DIAN Trials Unit Research Updates

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

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 25th 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,

Randall J. Bateman, MD

Director, DIAN and DIAN-TU

David Clifford, MD

Medical Director, DIAN-TU

Lon Schneider, MD

Atabecestat Project Arm Leader, DIAN-TU

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

1  Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Farlow, Martin et al. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, Volume 8, Issue 4, 261 – 271 https://doi.org/10.1016/j.jalz.2011.09.224

2  Higher dose Gantenerumab leads to Significant Reduction in Amyloid Plaque Burden – Results for the Marguerite and Scarlet Road Open Label Extension Studies. https://www.youtube.com/watch?v=yT-u7Ct6-Hc

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.

Read full article »