A Study of Donanemab, RG6289, or the Combination of Donanemab and RG6289 in Presenilin 1 (PSEN1) E280A Mutation Carriers for the Treatment of Autosomal-Dominant Alzheimer's Disease

NCT06996730 | Not Yet Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: API-21R01AG086363-01
• Study Type: interventional
• Target: 240
• Locations: 1 country
• Sites: 1

Brief Summary

The study will be conducted in 2 blinded parts (Part 1 and Part 2). In Part 1, study participants who are mutation carriers will receive active donanemab and non-mutation carriers will receive placebo-donanemab for up to 18 months (76 weeks), with a minimum treatment period of 9 months. Amyloid PET scans will be conducted at screening, 9, and 18 months in Part 1. Participants who are at or below 11 CL at screening or reach complete amyloid plaque clearance as measured by florbetapir F18 PET (defined as ≤11 CL) at 9 months will initiate Part 2. Participants who are ≤11 CL at screening may delay their entry into Part 2 for up to 6 months at the discretion of the Investigator. All remaining participants will start Part 2 after completing 18 months (76 weeks) in Part 1 independent of amyloid results. Non-carriers will receive placebo in both Parts 1 and 2. In Part 2, study participants who are mutation carriers will be randomized 1:1:1:1 in a full factorial design to receive either RG6289 + placebo-donanemab (RG6289 alone group), donanemab + placebo-RG6289 (donanemab alone group), the combination of RG6289 and donanemab (combination group), or placebo-RG6289 and placebo-donanemab (placebo group). All non-carriers will be assigned to the placebo group. CDR-GS at the end of Part 1 and the amyloid level using the last completed amyloid PET scan in Part 1 will be used for stratification. All study participants will participate in a double-dummy design for the duration of Part 2 receiving both an intravenous (IV) infusion at the required interval for the donanemab or matching placebo as well as a daily oral treatment of RG6289 or matching placebo. An exploratory outcome of Part 1 is a comparison of the amyloid clearance between this ADAD cohort and historical controls using propensity score matching. The primary outcome in Part 2 is change from the start of Part 2 through the end of Part 2 in brain amyloid load in PSEN1 E280A mutation carriers as measured by amyloid PET imaging. Other endpoints will include fluid and imaging biomarkers and measures of cognition and functioning. The maximum study duration for any individual participant will be 3 years, not including the screening or follow-up periods

Conditions

Autosomal Dominant Alzheimers Disease; Early Onset Alzheimer Disease; Alzheimers Disease

Keywords

Dementia

Outcome Measures

Primary Outcomes (2)

• Part 1: Change in amyloid load as measured by centiloid (CL) [F18]Florbetapir-PET as biomarker endpoint

  Evaluate the efficacy and safety of donanemab on change in amyloid load as measured by centiloid (CL) \[F18\] Florbetapir-PET in presenilin 1 (PSEN1) E280A mutation carriers (Part 1). CL calculated using \[f18\] Florbetapir PET non-partial volume corrected (regional spread function) standardized uptake value ratio cortical composite (F18 Florbetapir PET SUVR).

  Part 1: Screening, Month 9, and Month 18

• Part 2: Maintenance of Low Levels of Brain Amyloid as Measured by centiloid (Cl) [F18]Florbetapir-PET Following Combined Intervention of Donanemab and RG6289

  Evaluate the individual and relative efficacy and safety, as well as potential synergy, of donanemab, RG6289, and the combination of RG6289 with donanemab, to achieve and/or maintain low levels of brain amyloid as measured by centiloid (CL) \[F18\] Florbetapir-PET in asymptomatic and symptomatic PSEN1 E280A mutation carriers. CL calculated using \[F18\] Florbetapir-PET non-partial volume corrected (regional spread function) standardized uptake value ratio cortical composite (F18 Florbetapir-PET SUVR)

  Duration of Part 2 Participation (up to 18 months)

Other Outcomes (3)

• Cerebrospinal Fluid Amyloid, TAU, and Other Biomarker Endpoints

  Total duration of study participation (Up to 27 months)

• Plasma Amyloid, TAU, and Other Biomarker Endpoints

  Total duration of study participation (Up to 27 months)

• Magnetic Resonance Imaging - Volumetric Measurements

  Total duration of study participation (Up to 27 months)

Study Arms (6)

Part 1: Donanemab

EXPERIMENTAL

Donanemab will be administered per the schedule specified in the treatment arm for all PSEN1 E280A Carriers

Drug: Donanemab

Part 1: Donanemab placebo

PLACEBO COMPARATOR

Donanemab placebo will be administered per the schedule specified in the treatment arm for all PSEN1 E280A Non-Carriers

Drug: Donanemab placebo

Part 2: Donanemab + RG6289 placebo

EXPERIMENTAL

Donanemab plus RG6289 placebo will be administered per the schedule specified in the treatment arm for all PSEN1 E280A Carriers

Drug: Donanemab; Drug: RG6289 placebo

Part 2: RG6289 + Donanemab placebo

EXPERIMENTAL

RG6289 plus donanemab placebo will be administered per the schedule specified in the treatment arm for all PSEN1 E280A Carriers

