DIAN Trials Unit Research Updates

Here are the latest research updates related to our clinical trials:

Update: May 21, 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

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.

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Update: May 7, 2024

The Knight Family DIAN-TU Primary Prevention Trial

The statement below is an update to the 20 December 2022 announcement by the Knight Family Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) regarding the DIAN-TU-002 Primary Prevention Trial.

In late 2022, the Knight Family DIAN-TU paused the launch of the DIAN-TU-002 Primary Prevention Trial of gantenerumab due to discontinuation of the drug development program. We are now pleased to announce plans to re-launch the DIAN-TU-002 Primary Prevention Trial with remternetug in collaboration with Eli Lilly and Company (Lilly).

Remternetug is an investigational monoclonal antibody developed by Lilly that targets and removes amyloid plaque in the brain. Other amyloid targeting therapies with similar activity have been found to slow the progression of cognitive and functional decline in individuals with symptomatic, non-autosomal dominant, Alzheimer’s disease. Remternetug can be administered subcutaneously, potentially offering a convenient treatment option to patients across the AD spectrum.

“We are extremely pleased to resume the DIAN-TU-002 Primary Prevention trial in partnership with Lilly”, said Eric McDade, DO, a professor of neurology at Washington University and the trial’s principal investigator. “Since the pause of the Primary Prevention trial, there has been clear demonstration of clinical benefit from amyloid lowering therapies at the symptomatic stage of Alzheimer’s disease. This only strengthens our need to resume the first true prevention study in Dominantly Inherited Alzheimer disease targeting amyloid pathology at the earliest possible stage.”

Unlike historical Alzheimer’s disease trials, the DIAN-TU-002 Primary Prevention Trial will treat individuals prior to onset of significant amyloid plaque build-up in the brain – up to 25 years before the expected onset of dementia. Results from recent trials and FDA approved drugs for Alzheimer’s disease have demonstrated the benefit of removing amyloid plaques from the brain. This trial will demonstrate whether remternetug can prevent amyloid plaque accumulation in participants with dominantly inherited Alzheimer’s disease (DIAD), and if prevention of amyloid build-up in DIAD can prevent or substantially slow this form of the disease.

The DIAN-TU-002 Primary Prevention Trial will utilize the current network of the Knight Family DIAN-TU sites all over the world – nearly 40 research institutes in North America, Australia, Europe, and South America to recruit individuals from families with DIAD. Trial participants will be 11 to 25 years before their expected age of dementia onset and have no or very few amyloid deposits in the brain.

Preventing or halting the earliest stages of disease could be transformative in the world of Alzheimer’s prevention. Results will further our understanding of all forms of Alzheimer’s disease, which could benefit the millions of people living with the more common late onset form of the disease.

The trial is supported with funds from the National Institute on Aging (NIA), the Alzheimer’s Association, GHR Foundation, Washington University, as well as St. Louis resident, Joanne Knight, a longtime benefactor of Washington University, and her family. The trial is being conducted in close partnership with Lilly, which also is providing significant funding.

This international effort to find ways to prevent Alzheimer’s disease would not be possible without the support of many partners, as well as the active involvement of DIAD families. We thank our partners and the trial participants and their families for their ongoing commitment.

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Update: December 18, 2023

The Knight Family DIAN-TU Amyloid Removal Trial

The statement below is an update to the 18 August 2023 announcement by the Knight Family Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) regarding the DIAN-TU-001 Open Label Extension (OLE) Study [Clinicaltrials.gov #NCT01760005].

On August 18th, 2023, the Knight Family DIAN-TU announced the discontinuation of the DIAN-TU-001 OLE based on findings from an interim efficacy analysis and the status of the drug program. Base on findings from the interim analysis that removing amyloid plaques may be beneficial, and recognizing the commitment of our participants and their families, the Knight Family DIAN-TU is pleased to announce our plans to launch the DIAN- TU Amyloid Removal Trial to enable continued study treatment for the DIAN-TU-001 OLE participants and address questions regarding the effects of removing amyloid plaques to normal levels on the disease process.

“The Knight Family DIAN-TU is delighted to continue to work with these participants who have been in trials for a decade to determine the long-term effects of amyloid plaque removal on Alzheimer’s disease prevention,” said Dr. Randall J. Bateman, Director of the DIAN-TU. “The findings indicate large beneficial effects on the biology, and the goal now is to confirm if removing amyloid plaques can delay or prevent the onset of memory loss and dementia in these unique individuals who are otherwise destined to dementia.”

