A Phase 2 Double-Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Intravenous Sabirnetug in Early Alzheimer’s Disease

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Acumen Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

12 Aug 2024 → ongoing

Decision date (initial)

2024-07-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Acumen Pharmaceuticals,.Inc

External identifiers

EU CT number

2023-509807-34-00

WHO UTN

U1111-1300-2516

ClinicalTrials.gov

NCT06335173

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Efficacy, Pharmacokinetic

The primary objective of this study is to evaluate the efficacy of sabirnetug infusions administered Q4W in slowing cognitive and functional decline compared to placebo based on change from Baseline to Week 80 in the Integrated Alzheimer’s Disease Rating Scale (iADRS) score.

Secondary objectives 6

1. 1. To evaluate the efficacy of Q4W infusions of sabirnetug in slowing cognitive and functional decline compared to placebo based on change from Baseline to Week 80 in the following scale scores: ADCS-iADL, ADAS-Cog13, CDR-SB, and MMSE.
2. 2. To evaluate the efficacy of Q4W infusions of sabirnetug in slowing decline in quality of life compared to placebo based on change from Baseline to Week 80 in QoL-AD.
3. 3. Further Clinical, Safety, Pharmacodynamic, Pharmacokinetics, Blood and CSF Biomarkers and Exploratory Objectives are visible in the study protocol.
4. 4. OLE: To evaluate the long-term safety and tolerability of Q4W infusions of sabirnetug.
5. 5. OLE: To assess the effect of the delayed-start of sabirnetug on clinical efficacy in participants who switched from placebo to active treatment during the OLE relative to those who continued active treatment from the double-blind portion of the study on measures of cognitive and functional decline.
6. 6. OLE:To assess the long-term effects of sabirnetug on plasma, CSF, and imaging.

Conditions and MedDRA coding

Early Alzheimer’s Disease (Mild Cognitive Impairment and Mild Dementia Due to Alzheimer’s Disease)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration, European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Age 50 to 90 years (inclusive) at the time of signing the Informed Consent Form (ICF).
2. 6. If using cholinesterase inhibitors or memantine to treat symptoms related to AD, doses must be stable for at least three months (12 weeks) prior to Baseline (Week 0) and every attempt should be made to keep them at stable doses throughout the study.
3. 7. If on anticoagulants, must have their anticoagulation status optimized and stable for at least one month (four weeks) before Screening, and are not permitted to participate in CSF assessments due to bleeding risk.
4. 8. Have a reliable informant or study partner who is willing and able to perform the roles specified in the study partner ICF, including providing support and accompanying the participant to study visits or be available by telephone at designated times.
5. 9. Individuals with prior childbearing potential who are: a. Infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation) or b. Post-menopausal – defined as 12 months with no menses without an alternative medical cause.
6. 10. Sperm-producing individuals in a sexual relationship with individuals of childbearing potential must use adequate contraception (e.g., condom) and must not donate sperm during the study and for 180 days after the last dose of the study drug.
7. 11. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
8. 2. Able to give written informed consent.
9. 3. Body weight of at least 30 kg (66 lbs) and no more than 160 kg (352 lbs) at Screening
10. 4. Consent to APOE4 genotype status assessment.
11. 5. Meet all the following criteria: a. NIA-AA criteria for MCI or mild dementia due to AD. b. Screening and Baseline score between 22 and 30 (inclusive) on the Mini-Mental State Examination (MMSE). c. Screening and Baseline score of 0.5 or 1.0 on the CDR-GS and Screening and Baseline score ≥0.5 on the CDR Memory Box score. d. Evidence of cerebral amyloid accumulation by either PET scan or CSF. (CSF should not be collected from participants on anticoagulation treatment.) Participants will have only one assessment to determine evidence of cerebral amyloid accumulation – CSF or amyloid PET.
12. 12. OLE: Participants who complete treatment in the double-blind treatment period will be eligible for the OLE after signing consent.

