A Study to Evaluate the Safety, Tolerability, and Blood Levels of ACU193 in Participants With MCI or Mild AD (INTERCEPT-AD)

• ClinicalTrials.gov Identifier: NCT04931459
• Recruitment Status: Active, not recruiting
• First Posted: June 18, 2021
• Last Update Posted: February 9, 2023
• Sponsor: Acumen Pharmaceuticals
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): Acumen Pharmaceuticals

Study Description

Brief Summary:

This Phase 1 study is a single ascending dose (SAD) and multiple ascending dose (MAD), placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenous ACU193 when administered to participants diagnosed with Mild Cognitive Impairment (MCI) or Mild Dementia due to Alzheimer's disease (AD).

Condition or disease	Intervention/treatment	Phase
Alzheimer Disease	Drug: ACU193; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Study ACU-001 is a placebo-controlled study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple escalating doses of intravenous ACU193. A two-part single-ascending dose (SAD)/multiple-ascending dose (MAD) study design will be conducted in a population of individuals with early AD (MCI or mild dementia due to AD).
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Placebo-Controlled, Single- and Multiple-Dose Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous ACU193 in Mild Cognitive Impairment or Mild Dementia Due to Alzheimer's Disease
• Actual Study Start Date: June 21, 2021
• Estimated Primary Completion Date: March 2023
• Estimated Study Completion Date: June 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: ACU193 Administration; Participants will receive 1 to 3 doses of ACU193 by intravenous (IV) infusion.	Drug: ACU193; Intravenous ACU193
Placebo Comparator: Placebo Administration; Participants receive 1 to 3 doses of matching ACU193 placebo by intravenous (IV) infusion. 2 participants per cohort will receive placebo.	Drug: Placebo; Intravenous Placebo

Outcome Measures

Primary Outcome Measures :

1. Incidence and Nature of Treatment-Related Adverse Events (AE) or Serious Adverse Events (SAE) as Assessed by Common Terminology Criteria for Adverse Events (CTCAE) [ Time Frame: Baseline up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD) ]
   Proportion of participants with AE, discontinuations due to AE or SAE, and withdrawals from the study due to AE
2. Change in Clinical Laboratory Tests [ Time Frame: Baseline up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD) ]
   Incidence and clinically significant abnormal changes in clinical laboratory assessments (hematology, clinical chemistry, urinalysis)
3. Changes in 12-Lead ECGs [ Time Frame: Baseline up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD) ]
   Clinically significant abnormal changes in 12-Lead ECGs for PR, QRS, QT, QTcF, and QTcB
4. Changes in the Columbia-Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Baseline up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD) ]
   Presence of suicidal ideation as defined by a positive response to Question 5 on the C-SSRS suicide ideation section
5. Changes in Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline (predose) up to 20 weeks (SAD); 14, 18 or 28 weeks (MAD) ]
   Brain magnetic resonance imaging (MRI) findings to assess amyloid-related imaging abnormalities (ARIA), including incidence of ARIA-E (edema) or ARIA-H (hemosiderosis)

Secondary Outcome Measures :

1. Estimate Blood Levels of ACU193 [ Time Frame: Up to 140 days post dose ]
   Area under the concentration-time curve (AUC) from time zero to the time of last measurable concentration (AUCt)
2. Estimate Maximum Blood Levels of ACU193 [ Time Frame: Up to 140 days post dose. ]
   Maximum observed blood concentration Cmax(obs).
3. Estimate Time to Reach Maximum Blood Levels of ACU193 [ Time Frame: Up to 140 days post dose. ]
   Time to reach Tmax(obs)
4. Estimate Blood Levels of ACU193 [ Time Frame: Up to 140 days post dose. ]
   Area under the plasma concentration-time curve from time 0 to infinity (AUC∞)
5. Estimate Clearance of ACU193 [ Time Frame: Up to 140 days post dose ]
   Clearance (CL)
6. Estimate Volume of Distribution of ACU193 [ Time Frame: Up to 140 days post dose ]
   Apparent volume of distribution at terminal phase (Vz)

Eligibility Criteria

• Ages Eligible for Study: 55 Years to 90 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Males or females ages 55 to 90 (inclusive).
2. Participant weighs at least 41 kg (90 lbs) and no more than 113 kg (250 lbs) before study drug administration.
3. Female participants must be surgically sterile or be at least two years post-menopausal or at least one year post-menopausal with an elevated follicle stimulating hormone (FSH). Male participants with a female partner of child-bearing potential must use adequate contraception.
4. Individual (or the participant's Legally Authorized Representative [LAR]) is able to give informed consent.
5. Are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

6. Must meet all of the following clinical criteria for MCI due to AD or mild AD at Screening:

   1. Participant meets NIA-Alzheimer's Association (NIA-AA) criteria for MCI due to AD or probable AD.
   2. A global Clinical Dementia Rating (CDR) of 0.5 or 1.0.
   3. A Mini-Mental State Examination (MMSE) score between 18 and 30 (inclusive).
   4. A positive amyloid positron emission tomography (PET) scan.
7. Must consent to apolipoprotein E (APOE) genotyping.
8. If using cholinesterase inhibitors or memantine to treat symptoms related to AD, doses must be stable for at least four weeks prior to Baseline and the participant must be willing to keep the doses stable throughout the duration of the study.
9. Must have a reliable informant or caregiver who is willing and able to perform all caregiver roles as specified in the caregiver Informed Consent Form (ICF).