The DIAN-TU has received funding from the Alzheimer’s Association and GHR Foundation to launch the DIAN-TU Amyloid Removal Trial. DIAN-TU plans to implement study treatment with an amyloid-removing therapy. We expect to launch the study in 2024.

We thank the DIAN-TU participants and their families for their commitment and patience while we finalize the details for this study. We also thank the Alzheimer’s Association and GHR Foundation for providing funding to enable the DIAN-TU Amyloid Removal Trial.

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Update: August 18, 2023

Update on the DIAN-TU-001 Gantenerumab Open Label Extension

This announcement is regarding the Knight Family DIAN-TU Open Label Extension (OLE) Study with gantenerumab (made by Roche and Genentech) [Clinicaltrials.gov #NCT01760005].

Based on the results of the completed Roche Phase 3 GRADUATE studies of gantenerumab in sporadic AD in late 2022, it was decided to determine if dominantly inherited Alzheimer’s disease (DIAD) participants in the DIAN-TU-001 OLE study were benefiting from gantenerumab high-dose treatment. The DIAN-TU and Roche performed an interim efficacy analysis of the DIAN-TU-001 OLE to:

1. determine if gantenerumab OLE treatment and/or long-term treatment results in clinical benefit and determine the extent of amyloid removal compared to the double-blind period.
2. determine the potential effects of gantenerumab on clinical and cognitive measures to support decision-making regarding next steps for the DIAN-TU-001 OLE.

The primary outcome did not show pre-specified threshold changes in outcomes between the gantenerumab treated and controls.  One of the subgroups did meet the pre-specified threshold.  Based on these findings, and the status of gantenerumab development plan, Roche and the DIAN-TU have decided to discontinue the DIAN-TU-001 gantenerumab OLE.  Other measures are being analyzed and will be communicated in scientific meetings and publications.

The Knight Family DIAN-TU and Roche recognize and truly appreciate the commitment of our participants and their families. The DIAN-TU understands the uncertainty and concerns with stopping treatment, and we are actively working to identify treatment continuation and trial options for the DIAN-TU-001 OLE participants with expected announcements in the next few months.  A wash-out period after last dose may be necessary prior to starting treatment with another anti-amyloid drug and potentially other AD treatments.  Based on observations in other studies, the effect of the drug on brain amyloid removal likely lasts many years after the last dose.  In addition, the drug remains in the body (i.e. keeps working) at decreasing concentrations for as long as 6 months after the last dosing, and it takes many years for amyloid deposits in plaques to accumulate in the brain.  Thus, a break in treatment between studies should have minimal, if any, effect on amyloid removed from the brain in the DIAN-TU-001 OLE participants treated with gantenerumab.

In June 2020, the Knight Family DIAN-TU, in collaboration with Roche and Genentech, launched an exploratory Open Label Extension (OLE) with gantenerumab [Clinicaltrials.gov #NCT01760005] following the close of the DIAN-TU-001 secondary prevention trial of gantenerumab and solanezumab.  The DIAN-TU-001 gantenerumab OLE protocol enrolled eligible individuals who participated in the DIAN-TU-001 double-blind trial of solanezumab or gantenerumab and was designed to provide up to 3 years of treatment with higher doses of gantenerumab.  The goals of the DIAN-TU-001 OLE were:

• to allow participants, who have committed 4 to 7 years to the double‐blind treatment period of the study, to continue or begin to receive gantenerumab, which improved some biological markers of their progressive disease;
• to determine if continued treatment with gantenerumab at its target dose can result in complete removal of brain amyloid;
• to investigate which non‐amyloid related downstream biological measures (e.g. tau and neurodegeneration) can be improved or normalized with complete removal of amyloid at different stages of disease; and
• to investigate the relationship of these biological measures with cognitive and clinical findings.

In late 2022, when it was learned that the GRADUATE studies of gantenerumab, in patients with sporadic AD, were negative, it was decided that an interim efficacy analysis of the DIAN-TU-001 OLE should be performed to see if the higher doses of gantenerumab used in the OLE were providing a benefit to patients with DIAD.  The primary outcomes for the interim were slowing of clinical and cognitive decline as measured by the Clinical Dementia Rating (CDR) – global score and the CDR Sum of Boxes (CDR-SB) – of participants who were asymptomatic at their baseline visit.  Secondary outcomes included amyloid removal and tau accumulation in the brain as measured by Positron Emission Tomography (PET), changes in amyloid and tau protein levels in cerebrospinal fluid (CSF), and other measures of memory and cognition.

DIAN-TU researchers will continue to analyze data according to the DIAN-TU-001 OLE Statistical Analysis Plan to further understand the outcomes of the study.  A more detailed presentation of the study results will be presented to stakeholders in the coming months.

