Date: July 8, 2021
Subject: Aducanumab (ADUHELMTM) gains FDA accelerated approval in the U.S.
Dear DIAN-TU Participant and Family Member,
You may be aware that a new antibody, aducanumab, or AduhelmTM, was granted accelerated approval by the United States Food and Drug Administration (FDA) for the treatment of Alzheimer’s disease. As a vital participant in the DIAN-TU studies you may have questions related to the introduction of this new therapeutic option for Alzheimer’s disease.
The DIAN-TU team has provided a list of Frequently Asked Questions (FAQs) about aducanumab to help you consider ongoing research and treatments. Please reach out to the research team with any further questions.
The FDA normally approves the use of new drugs only after a clinical trial shows that the medication demonstrates a clinical benefit to patients. However, the process of obtaining data to demonstrate clinical benefit can take a very long time, especially in slow progressing diseases such as Alzheimer’s disease.
The FDA’s Accelerated Approval Program speeds up the approval of drugs for serious or life-threatening illnesses. For accelerated approval, investigators and drug manufacturers have to show that something thought to predict clinical benefit, called a surrogate endpoint, was improved due to the treatment. Surrogate endpoints may occur before clinical benefits.
The FDA considered the reduction of amyloid plaques in the brain by aducanumab as reasonably likely to predict a clinical benefit, thus meeting the standard for accelerated approval.
Accelerated approval requires the manufacturer (Biogen) to demonstrate clinical benefit, such as improvement of symptoms and memory, by conducting a post-approval confirmatory trial in the future. The FDA may withdraw the approval of the drug and remove it from the market if a confirmatory trial does not show clinical benefit.
Aducanumab is approved for the treatment of “mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied”. This approval was based on studies of patients who had amyloid beta plaques in the brain and were diagnosed with either mild cognitive impairment due to Alzheimer or mild Alzheimer dementia.
Aducanumab was not tested in patients who did not have symptoms of Alzheimer’s disease, had advanced Alzheimer’s disease, or had dominantly inherited Alzheimer’s disease (DIAD). Aducanumab is not approved for the prevention of Alzheimer dementia.
No. Participants who plan to start treatment with aducanumab must withdraw from the DIAN-TU-001 gantenerumab exploratory open-label extension study before starting aducanumab. This is for both safety and scientific reasons, because aducanumab has a similar effect of gantenerumab and may increase side effects creating a potentially unsafe condition.
Before leaving the study, participants should confirm with their doctor that they can receive aducanumab. There are several important factors to consider:
- The participant meets prescribing guidelines.
- The availability of aducanumab in the participant’s region.
- The risks and potential benefits of aducanumab compared to stopping treatment or continuing with gantenerumab
- Insurance coverage for the substantial cost of the medication.
If a participant decides not to continue in the gantenerumab study, they must contact the research team to complete early discontinuation visit procedures. This visit is important for both participant health and safety and to assure we learn as much as possible about the risks and benefits of gantenerumab for people with DIAD.
Participation in clinical research is completely voluntary and the decision to continue participation is the participant’s, with input from family and DIAN-TU Site personnel.
Participation in the gantenerumab open-label extension study is important for several reasons:
- This study will determine the effect of long-term, high dose gantenerumab on amyloid plaques in the brains of patients with dominantly inherited Alzheimer’s disease. This population was not studied in the aducanumab trials.
- A previous study phase showed that gantenerumab reduced amyloid plaques in the brain and affected other disease biomarkers, such as tau in the cerebrospinal fluid. The study team does not have evidence that aducanumab is substantially different from gantenerumab.
- The safety of gantenerumab, but not aducanumab, has been and will continue to be evaluated in dominantly inherited Alzheimer’s disease participants.