Exclusion criteria 22

1. 1. Contraindications for magnetic resonance imaging (MRI) studies, including claustrophobia, the presence of metal (ferromagnetic) implants, or a cardiac pacemaker and/or defibrillator that is not compatible with MRI.
2. 8. Modified Hachinski Ischemic Scale score >4.
3. 9. Current serious or unstable clinically important illness that, in the judgment of the site investigator, is likely to affect cognitive assessment including visual and hearing impairment or affect the participant's safety or ability to complete the study, including psychiatric, hepatic, renal, gastroenterological, respiratory, cardiovascular, endocrinological, immunologic, or hematologic disorders
4. 12. Malignant disease in the last five years except for resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with a normal posttreatment prostate-specific antibody (PSA).
5. 13. Geriatric Depression Scale-Short Form (GDS-SF) score >10 or current symptoms meeting Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), criteria for major depressive disorder or any current primary psychiatric diagnosis other than AD if, in the judgment of the site 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.
6. 14. Suicide risk, as determined by meeting any of the following criteria: a. Any suicide attempt or preparatory acts/behavior on the Columbia-Suicide Severity Rating Scale (C-SSRS) Baseline/Screening in the last six months. b. Suicidal ideation in the last six months as defined by a positive response to Question 5 (Suicidal Ideation) on the C-SSRS Baseline/Screening. c. Significant risk of suicide, as judged by the site investigator.
7. 15. Alcohol use disorder and/or substance use disorder within the last five years.
8. 16. Conditions that may affect cognitive assessments during the study (e.g., planned surgery requiring general anesthesia).
9. 17. Known genetic mutation that causes autosomal dominant AD.
10. 18. Known hypersensitivity to any component of sabirnetug, including excipients.
11. 19. A result below the cut-off value in an amyloid screening blood test at Screening 1. This test is being used as an enrichment strategy. In all regions except the EU (European Union) and UK (United Kingdom), this test is a mandatory part of the screening process. Exceptions apply for participants with prior PET or CSF evidence of amyloid positivity; these cases should be discussed with a medical monitor to determine if they can proceed to Screening 2 without the amyloid screening blood test.
12. 10. Ongoing or new clinically significant laboratory abnormality, as determined by the site investigator.
13. 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 (e.g., significant valvular disease, hypertrophic cardiomyopathy), hospitalization for arrhythmia, uncontrolled hypertension or clinically significant abnormalities in ECG, or history or presence of clinically significant QTc interval prolongation or family history of long QTc.
14. 2. MRI of brain that is inconsistent with MCI or AD or 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.
15. 3. History of significant or unstable neurological disease, other than AD, which may affect cognition or ability to complete the study, such as other dementias, serious infection of the brain, significant head trauma, uncontrolled seizures, stroke, or Parkinson´s disease, or any other neurological condition that may be contributing to cognitive impairment beyond that caused by the participant’s AD in the judgement of the investigator.
16. 4. Received any investigational product within six months (24 weeks) prior to Baseline (Week 0).
17. 5. Received any monoclonal antibody within six months (24 weeks) prior to Baseline (Week 0) that reduces amyloid plaques or tau load in the brain, including sabirnetug
18. 6. Known allergy to biological products.
19. 7. Immunologic disease requiring treatment with plasmapheresis. If a participant is on immunosuppressive drugs, the investigator should discuss the case with the medical monitor.
20. 20. OLE:They were discontinued from study treatment during the double-blind treatment period.
21. 21. OLE:Their participation in the OLE is deemed inappropriate by the investigator (e.g., any serious medical condition or concerns that preclude the participant’s safe participation in the OLE or ability to comply with the required procedures.
22. 22. OLE:They have unresolved ARIA findings at the end of the double-blind treatment period scan that have required suspension or discontinuation of dosing (see Section 7.1.1).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from Baseline to Week 80 in the iADRS score.

Secondary endpoints 4

1. 1. Change from Baseline to Week 80 in the ADCS-iADL, ADAS-Cog13, CDR-SB, and MMSE.
2. 2. Change from Baseline to Week 80 in QoL-AD
3. 3. Further Secondary, Clinical, Safety, Pharmacodynamic, Pharmacokinetics, Pharmacogenomic, Blood and CSF Biomarker and Exploratory Endpoints are visible in the study protocol.
4. 4. OLE: Changes from Baseline to Week 104 and Week 132 for iADRS, CDR-SB, ADCS-iADL, ADAS-Cog13, and MMSE as measured by delayed-start analysis.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Acumen Pharmaceuticals Inc.

Sponsor organisation

Acumen Pharmaceuticals Inc.

Address

1210-1220 Washington Street Suite 210

City

Newton

Postcode

02465-2147

Country

United States

Scientific contact point

Organisation

Acumen Pharmaceuticals Inc.

Contact name

Chief Regulatory Officer

Public contact point

Organisation

Acumen Pharmaceuticals Inc.

Contact name

Chief Regulatory Officer

Third parties 14

Locations

3 EU/EEA countries · 23 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 59 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications