The Knight Family DIAN-TU-003 Amyloid Removal Trial

May 22, 2024

MEMO

DATE:  15 April 2024

TO:  DIAN-TU-001 Gantenerumab Open Label Extension Participants

FROM: Dr. Randall Bateman, Director, Knight Family DIAN-TU and Dr. Eric McDade, Associate Director, Knight Family DIAN-TU

RE: DIAN-TU-003 Amyloid Removal Trial

As previously announced by the DIAN-TU on 18 December 2023 and the Alzheimer’s Association on 09 April 2024, the Knight Family Dominantly Inherited Alzheimer Disease Trials Unit (DIAN-TU) is launching the DIAN-TU-003 Amyloid Removal Trial (ART) to enable continued treatment for the DIAN–TU-001 Gantenerumab Open Label Extension (OLE) participants and address questions regarding the effects of removing amyloid plaques to normal levels on cognitive symptoms, clinical progression and disease processes.  The DIAN-TU-003 ART is an important study for the field of Alzheimer’s disease (AD) with the potential to answer key scientific questions regarding drug dose and duration, mechanism of action, safety, and optimal timing, exposure and effects of treatment to provide the greatest clinical benefit.  DIAN-TU-001 OLE participants were treated with the anti-amyloid therapy gantenerumab for 2 to 10 years, representing the longest treated group of patients with amyloid removing antibodies. Findings show that for this group of participants, overall, there was partial but not full amyloid removal.  The DIAN-TU-003 ART will enable continued evaluation of the long-term effects of amyloid removal on disease progression in these participants and may provide important information regarding whether removing amyloid plaques can delay, slow, or prevent symptom onset and clinical progression in dominantly inherited Alzheimer’s disease (DIAD).

Trial Design
The DIAN-TU-003 ART is an open-label study to treat DIAN-TU-001 OLE participants with lecanemab for a minimum of 5 years, utilizing a common close design.  Lecanemab is an anti-amyloid monoclonal antibody passive immunotherapy which demonstrated robust amyloid removal capabilities and clinical efficacy in early-stage symptomatic AD.  Currently available clinical trial data suggest that, with monitoring and management, lecanemab treatment has acceptable safety and is generally well tolerated.  Participants will be co-enrolled in the Dominantly Inherited Alzheimer Network Observational (DIAN Obs) natural history study (NCT00869817) through which clinical, cognitive, imaging and fluid biomarker assessments will be conducted.  The main objectives of the 5-year DIAN-TU-003 ART are:

• To determine the effects of amyloid removal on age of onset and clinical progression
• To determine if amyloid plaque can be fully removed in DIAD
• To determine the effects of amyloid removal on biomarkers of disease progression

Main Eligibility Criteria

• Inclusion:
  • Participants who previously participated in DIAN-TU-001 gantenerumab OLE period
  • Co-enrollment in the DIAN Observational Study (DIAN Obs, NCT00869817)
• Exclusion:
  • Participants with excessively high risks associated with amyloid-related imaging abnormalities

Safety – Amyloid Related Imaging Abnormalities (ARIA) and ApoE ε4 Status
Monoclonal antibodies directed against aggregated forms of beta amyloid, including lecanemab, can cause brain changes known as amyloid related imaging abnormalities (ARIA), characterized as ARIA with edema (ARIA-E) and ARIA with hemosiderin deposition (ARIA-H). With detection, monitoring and management approaches, ARIA is typically mild to moderate in extent, is transient, and does not cause symptoms. However, in rare cases, ARIA can be serious and may lead to life-threatening problems, such as significant brain bleeding, known as intracerebral hemorrhage; and may cause lasting disability or death. People who have two copies of a specific genetic variant, called ApoE ε4, are at a higher risk of experiencing ARIA when taking amyloid plaque-lowering monoclonal antibody medications like lecanemab, compared to those with only one or no copies of this variant. Before starting lecanemab, it is important to test for the ApoE ε4 variant to understand the risk of developing these brain changes better. Other factors that may increase the risk of ARIA include cerebral amyloid angiopathy (a condition related to AD with amyloid-related deposits weakening or damaging small brain vessels), and prior experience with gantenerumab treatment and development or effects of ARIA.

Individuals’ risks will be discussed and reviewed during the participant-centered, shared decision-making informed consent process when assessing interest and plausibility in participating in this study. Experts advise being particularly cautious about using amyloid plaque-lowering monoclonal antibody treatments under certain conditions including having larger brain bleeds, more than four microhemorrhages (a type of brain bleed that may be related to cerebral amyloid angiopathy), the ApoE-ε4 gene, several past episodes of ARIA, or other risks for bleeding. These do not necessarily restrict inclusion, but it is recommended that these risks are considered and discussed with the study doctor when considering whether to participate in the trial and undertake this intervention.  Individuals may need to check their ApoE ε4 status to assure it is available for consideration prior to starting this trial. Upon participant request, the DIAN-TU study team, along with the study doctor, will assist individuals with obtaining genetic testing to determine an individual’s ApoE ε4 status and to receive the necessary information to make an informed decision regarding participation in the study.

Participation Details
Administration of the study drug and critical safety monitoring will be organized by a limited number of DIAN-TU sites. Measurements of disease status, cognitive performance, and biomarkers will be accomplished by co-enrollment in the DIAN Obs study. All other protocol-related study visits (e.g., for administration of study drug) may be performed by trial-designated and Good Clinical Practice (GCP) trained home health nurses or other trial-identified satellite sites. The safety magnetic resonance imaging (MRIs) that are not part of an annual DIAN Obs study visit may be performed at the participant’s DIAN-TU or DIAN Obs site, or a trial-identified location qualified for the study near the participant’s home. If/when possible, participants will enroll in DIAN Obs at their DIAN-TU study site.  Based on the enrollment timeframe, it is expected that the trial may take up to 7 years for all participants to receive at least 5 years of treatment.

Timing for Launch
The DIAN-TU-003 ART is targeted to launch by the end of Q2 – early Q3 2024 in the United States and by the end of 2024 in the United Kingdom, Europe, and Australia.

Next Steps:

• Eligible participants will be contacted by DIAN-TU-001 OLE study coordinators to assess interest; however, you may also reach out to your site Principal Investigator, study coordinator or the DIAN Expanded Registry (DIAN EXR) at dianexr@wustl.edu for more information.
• If you are not already registered with the DIAN EXR, please consider enrolling by visiting dian.wustl.edu. DIAN EXR participants receive the most up-to-date information via email blasts, newsletters and webinars with DIAN-TU directors.