus injections of study drug or placebo every 72 hours.

Detailed Description
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This is a randomized, double-blind, placebo-controlled study in HV and in APOE4 carriers. Phase 1A Single Ascending Dose (SAD): In 5 or more sequential SAD cohorts of 8 (6 active:2 placebo) HVs a single IV bolus injection (CS6253 1, 2.4, 6, and 10 mg/kg or placebo) will be administered and PK, safety, and biomarkers will be assessed. The first 4 cohorts will include males only. In the fifth cohort 8 (6 active:2 placebo) subjects, male and female of non-childbearing potential and at least 50 years old, will be administered CS6253 at equal to or lower doses than the maximum safe SAD dose in HV. CSF will not be collected in the first 2 SAD cohorts. In the following cohorts, CSF will be collected before dosing and over 24 hours after dosing. Additional cohorts may be added as needed and deemed safe and appropriate by the Data Safety Monitoring Board (DSMB). Phase 1B Multiple Ascending Dose (MAD): In 2 or more sequential MAD cohorts of 8 (6 active:2 placebo) male and female HVs at least 50 years old on average ≥ 3/sex/cohort; ≥ 4 APOE4 carriers/cohort, will be administered multiple IV bolus injections. Cohort 1 will be administered CS6253 at 75% of the maximum safe SAD dose in subjects at least 50 years old or placebo, and if no Treatment Emerging Adverse Events (TEAEs), in Cohort 2 at 100% of the maximum safe SAD dose or placebo will be administered every 72 hours x 4 doses and PK, safety, and biomarkers will be assessed. Plasma PK will be assessed after first and fourth dose in all cohorts. CSF will be collected before dosing and over 24 hours in conjunction with the fourth dose. Cohorts of 8 subjects (6 active:2 placebo) may be added at doses equal to or lower than the maximum safe MAD dose to further explore CS6253 brain exposure and Pharmacodynamics (PD) dependency on APOE4 isoform and sex.

Official Title
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A Phase 1 Randomized, Double-Blind, Placebo Controlled Study to Evaluate the Safety and Pharmacokinetics of Single Ascending Doses and Multiple Ascending Doses of CS6253 in Healthy Volunteers and in APOE4 Carriers

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: CS6253 Solution for Injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). b) 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. Exclusion Criteria: Subjects who meet any of the following criteria will not be enrolled: The subject has any clinically significant deviations from normal in physical examination, ECG, or clinical laboratory tests, as determined by the investigator. 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 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. 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 changed the frequency or dose of chronic medication within the last 8 weeks. The subject has a history of substance abuse or a positive alcohol or urine drug screen at screening or at check-in. The subject has a positive serum hepatitis B surface antigen or positive anti-hepatitis C virus test at the Screening Visit. Have positive test results for, or evidence of active infection with, human immunodeficiency virus type 1 or 2, or hepatitis B, or C. The subject has received an investigational drug within 30 days of Check-in.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: SAD: 5 cohorts 8 of healthy volunteers each will receive single ascending doses of either study drug or placebo (6 active:2 placebo). MAD: 2 or more cohorts 8 of healthy male and female volunteers each will receive single ascending doses of either study drug or placebo (6 active:2 placebo). The subjects will be stratified on their APOE4 status. Each cohort needs to have at least 4 APOE4 carriers.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CS6253 Solution for Injection<br>SAD: Single ascending doses: CS6253 Solution for Injection dosing, 50 mg/mL, will be weight based and provided from single use 2 mL vials containing approximately 100 mg CS6253 in phosphate buffered saline (PBS) solution MAD: Multiple ascending doses (4x every 72 hours): CS6253 Solution for Injection dosing, 50 mg/mL, will be weight based and provided from single use 2 mL vials containing approximately 100 mg CS6253 in phosphate buffered saline (PBS) solution | Drug: CS6253 Solution for Injection<br>* Solution for intra-venous injection, 50mg CS6253 /mL. Single-use vials containing 100 mg CS6253 (2 mL of 50 mg/mL concentration)<br>|
| Placebo Comparator: Placebo<br>SAD and MAD: Placebo control will be provided from vials containing physiological saline for injection in an equal amount as necessary for the active arm. | Drug: Placebo<br>* Physiological saline solution for intra-venous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of CS6253 | All treatment emerging Adverse Events (TAEs) will be recorded until the SAD: Day 4 and MAD: Day 13 | SAD: After dosing and until 72 hours after dosing; MAD: After dosing until day 13 (72 hours after the last dosing on day 10) | 
| SAD-Plasma: AUC0-last | Area under the concentration-time curve until the last quantifiable concentration | Pharmacokinetics (PK) samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD: | 
| SAD-Plasma: AUC0-inf | Area under the concentration time curve from time 0 extrapolated to infinity | PK samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD: | 
| SAD-Plasma: Cmax | Maximum observed plasma concentration (eg C0) | PK samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD: | 
| SAD-Plasma: Kel | Terminal elimination rate constant | PK samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD: | 
| SAD-Plasma: t1/2 | Terminal elimination half-life | PK samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD: | 
| SAD-Plasma: Clearance (CL/F) | Apparent clearance | PK samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD: | 
| SAD-Plasma: Vd/F | Apparent volume of distribution | PK samples will be collected at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 hours postdose; MAD: | 
| SAD-Cerebrospinal Fluid (CSF): AUC0-last | In cohorts 3-5:Area under the concentration-time curve in CSF until the last quantifiable concentration | PK samples will be collected by lumbar catheter starting predose, and at 0.5, 2, 8, 12 and 24 hours postdose. | 
| SAD-CSF: Cmax | In cohorts 3-5:Maximum observed CSF concentration (eg C0)concentration | PK samples will be collected by lumbar catheter starting predose, and at 0.5, 2, 8, 12 and 24 hours postdose. | 
| MAD-Plasma: AUC0-last | Area under the concentration-time curve until the last quantifiable concentration | PK samples will be collected after the first and fourth doses (Day 1 and Day 10) at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 hours postdose. | 
| MAD-Plasma: Cmax | Maximum observed plasma concentration (eg C0) | PK samples will be collected after the first and fourth doses (Day 1 and Day 10) at predose and at 0.16, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72 hours postdose. | 
| MAD-CSF:AUC0-last | Area under the concentration-time curve until the last quantifiable concentration | CSF collection by lumbar puncture (LP) will be performed before the first dose. At the fourth dose, on Day 10, serial CSF samples will be collected by lumbar catheter starting predose, and at 0.5, 2, 8, 12 and 24 hours postdose. | 
| MAD-CSF: Cmax | Maximum observed CSF concentration (eg C0) | CSF collection by lumbar puncture (LP) will be performed before the first dose. At the fourth dose, on Day 10, serial CSF samples will be collected by lumbar catheter starting predose, and at 0.5, 2, 8, 12 and 24 hours postdose. |