We thank the DIAN-TU participants and their families, site investigators and coordinators, Pharma Collaborators, our funders (the NIA/NIH, Alzheimer’s Association, GHR Foundation, and other organizations), regulators, the DIAN-TU Study Team, Washington University Leadership, vendors, and many others for their continued support of the DIAN-TU trials.  We remain committed to our participants who have dedicated many years, some more than 10, to the DIAN-TU trials and whose contributions have provided key insights into the progression and treatment of AD, led to the identification of stage dependent changes with amyloid removal, and helped in the development of potential surrogate biomarkers. 

The DIAN-TU is informing study participants and applicable health authorities, study ethics committees, and institutional review boards about the decision on the DIAN-TU-001 OLE.

The DIAN-TU-001 OLE is supported by Roche, the Alzheimer’s Association, GHR Foundation, and the Knight Family DIAN-TU.  The DIAN-TU-001 trial of solanezumab and gantenerumab was supported by Eli Lilly & Company, Roche, the Alzheimer’s Association, the National Institutes of Health (NIH U01AG042791, PI RJ Bateman; NIH R01AG046179, PI RJ Bateman), GHR Foundation, and FBRI.

MOD01791343

Update: April 19, 2023

Update on the DIAN-TU-001 Open Label Extension with Gantenerumab (Roche/Genentech)

The statement below is in response to questions and concerns from sites and participants regarding the status of the DIAN-TU-001 gantenerumab open label extension (OLE) study and next steps in the study.

As stated in a previous announcement, although Roche announced its decision to discontinue the company’s clinical trials of gantenerumab in sporadic Alzheimer’s disease (AD), and the DIAN-TU decided to pause the DIAN-TU-002 Primary Prevention Trials with gantenerumab, dosing in the DIAN-TU-001 gantenerumab OLE has continued [Clinicaltrials.gov #NCT01760005] as designed. Gantenerumab is still under study for dominantly inherited AD (DIAD), and there is ample drug available for the DIAN-TU-001 OLE trial.

As also noted in another announcement, the DIAN-TU is continuing the OLE for multiple reasons:

• The Roche GRADUATE trials were conducted in sporadic AD, not DIAD, and it is possible that treatment outcomes from gantenerumab may be different in DIAD because DIAD is known to be caused by mutations in amyloid-beta processing.
• The DIAN-TU trials include individuals that have no symptoms of AD and may provide an opportunity to test the effect of gantenerumab on preventing symptom onset.
• The DIAN-TU-001 OLE is testing a much higher dose of gantenerumab than was tested in the GRADUATE trials and includes participants who will have been treated for 7-10 years, much longer than the GRADUATE I and II studies, providing an opportunity to test higher doses and longer treatment.

The DIAN-TU-001 gantenerumab OLE protocol provides 3 years of treatment with gantenerumab for each participant. The last participant will reach 3 years of treatment in June 2024. However, many participants will be reaching 3 years of treatment sooner and have expressed concerns about discontinuation of treatment with gantenerumab. The DIAN-TU is actively working on trial designs for the DIAN-TU-001 OLE participants after the trial ends (June, 2024). To help ease concerns about a break in treatment, it is important to note that the drug remains in the person’s body (i.e. keeps working) at decreasing concentrations for as long as 6 months after the last dosing. In addition, the drug’s effect of brain amyloid removal likely lasts many years after the last dose based on observations in other studies. Lastly, it takes many years for amyloid deposits in plaques to accumulate in the brain.

We recognize and truly appreciate the commitment of the participants and their families, and we remain committed to them and to finding a treatment for this disease. We will continue to provide updates as we identify opportunities and finalize future plans for the DIAN-TU-001 gantenerumab OLE participants.

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Update: January 7, 2023

Update on the DIAN-TU-001 Trial with E2814 and Lecanemab (Eisai Co., Ltd)

The statement below is in response to Eisai’s 06 January 2023 announcement regarding the FDA’s accelerated approval of lecanemab for the treatment of symptomatic Alzheimer’s disease (AD).

On January 6^th, 2023, the FDA announced approval of lecanemab (an anti-amyloid beta (Aβ) protofibril antibody) through its Accelerated Approval Program for the treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and mild AD (collectively known as early AD) with confirmed presence of amyloid pathology in the brain.

DIAN-TU recognizes the importance of this approval for patients with Alzheimer’s disease symptoms.  Eisai and the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) at Washington University in St. Louis, Missouri have previously announced a collaboration to include lecanemab in the DIAN-TU Tau NexGen trial to be tested with  E2814 – an experimental immunotherapy targeting the microtubule binding domain of the tau protein.