Drug: RG6289; Drug: Donanemab placebo

Part 2: RG6289 plus donanemab

EXPERIMENTAL

RG6289 plus donanemab will be administered per the schedule specified in the treatment arm for all PSEN1 E280A Carriers

Drug: Donanemab; Drug: RG6289

Part 2: RG6289 placebo plus donanemab placebo

PLACEBO COMPARATOR

RG6289 placebo plus donanemab placebo will be administered per the schedule specified in the treatment arm for all assigned PSEN1 E280A Carriers and all PSEN1 E280A Non-Carriers

Drug: Donanemab placebo; Drug: RG6289 placebo

Interventions

Donanemab DRUG

IV Infusion

Part 1: Donanemab; Part 2: Donanemab + RG6289 placebo; Part 2: RG6289 plus donanemab

RG6289 DRUG

Oral tablet

Part 2: RG6289 + Donanemab placebo; Part 2: RG6289 plus donanemab

Donanemab placebo DRUG

IV placebo

Part 1: Donanemab placebo; Part 2: RG6289 + Donanemab placebo; Part 2: RG6289 placebo plus donanemab placebo

RG6289 placebo DRUG

Oral tablet placebo

Part 2: Donanemab + RG6289 placebo; Part 2: RG6289 placebo plus donanemab placebo

Eligibility Criteria

• Age: 25 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Membership in PSEN1 E280A mutation carrier kindred.
• Agrees to conditions of, and is willing to undergo, genetic testing (e.g., APOE, PSEN1 E280A, and other genetic testing allowed by local regulatory requirements).
• Males and females aged 25-65 inclusive.
• Must meet one of the following criteria:
• a. Determined to be cognitively normal as defined by an MMSE of ≥24 for participants with less than 9 years of education or MMSE of ≥26 for participants with 9 or more years of education. b. Or determined to have MCI with amnestic presentation as defined by:
• \. Cognitive concern in the judgment of the Investigator, based in part on the: i. CERAD Word List: Recall \<3 for participants with less than 9 years of education. ii. CERAD Word List: Recall \<5 for participants with 9 or more years of education. iii. Preservation of independence in functional activities in the judgment of the Investigator. c. Or determined to have mild AD dementia as defined by:
• Meets the 2011 National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria for probable AD, and
• Has a CDR-GS of 0.5 or 1, with the memory box score ≥0.5.

You may not qualify if:

• Significant medical, psychiatric, or other neurological condition or disorder documented by history, physical, neurological, laboratory examinations that would place the participant at undue risk in the Investigator's judgment or impact the interpretation of efficacy.
• History of stroke.
• History of severe, clinically significant (persistent neurological deficit or structural brain damage) CNS trauma (e.g., cerebral contusion).
• Current presence of bipolar disorder or other clinically significant major psychiatric disorder according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) or symptom (e.g., hallucinations, agitation, paranoia) that could affect the participant's ability to complete evaluations.
• History of seizures (excluding febrile seizures of childhood, or other isolated seizure episodes that were not due to epilepsy in the judgment of the Investigator, and required at most time-limited anticonvulsant treatment, and which occurred more than 7 years prior to the screening visit).
• Women who are pregnant or intend to become pregnant during the conduct of this study.
• Women who are nursing infants or intend to nurse infants during the conduct of this study.
• Known (or prior) hypersensitivity to donanemab, RG6289, or any excipients of RG6289.
• History of or active inflammatory bowel disease (e.g., Crohn disease or ulcerative colitis).
• Medical history of malignancy in the past 5 years, with the following exceptions:
• If considered to be cured or,
• If not being actively treated with anti-cancer therapy or radiotherapy and, in the opinion of the Investigator, is not likely to require treatment in the ensuing 5 years and,
• For prostate cancer or basal cell carcinoma, no significant progression over the previous 2 years.
• In-situ cervix carcinoma that has been successfully treated.
• Fully excised non-melanoma skin cancers or in-situ melanoma.

Sponsors & Collaborators

• Banner Health: lead
• National Institute on Aging (NIA): collaborator
• Universidad de Antioquia: collaborator

Study Sites (1)

Neurosciences Group of Antioquia, University of Antioquia

Medellín, Antioquia, Colombia

Location

MeSH Terms

Conditions

Alzheimer Disease; Dementia

Interventions

donanemab

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Robert Alexander, M.D.

  Banner Alzheimer's Institute

  PRINCIPAL INVESTIGATOR

• Jessica Langbaum, Ph.D.

  Banner Alzheimer's Institute

  PRINCIPAL INVESTIGATOR

• Eric Reiman, M.D.

  Banner Alzheimer's Institute

  PRINCIPAL INVESTIGATOR

• Yakeel T. Quiroz-Gaviria, Ph.D.

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

David Gordon, M.S.

CONTACT

(602) 839 - 6020; David.Gordon@bannerhealth.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 29, 2025
• First Posted: May 30, 2025
• Study Start: January 15, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): June 1, 2030
• Last Updated: August 3, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share

Locations

CO (1)