Understanding What the FDA’s Accelerated Approval of Aduhelm Means for the Alzheimer’s Community

Alzheimer's disease is pathologically defined as abnormal accumulation of amyloid plaques and tau tangles in the brain, leading to degeneration of nerve cells, memory problems, cognitive decline, and dementia. In the past two decades, we’ve watched an extremely active industry of Alzheimer's disease clinical trials − most showing tentative steps forward with only a few appearing promising.

On June 7, 2021, early in Alzheimer's & Brain Awareness Month, the U.S. Food and Drug Administration (FDA) granted accelerated approval to Aduhelm (aducanumab), the first drug in 18 years for Alzheimer’s disease. The FDA then followed up by granting two other antibodies Breakthrough Therapy designation for treatment of Alzheimer's disease. This news was long-awaited for more than 6 million Americans and more than 30 million people worldwide with the disease, one can say Alzheimer’s history was made in June. But the news also sparked controversy and debate on what the approval means for the Alzheimer’s community.

What does FDA accelerated approval mean?

The FDA first initiated the accelerated approval pathway in 1992 in wake of HIV crisis to expedite availability of certain drugs providing meaningful therapeutic benefit over existing treatments for serious/life-threatening illnesses. In recent years, more and more new drugs are approved via an expedited pathway says a recent evaluation published in JAMA.

Accelerated approval is based on surrogate measures reasonably likely to predict a clinical benefit. Surrogate measures are laboratory tests, radiologic tests, or other biomarkers, in contrast to clinical endpoints measuring how patient feels, performs, or survives the disease. The use of surrogate endpoint could help provide earlier access to potentially effective therapies for patients who have no other choice, as well as inspiring further innovation and investment in drug development. Nonetheless, accelerated approval requires conducting a post-approval confirmatory study using clinical endpoints, or the FDA has the authority to withdraw approved indication.

How does Aduhelm drug work?

Aduhelm is a monoclonal antibody treatment administered via an intravenous (IV) infusion every four weeks, and most likely for the rest of an Alzheimer’s patient’s life. This monoclonal antibody is engineered to stick to the amyloid protein that forms plaques in the brains of people with Alzheimer’s. The body’s own immune system will then remove the plaque, thinking it is a foreign invader. The premise is that the removal of the amyloid plaques from the brain cells will stop formation of tau tangles and dying of nerve cell, and therefore stop or slow down cognitive and behavioral functions deteriorating.

So, does Aduhelm work?

There were two large clinical trials to assess efficacy of the drug and target engagement. Here is a summary of their findings:

• A dose dependent reduction in amyloid PET scans of trial participants in both studies provides convincing evidence for target engagement. It’s worth noting that amyloid is not an established surrogate measure for clinical improvement in Alzheimer’s disease.
• Looking at the two objective clinical outcome measures of cognitive performance, not all but the participants who had the high dose treatment showed a 0.6-point change on the 30-point Mini-Mental State Examination. On the 85-point Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog)-13, the high dose made a 1.4-point change. There was a 22% reduction in Clinical Dementia Rating – Sum of Boxes outcome, reflecting an absolute difference of 0.39-point. Although these results were considered positive, meaning that the drug worked to slow down the decline of thinking, memory, and daily function, the potential benefit was fairly small.
• Finally, there is not enough biomarker data in terms of downstream neurodegenerative changes that have been presented yet to conclude whether there was disease modification. In a non-random subsample of participants, some reduction was also observed in tau protein levels in cerebral spinal fluid, surrounding the brain tissue and reflecting some of the pathophysiological changes such as tau tangle accumulation in the actual brain tissue. Although this was an encouraging result, the number of participants in this subsample was very small and the biomarker data was limited.

In the view of the FDA advisory panel, these results meant that we do not yet know if the drug works or not, hence the conditional approval requiring the company to complete a post-approval confirmatory trial to verify these outcomes over the next nine years.  

Who is a good candidate for Aduhelm?

Based on the clinical trials, Aduhelm can be potentially considered for individuals who have Alzheimer’s in its mild cognitive impairment or mild dementia stage − those who may be able to function normally or require a little bit of help with complicated daily activities. There's no evidence indicating that the drug could be beneficial for any other stage of Alzheimer's. For example, patients who need help with basic daily activities. In a recent reversal, the FDA now limits the drug’s use to people with mild disease, which is highly unusual for a drug that has been available for only a few weeks.  

It is worth noting that not everyone with a clinical diagnosis of mild cognitive impairment or mild dementia has Alzheimer’s disease pathology. As the drug target engagement requires presence of Alzheimer’s amyloid pathology in the brain, Aduhelm treatment candidates should have biomarker evidence for Alzheimer’s amyloid pathology to know whether or not they would potentially benefit from the therapy.

What is the role of amyloid PET imaging and other emerging tests for both safety and qualifying patients for Aduhelm therapy? 

Amyloid PET scans and lumbar puncture for fluid biomarker assessment will be an indispensable component of qualifying patients, at least for foreseeable future. The use of these diagnostic methods has been greatly limited particularly by the high cost of PET scans, and the failure of Medicare and insurers to provide reimbursement. Emerging tests such as the blood plasma biomarkers that are easy to administer and that are accurate are going to be the way of the future. See these two recent publications from UCSF and the San Francisco Veterans Affairs Medical Center:

• “Detection of β-amyloid positivity in Alzheimer's Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers” (Brain Communications), February 2021
• “The search for a convenient procedure to detect one of the earliest signs of Alzheimer's disease: A systematic review of the prediction of brain amyloid status” (Alzheimer's & Dementia®), May 2021 

Safety of Aduhelm is an important factor to consider when qualifying patients. In spite of the fact there were no contraindications reported in the label, based on the two clinical trials in which it was studied, amyloid-related imaging abnormalities including MRI signal abnormalities suggestive of swelling of the brain and tiny brain bleeds were reported in 10-30% of participants who received the active treatment. Although swelling of the brain cleared by itself, these side effects need to be watched closely by MR imaging and a team of neurologists and neuroradiologists who are experts in how to monitor these events and who know when to dose adjust, pause, or stop the drug.

Another unanswered question is who should be excluded as we do not know much on how preexisting medical conditions could interfere with treatment and safety of the drug.

Will Aduhelm be covered by Medicare, Medicaid or other private health insurance companies?

It is not yet clear if Medicare, Medicaid, or private insurance companies will cover the cost of the drug. Concerns around affordability and sustainable access to the treatment might further deepen issues around the inequities in health care for dementia in particular for Alzheimer's disease.

What does the approval of Aduhelm mean for the Alzheimer’s community?

History has shown us that approvals of the first drug in a new category invigorates the field. It increases investments in new treatments and encourages greater innovation. For many this approval represents a step forward and progress in dementia clinical research. This could be considered as much-anticipated proof of the depth and strength of Alzheimer’s research and add to the growing body of recognition of the critical value of biomarkers in both Alzheimer’s research and clinical trials. Neuroimaging and fluid biomarkers show potential to design more rigorous trials targeting individuals most likely to benefit from the therapy.

Disclaimer:

No content on this blog, regardless of date, should ever be used as a substitute for direct medical advice from your doctor or other qualified clinician.