“This approval is a very important step forward in the treatment of Alzheimer’s disease. Our partnership with Eisai to include lecanemab in our combination trial will continue to move the field forward,” said principal investigator Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology and the director of DIAN-TU.

The DIAN-TU NexGen trial of E2814 and lecanemab is currently recruiting participants [Clinicaltrials.gov NCT05269394].

MOD01531540

Update: December 20, 2022

Update on the DIAN-TU-002 Primary Prevention Trial

The statement below is an update to the 15 November 2022 announcement by the Knight Family Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) regarding the DIAN-TU-002 Primary Prevention Trial with Gantenerumab.

During the presentation of topline results from GRADUATE I and II studies at the Clinical Trials in Alzheimer’s Disease (CTAD) conference in San Francisco, Roche announced its decision to discontinue the company’s clinical trials of gantenerumab, including the GRADUATION, OpenRoAD, PostGraduate and SKYLINE trials.  After further consideration and consultation, the DIAN-TU has decided to pause the DIAN-TU-002 Primary Prevention Trial launch activities related to gantenerumab while continuing to evaluate the risk and benefits of gantenerumab in the DIAN-TU-001 trial [Clinicaltrials.gov #NCT01760005].  “Based on the effect of gantenerumab on amyloid biomarkers in the previous DIAN-TU-001 study and the recent GRADUATE studies, and because we are testing higher doses than those tested in the GRADUATE studies, we still believe there is good reason to evaluate gantenerumab in the Primary Prevention Trial,” said Dr. Eric McDade, Co-Director of the DIAN-TU and Principal Investigator of the DIAN-TU-002 Primary Prevention Trial.  “However, we have a responsibility to our participants and stakeholders to ensure the treatment is available to enable completion of the Primary Prevention Trial.  This is no longer possible with gantenerumab.”

To prepare for the inclusion of another study drug in the DIAN-TU-002 platform, the DIAN-TU is resuming enrollment of Primary Prevention participants in the cognitive run-in period.  This run-in period is intended to improve the study’s statistical power, continue engagement of participants, and decrease total duration of the trial once a drug arm opens for enrollment.

“The Alzheimer’s Association fully supports making decisions about the 002 primary prevention trial based on the latest science, while always keeping the study participants’ needs at the center of all study-related actions,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer. “We trust the DIAN-TU study leaders to make the right decision and then move forward with this important clinical trial.”

The DIAN-TU trial platform was designed to quickly adapt to new information about investigational drugs so drug arms could be terminated or added as needed.  With current funding from the NIA/NIH (U01AG059798, PI EM McDade) and the Alzheimer’s Association, the DIAN-TU will continue site and vendor readiness activities while evaluating multiple drug programs for potential use in the DIAN-TU-002 Primary Prevention Trial.

The DIAN-TU is informing study participants and applicable health authorities, study ethics committees, and institutional review boards about the decision on the DIAN-TU-002 trial.  Dosing in the DIAN-TU-001 Open Label Extension will continue [Clinicaltrials.gov #NCT01760005] as designed.

DIAN-TU-001: MOD01531541
DIAN-TU-002: MOD01531508

Update: November 15, 2022

Update on the DIAN-TU-001 Open Label Extension and DIAN-TU-002 Primary Prevention Trials with Gantenerumab (Roche/Genentech)

The statement below is in response to the 14-November-2022 announcement regarding the results from the GRADUATE I and II AD studies found on Roche’s website https://www.roche.com/media/releases/med-cor-2022-11-14.

Roche, known as Genentech in the United States, and the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) at Washington University in St. Louis have been evaluating gantenerumab in the DIAN-TU-001 secondary prevention trial, currently in an open label extension, and the two organizations previously announced a collaboration to evaluate gantenerumab in the DIAN-TU-002 primary prevention trial. The GRADUATE trials were not conducted in a dominantly inherited AD (DIAD) population, and it is possible that treatment outcomes from gantenerumab may be different in DIAD because DIAD is known to be caused by mutations in amyloid-beta processing. Importantly, the DIAN-TU trials include individuals that have no symptoms of AD and may provide an opportunity to test the effect of gantenerumab on preventing symptom onset. Further, the DIAN-TU-001 open label extension is testing a higher dose of gantenerumab than was tested in the GRADUATE trials and includes participants who will have been treated for 7-10 years, much longer than the GRADUATE I and II studies, providing an opportunity to test higher doses and longer treatment.

Dosing in the DIAN-TU-001 open label extension will continue [Clinicaltrials.gov #NCT01760005] with the primary prevention trial of gantenerumab scheduled to begin recruitment by the end of 2022 [Clinicaltrials.gov #NCT05552157]. Safety data from both trials will continue to be monitored by the DIAN-TU Data Safety Monitoring Board.  The data from the GRADUATE I and II studies will be analyzed in depth to assess potential implications for the DIAN-TU studies.  “Although the primary outcome was negative in the top-line results of the GRADUATE I and II trials, moderate amyloid removal and modest trends towards benefit across multiple clinical and cognitive outcomes in pre-specified analyses were observed,” said principal investigator Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology and the director of the DIAN-TU.  “In our ongoing secondary prevention open label extension trial in dominantly inherited Alzheimer’s disease, all participants receive higher doses of gantenerumab than used in the GRADUATE trials.  DIAD is a purer form of Alzheimer’s disease that is caused by amyloid, and with much higher doses of gantenerumab being used, these patients may have a better response.”  The DIAN-TU-001 open label extension followed the DIAN-TU-001 secondary prevention trials of gantenerumab and solanezumab with an additional 3 years of treatment with gantenerumab.  Results are expected in mid to late 2024.  Dr. Eric McDade, Co-Director of the DIAN-TU and Principal Investigator of the DIAN-TU-002 primary prevention trial added “Based on the effect of gantenerumab on amyloid biomarkers in the previous DIAN-TU-001 study, there is good reason for evaluating this investigational medicine before amyloid pathology begins to assess the benefit of amyloid prevention in DIAD.  However, further analysis of the GRADUATE study data will be necessary to best determine potential impact for long-term prevention.

DIAN-TU-001: MOD01496279
DIAN-TU-002: MOD01496284

Update: September 28, 2022

Update on the DIAN-TU-001 Trial with E2814 and Investigational Lecanemab (Eisai Co., Ltd)

The statement below is in response to the 28 September 2022 announcement found on Eisai’s website.

Eisai Co., Ltd. (Headquarters: Tokyo, CEO: Haruo Naito, “Eisai”) and Biogen Inc. (Nasdaq: BIIB, Corporate headquarters: Cambridge, Massachusetts, CEO: Michel Vounatsos, “Biogen”) announced positive topline results from the large global Phase 3 confirmatory Clarity AD clinical trial of lecanemab (development code: BAN2401), an investigational anti-amyloid beta (Aβ) protofibril antibody for the treatment of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) and mild AD (collectively known as early AD) with confirmed presence of amyloid pathology in the brain.

Eisai and the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) at Washington University in St. Louis have previously announced a collaboration to include lecanemab in the DIAN-TU NexGen trial to be tested with  E2814 – an experimental immunotherapy targeting the microtubule binding domain of the tau protein. The positive results reported in the Clarity AD trial are highly impactful for the treatment of Alzheimer’s disease. “We are delighted about the report of beneficial effects in the Clarity Alzheimer’s disease trial and what this could mean for millions of Alzheimer’s disease patients,” said principal investigator Randall J. Bateman, MD, the Charles F. and Joanne Knight Distinguished Professor of Neurology and the director of DIAN-TU.  “In our symptomatic and secondary prevention trials in dominantly inherited Alzheimer’s disease, all participants will receive lecanemab and in combination will be randomized to receive an anti-tau drug (E2814) or placebo.  We have scientific rationale that targeting both amyloid and tau could provide an even greater benefit than either alone.”

Because the Clarity AD trial was conducted in a non-dominantly inherited form of AD, it is possible that treatment benefits from lecanemab may be different in dominantly inherited AD (DIAD). The results of the Clarity AD trial support the investigational use of lecanemab in DIAD, and the DIAN-TU NexGen trial will continue with lecanemab as designed.  Safety data will continue to be monitored by the DIAN-TU Data Safety Monitoring Board.  The DIAN-TU NexGen trial of E2814 and lecanemab is currently recruiting participants [Clinicaltrials.gov NCT05269394].

