The Alzheimer’s Association International Conference (AAIC) 2021 is being held this week and the controversial approval of Biogen’s Aduhelm (aducanumab) is among the topics front and center at the largely virtual meeting this year. To kick start the Aduhelm discussions, an expert Alzheimer’s disease panel has unveiled the first set of published recommendations for use of the drug. Aduhelm is indicated for individuals with mild cognitive impairment due to Alzheimer’s and mild Alzheimer’s dementia.
As the first approved Alzheimer’s treatment in nearly 20 years, Aduhelm has been causing a stir in the Alzheimer’s disease space, with questions revolving around patient selection, efficacy and dosing among other things, given its history of mixed and inconsistent trial results. To help navigate the approval and offer clarity on its use, the expert panel shared their recommendations at AAIC.
In comments to Xtalks, Jeffrey Cummings, MD, ScD, Joy Chambers-Grundy professor of Brain Science and director, Chambers-Grundy Center for Transformative Neuroscience at the University of Nevada, Las Vegas (UNLV), and lead author on the paper, says that among the recommendations, the panel, “emphasized how to monitor for amyloid-related imaging abnormalities (ARIA), how to manage ARIA if discovered and best practices for patient care in the context of aducanumab.”
The anti-amyloid beta monoclonal antibody was initially handed a broad label approval by the US Food and Drug Administration (FDA) in June. Without indicating a specific disease population, the approval would allow Biogen access to the over six million Alzheimer’s disease patients in the US.
The controversial approval was met with a lot of disapproval from Alzheimer’s medical and scientific communities, which led the FDA to narrow the broad label to mild disease.
In a press release issued today at AAIC, Dr. Cummings says clinicians have been requesting clarity and more specific information about the appropriate use of the newly approved treatment, which prompted the expert panel to assemble the list of recommendations.
“The goal of the ‘Aducanumab: Appropriate Use Recommendations’ is to provide guidance for the safe and effective use of this new drug, in particular because aducanumab is an unprecedented therapy. It is the first drug approved for treatment of Alzheimer’s based on amyloid plaque removal, addressing the underlying biology of the disease.”
The paper outlining the recommendations is published online in the Journal of Prevention of Alzheimer’s Disease.
Four key recommendations are covered in the paper, which include appropriate population and dose selection, side effects monitoring and clinician communication with patients and care givers.
- Appropriate Patient Selection: It is recommended that aducanumab be restricted to patients with early Alzheimer’s (mild cognitive impairment due to Alzheimer’s and mild Alzheimer’s dementia) with confirmed brain amyloid through amyloid positron tomography or cerebrospinal fluid (CSF) findings consistent with Alzheimer’s disease. The efficacy and safety of the drug were evaluated in late-stage trials in this specific Alzheimer’s population.
- Treatment Management: Aducanumab should be titrated to the highest dose of 10 mg/kg over a six-month period to maximize the opportunity for efficacy.
- Safety Monitoring: Aducanumab can significantly increase the incidence of ARIA with brain effusion or hemorrhage; MRIs are therefore recommended prior to initiating therapy, during the titration of the drug and at any time a patient has symptoms of ARIA.
- Patient Engagement: It is important to engage patients and their caregivers in patient-centered communications and discussions to help informed decision-making. This includes clearly outlining requirements, expected outcome, potential risks, side effects and safety monitoring associated with the treatment. It also highlights the importance of engaging diverse and minority patient populations.
The recommendations also include guidance on the use of other Alzheimer’s drugs in combination with aducanumab; the potential impact of neurological, medical and psychiatric conditions on Aduhelm use (and non-use); patient preferences and care partner decisions that could lead to discontinuation of treatment; overall patient compliance and use of aducanumab in patients with moderate or severe Alzheimer’s, atypical Alzheimer’s and non-Alzheimer’s amyloid-bearing conditions.
Dr. Cummings says the advice fills the gap between the FDA’s prescribing information and the real-world implementation of aducanumab because the prescribing information lacks the needed detail for clinical use.
“How to choose appropriate patients, safely scale up to the full dose, monitor side effects and assess effectiveness are all described. Plus, we address when to stop therapy and what patients should not receive this drug,” Dr. Cummings says in the press release.
In his comments to Xtalks, Dr. Cummings says with respect to trial data, “More data are needed. There are sufficient data for the Accelerated Approval but more information, especially on efficacy in patients receiving the high dose for longer periods, is needed.”
Anti-Amyloid Beta Monoclonal Antibodies and Aduhelm Controversy
This is in light of conflicting results from trials over the past couple of years. In 2019, Biogen had nearly abandoned Aduhelm after disappointing results from two Phase III trials showed no clear clinical benefit of the treatment, despite its ability to reduce amyloid beta plaques, accumulation of which is a key hallmark of the disease, in the brain. However, in a recent re-analysis in late 2020 involving more patients, the Massachusetts-based biotech company resurrected Aduhelm and propelled it to becoming the first approved Azheimer’s drug in nearly two decades.
However, there were still problems with this because late-stage clinical trials included patients with early or mild Alzheimer’s and not patients with later stages of the disease, raising alarms on the FDA’s initial broad label approval.
Other anti-amyloid monoclonal antibodies have met with similar mixed results along the way during clinical trials, including Eli Lilly’s donanemab and solanezumab. Donanemab (LY3002813), a monoclonal antibody against a modified version of amyloid beta called N3pG, received Breakthrough Therapy designation from the FDA in June. Like aducanumab, most of the treatments were studied in, and indicated for, mild disease.
When asked about the overall position of amyloid blockers in offering clinical benefit, Dr. Cummings stands by the strategy, saying, “The monoclonal antibodies are the first drugs to remove plaque amyloid, they have evidence of clinical benefit, and it is a consistent observation across this group of drugs (Aduhelm, donanemab, lecanemab, gantenerumab). We should pursue this avenue of treatment very aggressively as it is the first to succeed.”
He adds, “However, amyloid is only part of the complex biology of Alzheimer’s and we need therapies addressing the tau protein, inflammation, synaptic function and bioenergetics, among others.”
Dr. Cummings says patients who receive Aduhelm should have confirmed brain amyloid by amyloid brain scanning or by lumbar puncture and measurement of the CSF markers of Alzheimer’s.
When asked about biomarkers used to select for patients and monitor Aduhelm treatment, he emphasizes that, “Amyloid is the target of Aduhelm and patients must have the target confirmed. MRI serves as a safety biomarker for ARIA. Other biomarkers are done only on a research basis.”
One of the main side effects of aducanumab is ARIA, which specifically relates to leakage of fluid and sometimes blood from the brain blood vessels, which Dr. Cummings says occurs in about 40 percent of patients. “ARIA has no symptoms and is discovered only by routine MRIs in 70 percent of cases. Four percent of patients have severe symptoms (seizures, stroke-like) and should not continue Aduhelm,” he said.
The expert panel says there is a need to build an appropriate infrastructure for the use of aducanumab, which will require resources, time and creative planning. “Appropriate use of aducanumab requires a commitment to patient-centered care and best practices for the safe delivery of this new treatment,” they say.
When asked about timelines and building this infrastructure, Dr. Cummings says that The Appropriate Use Recommendations can be implemented right away upon their release today, saying that, “It is going to take six to 12 months to establish workflows and patient-friendly programs to deliver Aduhelm.”
The Alzheimer’s community is welcoming Aduhelm with due diligence, ensuring that appropriate guidance is made available for what could be a life-altering drug for some Alzheimer’s patients.