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
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.
Meets the 2011 National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria for probable AD, and
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.
Factorial
Donanemab
DrugIV Infusion
RG6289
DrugOral tablet
Donanemab placebo
DrugIV placebo
RG6289 placebo
DrugOral tablet placebo
6
Treatment groupsSee each treatment group below.
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 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)
Cerebrospinal Fluid Amyloid, TAU, and Other Biomarker Endpoints
Change from baseline in cerebrospinal fluid (CSF) biomarkers including Aβ1-42, Aβ1-40, Aβ1-37, Aβ1-38, alpha-synuclein, GFAP, neurogranin, neurofilament light (NfL), pTau217, sTREM2, total tau, and YKL-40. Each resulting value will allow for the determination of Amyloid, TAU, and other protein trajectories related to Alzheimer's Disease Dementia. While each assay will have their own unit of measurement, each test will allow for comparison and confirmation of the presence and amount of targeted markers.
Plasma Amyloid, TAU, and Other Biomarker Endpoints
Change from baseline in plasma biomarkers, including Aβ1-42, Aβ1-40, Aβ1-37, Aβ1-38, GFAP, NfL, pTau217, sTREM2, and YKL-4. Each resulting value will allow for the determination of Amyloid, TAU, and other protein trajectories related to Alzheimer's Disease Dementia within blood plasma. Each assay will have their own unit of measurement, and will allow for comparison and confirmation of the presence and amount of targeted markers.
Magnetic Resonance Imaging - Volumetric Measurements
Change from baseline in volumetric magnetic resonance imaging (MRI) measures including whole brain volume, ventricular volume, entorhinal cortex volume, hippocampal volume, and temporal lobe volume.
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Banner Health
Lead sponsor
National Institute on Aging (NIA)
Collaborator
Universidad de Antioquia
Collaborator