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Update: December 15, 2021

MEMO

DATE:  10 December 2021

TO:  Individuals eligible for DIAN and DIAN-TU research

FROM: Randall Bateman, MD, Director of DIAN-TU and Eric McDade, DO, Associate Director of DIAN-TU

RE: New eligibility criteria for participation in Tau NexGen E2814:  A requirement for participants to learn their genetic status prior to enrollment

The new Tau NexGen E2814 clinical trial planned for DIAN-TU will be launching at most sites in 2022. This new trial design will offer individuals who have a dominantly inherited Alzheimer’s disease (DIAD) mutation access to investigational drugs that target both amyloid and tau. All participants will receive the anti-amyloid drug and also be randomized to the anti-tau drug or placebo. The main goal of this trial is to determine if these drugs can delay or prevent the formation of tau neurofibrillary tangles and limit further disease progression. In previous DIAN-TU trials, individuals at risk for DIAD did not have to know their genetic status to participate in the trial. However, because all participants will receive active drug, this Tau NexGen trial requires participants to know their genetic status and have a mutation in order to participate. The DIAN-TU can assist in arranging clinical genetic counseling and testing and will cover the cost of these services. Note that the Primary Prevention trial, DIAN Observational, and potentially other trials still do not require participants to know their genetic status.

DIAN-TU researchers recognize the difficulties faced by family members struggling with finding out their genetic status, and have worked hard in the past to preserve the ability to participate in trials without testing. However, after careful deliberation and analysis of multiple factors related to the new trial, we can no longer offer this option for the Tau NexGen E2814 drug arm. Because an anti-amyloid therapy has been FDA approved, we believe anti-amyloid treatment should be made available in this trial. We also predict that future optimal therapies may require both amyloid and tau drugs. For these reasons, we have added an anti-amyloid treatment to the trial, in addition to the anti-tau/placebo drug. Below is a summary of the considerations involved in reaching the decision that only mutation carriers are eligible for the Tau NexGen E2814 trial:

• Prior discussions with family members and study site Principal Investigators (PIs) about requiring genetic counseling and testing have indicated a willingness to consider learning genetic status, if there is access to an active drug (see survey information below). The Tau NexGen E2814 trial provides all participants with an active anti-amyloid drug (Lecanemab) in combination with an anti-tau or placebo.
• Because there are two different drugs co-administered–each with their own scheduling and increased visits, assessments, and scans–there is an increase in study activities, or study “burden”, for both participants and study staff. Given the increased complexity of the trial for both participant and site staff, enrollment of mutation negative participants was determined to no longer be feasible or ethically advisable.
• Ethics committees (ECs) and Institutional Review Boards (IRBs), which approve and oversee clinical trials, have challenged designs that use healthy volunteers (for our studies, this means participants who are mutation negative), stating that the burden of participation (frequency of the visits, lumbar punctures, radiation) is too high if the participant is not at risk (i.e., not a mutation carrier). In these cases, such studies may not receive approval to conduct research. The DIAN-TU seeks to ensure that trials continue to be approved and available to the DIAD community.
• Individuals enrolled in the DIAN-TU clinical trial testing anti-amyloid therapies solanezumab and gantenerumab were offered participation in the gantenerumab Open Label Extension (gant OLE), which required knowledge of genetic status, as all enrolled were guaranteed to receive active treatment with gantenerumab. Ninety-one percent (91%f participants either already knew their status or elected to learn status to participate in OLE, while 9% declined to learn status (Figure 1). These findings indicate that most DIAD participants know or opt to learn their genetic status if guaranteed treatment with an active drug.

• Results of a survey sent to DIAN Expanded Registry participants in July 2021 also provided insight to researchers about the impact of requiring knowledge of genetic status prior to trial participation. The findings are summarized in the below pie chart (Figure 2). Sixty-nine percent (69%) of those surveyed already knew their genetic status. Of those who answered the survey and did not know their genetic status, 21% stated that they would be willing to learn their genetic status if guaranteed to receive an active anti-amyloid drug in addition to anti-tau or placebo during trial participation, while 10% said they would not.  In summary, 90% of survey respondents know or would be willing to learn their mutation status for the trial.

The DIAN Expanded Registry (DIAN EXR) has received several communications from family members and trial participants about this change. We understand the significance of this eligibility criteria change for some DIAD participants and hope this memo helps clarify why this decision was made. For more information, please see the press release posted on the DIAN website and the DIAD family webinar from November 20, 2021 DIAD family webinar.

If you are a current participant in Cognitive Run-In (CRI) and do not know your genetic status (and are unsure whether you are ready to find out your genetic status) or if you are not yet involved but are interested in learning more, you may take any of the following actions:

• Contact the DIAN EXR by registering at https://dian.wustl.edu/our-research/registry/ (if you are not yet registered)
• Consider the option to receive multiple sessions of supportive counseling with a local, professional therapist to assist in deciding whether learning your genetic status is right for you at this time.
• Discuss the Tau NexGen trial with your site Principal Investigator
• Review the consent form for the Tau NexGen trial to learn the risks/benefits of participating
• Schedule an initial genetic counseling session to get relevant information about risk and learning genetic status (Note: it is recommended to obtain life and long-term care insurance before contacting a genetic counselor)

Please contact your study coordinator or the DIAN EXR at dianexr@wustl.edu for more information.