Exclusion Criteria:

1. Receipt of any investigational biological drug within less than one year of Baseline or of any investigational small molecule drug within less than six months of Baseline. Receipt of any approved treatments that target amyloid plaques in the brain within less than one year of Baseline.
2. Currently receiving or likely to require the following types of anticoagulants: coumarins and indandiones, Factor Xa inhibitors, heparins, thrombin inhibitors.
3. Has known humanized monoclonal antibody allergy or hypersensitivity.
4. History of significant neurological disease, other than AD, that may affect cognition or ability to complete the study, including but not limited to, other dementias, serious infection of the brain, Parkinson´s disease, or adult epilepsy.
5. Has had magnetic resonance imaging (MRI) or computerized tomography (CT) of brain within previous two years showing pathology that would be inconsistent with a diagnosis of AD.
6. Has MRI with results showing greater than four amyloid-related imaging abnormalities hemorrhage/hemosiderin deposition (ARIA-H), presence of any amyloid-related imaging abnormalities edema/effusions (ARIA-E), or superficial siderosis.
7. Has any contraindications for MRI studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or a cardiac pacemaker that is not compatible with MRI.
8. Current serious or unstable clinically important illness that, in the judgment of the Investigator, is likely to affect cognitive assessment including visual and hearing impairment, deteriorate, or affect the participant's safety or ability to complete the study, including psychiatric, hepatic, renal, gastroenterological, respiratory, cardiovascular, endocrinological, immunologic, or hematologic disorders.
9. Has an ongoing or new clinically significant laboratory abnormality, as determined by the Investigator.
10. Has a history or presence of clinically significant abnormal 12-lead electrocardiogram (ECG) or an ECG with QT interval corrected using Fridericia's formula (QTcF) >470 msec for female participants or >450 msec for male participants. As the ECGs are obtained in triplicate and are meant to be interpreted together, if one of the three ECGs in the triplicate has a QTcF above the threshold, eligibility of the participant should be determined based on clinical judgment of the Investigator in consultation with the medical monitor. If two of the three ECGs in the triplicate have a QTcF above the threshold, then the participant would not be eligible.
11. Within one year before Screening, any of the following: myocardial infarction; moderate or severe congestive heart failure, New York Heart Association class III or IV; hospitalization for, or symptom of, unstable angina; syncope due to orthostatic hypotension or unexplained syncope; known significant structural heart disease (eg, significant valvular disease, hypertrophic cardiomyopathy), or hospitalization for arrhythmia.
12. History of seizure, transient ischemic attack (TIA), or stroke within the last 18 months.
13. History of clinically significant carotid or vertebrobasilar stenosis or plaque.
14. History of a malignant disease with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal prostate-specific antigen posttreatment within the last five years.
15. Current symptoms meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for major depressive disorder or any current primary psychiatric diagnosis other than AD if, in the judgment of the Investigator, the psychiatric disorder or symptom is likely to confound interpretation of drug effect, affect cognitive assessments, or affect the participant´s ability to complete the study.

16. Are a suicide risk, as determined by meeting any of the following criteria:

    1. Suicide attempt within the six months prior to Baseline.
    2. Suicidal ideation as defined by a positive response to Question 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation section.
    3. Significant risk of suicide, as judged by the site Investigator.
17. History of multiple concussions, significant head trauma, or objective change in neuropsychological function within the last five years.
18. History of human immunodeficiency virus (HIV).
19. History of alcohol or drug abuse/dependence within the last five years.

Contacts and Locations

Locations

United States, Arizona

Clinical Endpoints

Scottsdale, Arizona, United States, 85258

United States, California

Orange County Research Institute

Anaheim, California, United States, 92801

Hoag Hospital Newport Beach

Newport Beach, California, United States, 92663

United States, Florida

Velocity Clinical Research

Hallandale Beach, Florida, United States, 33009

Charter Research

Lady Lake, Florida, United States, 32159

Columbus Clinical Services

Miami, Florida, United States, 33125

Combined Research Orlando Phase I-IV

Orlando, Florida, United States, 32807

Progressive Medical Research

Port Orange, Florida, United States, 32321

Santos Research Center

Tampa, Florida, United States, 33615

United States, Georgia

Atlanta Center for Medical Research

Atlanta, Georgia, United States, 30331

iResearch Atlanta

Decatur, Georgia, United States, 30030

United States, New Jersey

Advanced Memory Research Institute of NJ

Toms River, New Jersey, United States, 08755

United States, New York

Columbia University

New York, New York, United States, 10032

United States, North Carolina

AMC Research

Matthews, North Carolina, United States, 28105

United States, Pennsylvania

Abington Neurological Associates

Abington, Pennsylvania, United States, 19001

United States, Texas

Kerwin Medical Center

Dallas, Texas, United States, 75231

Clinical Trials Network

Houston, Texas, United States, 77074

Sponsors and Collaborators

Acumen Pharmaceuticals

National Institute on Aging (NIA)

Investigators

• Principal Investigator: Eric Siemers, MD; Acumen Pharmaceuticals, Inc.
• Study Director: Russell Barton; Acumen Pharmaceuticals, Inc.

More Information

• Responsible Party: Acumen Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04931459
• Other Study ID Numbers: ACU-001; 3U01AG053247 ( U.S. NIH Grant/Contract )
• First Posted: June 18, 2021
• Last Update Posted: February 9, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Acumen Pharmaceuticals:

Alzheimer's Diseases; Mild Cognitive Impairment; Mild dementia

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders