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

Alzheimer's Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05965414
• Other study ID #: ATI-CS-001
• Secondary ID: 1R44AG076299
• Status: Recruiting
• Phase: Early Phase 1
• Start date: October 23, 2023
• Est. completion date: September 30, 2024

Study information

• Verified date: January 2024
• Source: Artery Therapeutics, Inc.
• Contact: Nikola Helmberg, PhD
• Phone: +4366488397558
• Email: nhelmberg[@]neuroscios.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

• 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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 64
• Est. completion date: September 30, 2024
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Male HVs at least 18 years old.

2. 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.

3. The subject has a body mass index (BMI) within 18-32 kg/m² (inclusive).

4. The subject is in reasonably good health as determined by medical history and physical examination and clinical laboratory tests.

5. The subject is willing and able to speak, read, and understand Spanish and give signed informed consent.

6. 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).

7. The subject is willing and able to comply with all testing and requirements defined in the protocol.

8. 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:

1. At least 50 years old and female need to be of non-childbearing potential

2. 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:

1. The subject has any clinically significant deviations from normal in physical examination, ECG, or clinical laboratory tests, as determined by the investigator.

2. The subject has an increased bleeding risk or is treated with anti-coagulation therapies including but not limited to aspirin, coumarin, warfarin and heparin.

3. The subject has had a clinically significant illness within 30 days of check-in, as determined by the investigator.

4. The subject has a history of significant neurological, hepatic, renal, endocrine, cardiovascular, gastrointestinal, pulmonary, or metabolic disease.

5. History of Type 2 diabetes mellitus or hemoglobin A1c (HbA1c) > 7%.

6. Fasting triglycerides > 400 mg/dL

7. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (Cockcroft-Gault formula)

8. The subject has changed the frequency or dose of chronic medication within the last 8 weeks.

9. The subject has a history of substance abuse or a positive alcohol or urine drug screen at screening or at check-in.

10. The subject has a positive serum hepatitis B surface antigen or positive anti-hepatitis C virus test at the Screening Visit.

11. Have positive test results for, or evidence of active infection with, human immunodeficiency virus type 1 or 2, or hepatitis B, or C.

12. The subject has received an investigational drug within 30 days of Check-in.

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease

Intervention

Drug:
• CS6253 Solution for Injection
Solution for intra-venous injection, 50mg CS6253 /mL. Single-use vials containing 100 mg CS6253 (2 mL of 50 mg/mL concentration)
• Placebo
Physiological saline solution for intra-venous injection

Locations

Country	Name	City	State
Spain	La Paz University Hospital	Madrid

Sponsors (2)

Lead Sponsor	Collaborator
Artery Therapeutics, Inc.	National Institute on Aging (NIA)

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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:
Primary	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:
Primary	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:
Primary	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:
Primary	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:
Primary	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:
Primary	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:
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.
Primary	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.