MOD01172222

Update: June 9, 2020

Gantenerumab improved markers of disease in rare, inherited form of Alzheimer’s disease

Further analysis of data from an international trial of two investigational drugs in people in the early stages of a rare, inherited form of Alzheimer’s disease has demonstrated that one of the drugs had a positive impact on biomarkers of the disease.

The study (ClinicalTrials.gov Identifier: NCT01760005) is a phase 2/3 trial led by Washington University School of Medicine in St. Louis through its Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU). The trial separately evaluated the effects of two drugs – solanezumab, made by Eli Lilly and Co., and gantenerumab, made by Roche – known as Genentech in the United States – in people with a rare, inherited, early-onset form of Alzheimer’s called dominantly inherited Alzheimer’s disease or autosomal dominant Alzheimer’s disease. Such people experience declines in memory and thinking starting in their 50s, 40s or even 30s.

The primary endpoint of the study was a slowing of cognitive decline as measured by multiple tests of thinking and memory. A February 10 press release issued by Washington University School of Medicine announced that an initial analysis indicated neither drug met the primary outcome nor demonstrated cognitive benefit. However, further analyses of trial data for gantenerumab demonstrated improvement in biomarkers of disease activity and progression, including measures of tauopathy and neurodegeneration. Gantenerumab reduced the pathology of amyloid plaques, reduced soluble cerebrospinal fluid (CSF) tau and phospho-tau and slowed increases in the neurofilament light chain (believed to be a marker of neurodegeneration) when compared to placebo.

The DIAN-TU thinks these findings are important indicators that gantenerumab can affect the biological course of the disease and have launched a multiyear exploratory open label extension in collaboration with Roche to continue studying the effects of gantenerumab in this rare form of Alzheimer’s. These findings were presented to the scientific community on April 2, 2020 during the Advances in Alzheimer’s and Parkinson’s Therapies annual meeting. Additional findings will be presented at the upcoming Alzheimer’s Association International Conference in July.

“By continuing the study of gantenerumab through an exploratory open label extension, we will determine whether the drug can completely remove amyloid plaques from the brain, and by doing so, determine if other pathologies related to disease progression (for example, neurodegeneration) are substantially improved as well,” said principal investigator Randall J. Bateman, MD, director of DIAN-TU and the Charles F. and Joanne Knight Distinguished Professor of Neurology at Washington University. “We will also track memory and thinking, and how long it takes for the disease to progress to dementia.”

The goals of the exploratory open label extension are:

• To allow participants, who have committed 4 to 7 years to the double‐blind treatment period of the study, to continue or begin to receive gantenerumab, which improves critical biological markers of their progressive disease;
• To determine if continued treatment with gantenerumab at its target dose can result in complete removal of brain amyloid;
• To investigate which non‐amyloid related downstream biological measures (e.g. tau and neurodegeneration) can be improved or normalized with complete removal of amyloid at different stages of disease; and
• To investigate the relationship of these biological measures with cognitive and clinical findings.

Individuals originally enrolled in the DIAN-TU trial of solanezumab and gantenerumab are potentially eligible for enrollment in the exploratory open label extension. Eligible trial participants will take the active form of the drug without placebo. The exploratory open label extension allows active drug to be given to all participants and follow them over time.  Since everyone in the extension will receive active drug, only people who carry the early-onset Alzheimer’s disease mutation will be able to participate.

The DIAN-TU is committed to starting the open label extension as soon as possible and is working with stakeholders to address challenges related to COVID-19 and minimize delays to initiation. Please visit the DIAN website to see an updated list of frequently asked questions about the exploratory open label extension.

A discussion about the exploratory open label extension by top researchers can be found on the Alzforum website, https://www.alzforum.org/news/conference-coverage/dian-tu-gantenerumab-brings-down-tau-lot-open-extension-planned.

The DIAN-TU is excited to offer this opportunity and looks forward to learning more about long-term effects of gantenerumab, removing amyloid plaques and the impact on Alzheimer’s disease. In addition, the DIAN-TU continues to expand its platform to investigate new drugs with novel biomarker targets of Alzheimer’s, such as tau-based therapies.

