It’s been more than 17 years since the FDA last approved an Alzheimer’s drug. Will Biogen’s drug called aducanumab end this drought? The FDA will make a decision by March 2021 based on its own analysis of clinical trial data and an advisory panel review of the evidence.
How does the drug work?
Aducanumab is a monoclonal antibody that was developed in a laboratory to attach to the amyloid molecule that forms plaques in the brains of people with Alzheimer’s disease. Most researchers believe that the plaques form first and damage brain cells, creating tau tangles in them and killing the cells. As soon as aducanumab sticks to the plaque, your body’s immune system comes in and removes the plaque as it is a foreign invader. The hope and expectation is that after the plaques are removed, the brain cells will no longer die and thinking, memory, function and behavior will no longer deteriorate.
Will the FDA’s decision matter?
When aducanumab works, it will be the first drug to slow the progression of Alzheimer’s disease. That said, we could potentially turn Alzheimer’s from a deadly disease into one that people could live with for many years, just like people with cancer, diabetes, and HIV / AIDS.
For researchers, this means that more than 20 years of scientific work suggesting that removing amyloid from the brain can cure Alzheimer’s disease may be right. But many of us have begun to doubt this theory because trial after trial has shown that amyloid can be cleared from the brain, but it hasn’t changed the progression of clinical disease.
So, is the drug working?
I attended the FDA’s one-day hearing on November 6, 2020 and also independently reviewed all of the publicly available data for aducanumab. There was a small (phase 2) clinical study evaluating the effectiveness and side effects and two large (phase 3) clinical studies evaluating the effectiveness, side effects, safety and possible use of the drug in clinical practice. The small phase 2 study and one of the large phase 3 studies were positive, which means the drug slows the decline in thinking, memory, and function that is normally unstoppable in Alzheimer’s disease. The other big study was negative. Hmm … are two out of three positive studies good enough? The Biogen scientific team had many plausible explanations for why this one study was negative.
However, the advisory body was not convinced. They pointed out that phase 2 trials are always positive or you wouldn’t move on to phase 3 so the trial doesn’t count. They also pointed out that while one can think of the positive Phase 3 study as the “true” one and try to understand why the negative one failed (which Biogen did), the negative study is true as well as the one , and try to understand why the other showed positive results.
The Advisory Board was concerned that “functional unblinding” occurred in both studies, as large numbers of participants in the treatment group required additional MRI and physical exams to manage side effects that did not occur in the placebo group. So if you were asked to do an additional MRI scan, you knew you were taking the real drug. This knowledge could have influenced the respondents ‘and their family members’ responses to their performance, which were the primary results of the study.
Should the FDA approve this?
Many factors must be considered in determining whether a drug should be approved. First is whether it works and as discussed above, there are questions about its effectiveness. You also need to consider side effects and other pressures for patients, families, and society.
You will need an amyloid PET scan first to make sure you have the amyloid plaques from Alzheimer’s. To take the drug, you need an intravenous infusion every four weeks – forever. Thirty percent of those who took the drug had reversible brain swelling, and more than ten percent had tiny cerebral hemorrhages. These side effects must be closely monitored by an experienced neurology / radiology team who understand how to monitor these events and when to interrupt or discontinue medication.
Another factor to consider is the level of performance. It was pretty small here. Looking at the two objective measures, the high dose in the positive study resulted in a change of 0.6 points in the 30-point mini mental state test (MMSE). On the 85-point scale for assessing Alzheimer’s disease – cognitive subscale-13 (ADAS-Cog-13) – the high dose changed by 1.4 points. In the negative study, the analogous results for the MMSE were -0.1 (deterioration) and for the ADAS-Cog-13 0.6.
The cost must also be taken into account. For aducanumab, this is estimated at $ 50,000 per patient per year. There are more than two million people with Alzheimer’s disease with mild cognitive impairment and mild dementia. If a quarter of respondents choose to take the drug, that’s $ 25 billion a year – excluding the cost of the PET scans and the neurology / radiology teams to monitor side effects. Since most people with Alzheimer’s disease are on Medicare, we will all share that cost.
In addition, Dr. Joel Perlmutter, a neurologist at Washington University in St. Louis and a member of the FDA advisory committee, said fewer people would want to participate in a study of a novel drug if the FDA approves aducanumab – and that would likely delay approval of better drugs.
What other treatments are there if they are not approved?
There are many other treatments for Alzheimer’s that are also being developed. Drugs that remove dew – the implications of Alzheimer’s disease – are being tested. Flashing light treatments to induce certain brain rhythms can protect the brain. Other treatments change the microbiome of the intestines or other parts of the body. Drugs are being developed that alter nitric oxide – a gas that has important functions in brain health. After all, in my lab we develop strategies to help people with mild Alzheimer’s disease and mild cognitive impairment remember things better because, in the end, this is the most important thing.