Gantenerumab and aducanumab are both monoclonal antibodies and work in similar ways to remove amyloid plaques in the brain. We cannot make direct comparisons of these two drugs because head-to-head comparison studies were not conducted. During the previous DIAN-TU-001 placebo-controlled trial, gantenerumab demonstrated clear benefit by improving disease biomarkers consistent with those reported for aducanumab. Aducanumab showed some evidence of clinical benefit in one, but not another, phase 3 study in patients with sporadic mild Alzheimer’s disease. To date, we do not know the clinical benefit of gantenerumab treatment at high doses because these studies are ongoing.
Both drugs share similar risks. The most serious side effect identified is amyloid-related imaging abnormalities-edema (ARIA-E). The rate of ARIA-E in the DIAN-TU-001 gantenerumab group was 19% in the DIAN-TU trial compared to an overall 35% in the aducanumab trial with older people with Alzheimer’s.
The safety of the FDA approved dose of aducanumab is based on studies in sporadic Alzheimer dementia populations. A safe dose of aducanumab in the dominantly inherited Alzheimer’s disease population has not been tested. We believe higher doses of antibodies are needed for the dominantly inherited Alzheimer’s disease population to achieve a similar effect to the one demonstrated in sporadic Alzheimer’s disease. The DIAN-TU-001 gantenerumab OLE trial tests a higher dose in a controlled way in this population.
Patients with dominantly inherited Alzheimer’s disease have a greater amount and higher growth rate of amyloid beta plaques in the brain compared to those with sporadic Alzheimer’s disease. It is reasonable to expect that higher doses of antibodies against amyloid will be required to remove plaques to the same degree as seen in sporadic Alzheimer’s disease.
It is important to determine the amount of amyloid plaque removal necessary to increase the chances of improving symptoms and memory. The effect of gantenerumab on amyloid removal from the brain was greater at higher doses in the DIAN-001 trial.
The safety of aducanumab at the FDA approved dose was based on studies in sporadic Alzheimer’s disease, and the dose needed for dominantly inherited Alzheimer’s disease is not known. In the DIAN-TU-001 gantenerumab open label extension, dose increases are made based on studies in DIAD, and are carefully monitored by experienced experts assessing for the adverse effects of edema (ARIA-E) and microhemorrhages, and for the extent of amyloid plaque removal using MRI and PET imaging.
Participation in clinical research is completely voluntary and the decision to continue participation is the participant’s, with input from family, and DIAN-TU Site personnel.
The DIAN-TU-001 cognitive run in (CRI) period enrolls individuals who are eligible for future Alzheimer’s disease prevention trials. It is important to note that aducanumab is not approved for the prevention of Alzheimer dementia and was not tested in participants without clinical symptoms or dominantly inherited Alzheimer’s disease.
The DIAN-TU Primary Prevention placebo-controlled trial will be a first of its kind to target amyloid beta plaques in subjects at risk for dominantly inherited Alzheimer’s disease before there is significant amyloid in the brain. Aducanumab was not tested at the stage of disease being tested in the DIAN-TU Primary Prevention study. This study represents the best opportunity for getting access to amyloid therapeutics at the earliest stages of the disease process.
The CRI is also enrolling future participants for the DIAN-TU Tau NexGen Secondary Prevention Trial that will determine if drugs that target tau protein tangles prevent, delay, or possibly even reverse Alzheimer’s disease changes in the brain. This study will include participants with or without symptoms, or are at risk for dominantly inherited Alzheimer’s disease, and who already have amyloid beta plaques.
The DIAN-TU team is assessing options for these prevention studies that consider the availability of aducanumab for participants with very mild dementia. This includes the possibility of participants receiving amyloid removing drugs in the Tau NexGen trial, potentially as combination treatment with an anti-amyloid drug and an anti-tau drug.
However, CRI participants considering starting aducanumab outside the trial should discuss this with their site PI prior to finalizing a plan, since that choice may disqualify participation in future DIAN-TU trials, including the Tau NexGen Secondary Prevention Trials.
We are committed to ensuring that our trials are ethically designed to provide standard of care practices in treating Alzheimer’s disease as we all work together to improve Alzheimer’s disease treatments.