The DIAN-TU trial platform is supported by the Alzheimer’s Association, the National Institute on Aging of the National Institutes of Health (NIH U01AG042791, NIH R01AG046179, NIH R01AG053267 – PI RJ Bateman; NIH U01AG059798 – PI EM McDade), GHR Foundation, FBRI, Eli Lilly and Co., Roche, Janssen, and Avid Radiopharmaceuticals. More information about the trial can be found on clinicaltrials.gov (ClinicalTrials.gov Identifier NCT01760005) and on Washington University’s Dominantly Inherited Alzheimer Network website.

MOD0687699

Update: Feb 10, 2020

Investigational drugs didn’t slow memory loss, cognitive decline in rare, inherited Alzheimer’s, initial analysis indicates

DIAN-TU-001

Update: Feb 7, 2020

A message from Dr. Bateman to DIAN-TU trial participants

Update: July 2018

Update on the DIAN-TU-001 TRIAL:  Janssen BACE Inhibitor (JNJ-54861911/atabecestat) DRUG ARM DISCONTINUATION

The statement below is an update to the May 25^th announcement found on Janssen’s website.

Previously, Janssen observed elevations of liver enzymes in some study participants who received atabecestat, including two patients who had high elevations of liver enzymes, placing them at increased risk for severe liver injury. These patients remain clinically stable, and their liver enzyme levels have normalized.

After further consideration and consultation, Janssen has concluded that the benefit-risk balance of JNJ‑54861911 (atabecestat) is no longer favorable to continue development of atabecestat (Read more here). Therefore, all randomized participants in the DIAN-TU-001 trial’s atabecestat arm will be instructed to stop dosing with study drug.  The DIAN-TU is informing study participants, health authorities, the study ethics committees, and institutional review boards about this decision.

To facilitate transitioning the trial arm to another study drug, the DIAN-TU is modifying the current protocol to include a cognitive run-in period prior to randomization into study drug arms. This run-in period is intended to improve power, continue engagement of participants, and decrease total duration of the trial.  This cognitive run-in period was included in the funded NIH DIAN-TU NexGen trial grant (NIH R01AG053267, DIAN-TU Next Generation Prevention Trials).

We are in the process of considering the next drug for the third drug arm.  The DIAN-TU trial platform was designed to quickly adapt to new information about drugs as they are developed, and we plan to be doing this soon.

Thank you and the participants for your continued commitment.

Best regards,

Update: April 2018

Notice to DIAN-TU Investigational Sites and Participants
RE: DIAN-TU-001 INTERIM ANALYSIS

April 25, 2018

DIAN-TU Site Leaders and Participants,

The original goal and intent of the biomarker interim analysis was to determine if the investigational drugs at the dosages used were modifying the amyloid-beta targets.  The biomarker Interim Analysis was designed to allow the DIAN-TU trial to adapt to the biomarker results by continuing, stopping, or modifying the dosage of a drug.  Several actions both inside and outside our clinical trial have changed the purpose of the biomarker Interim Analysis, as the aims to adapt dosing have already been met.

• Findings from other studies for both solanezumab and gantenerumab indicate that higher doses increase target engagement by binding more amyloid-beta or removing more amyloid-beta plaque (what the drug is designed to do) ^{1, 2}. Further, the lower doses tested in late onset Alzheimer’s disease (AD) did not significantly improve dementia.  Therefore, implementation of dose adjustment to higher doses has already occurred for each drug in the DIAN-TU trial.
• Upon review of the primary aims, the DIAN-TU trial has already met the goal of the interim analysis by increasing doses in both drugs by adapting to external data prior to the availability of the internal trial data.
• Therefore, the DIAN-TU Data Safety Monitoring Board (DSMB) (our external safety committee), leadership, and partners have unanimously agreed to continue the solanezumab and gantenerumab arms without stopping. Safety and biomarker data will continue to be monitored by the DIAN-TU DSMB on a quarterly basis for recommendations on how to continue the planned study.  However, no formal data will be released at this time to the DIAN-TU investigators or participants. The DIAN-TU trial of solanezumab and gantenerumab is scheduled to complete at the end of 2019.

Sincerely,

Randall J. Bateman, M.D.

Charles F. and Joanne Knight Distinguished Professor of Neurology
Principle Investigator, Department of Neurology
Director, Dominantly Inherited Alzheimer’s Network Trials Unit

Update: December 2015

The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) has completed the first stage of participant enrollment in the first Alzheimer’s prevention trial for autosomal dominant Alzheimer’s disease (ADAD), also referred to as early-onset Alzheimer’s disease. The goal of the first stage of the study is to determine the biomarker and cognitive effects of two different drugs targeting amyloid beta. With this enrollment milestone, first biomarker results may be available at the end of 2016 with the final cognitive endpoint data expected in late 2019.

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