A new Alzheimer’s drug: From advisory panel to FDA — what’s at stake here? – Harvard Health Blog

It was more than 17 years since the FDA last approved an Alzheimer’s disease drug. Will Biogen’s drug called aducanumab end this drought? The FDA will decide by March 2021, based on its own analysis of clinical trial data and review of the evidence by an advisory committee.

How does the drug work?

Aducanumab is a monoclonal antibody designed in the lab to stick to the amyloid molecule that forms plaques in the brains of people with Alzheimer’s disease. Most researchers believe that plaques form first and damage brain cells, causing tau tangles to form inside, killing the cells. Once aducanumab sticks to the plaque, your body’s immune system kicks in and removes the plaque, thinking it is a foreign invader. The hope and expectation is that once the plaques are removed, brain cells will stop dying, and thinking, memory, function, and behavior will stop deteriorating.

Will the FDA’s decision matter?

If aducanumab works, it would be the first drug that actually slows the progression of Alzheimer’s disease. This means that we might be able to turn Alzheimer’s disease from a deadly disease into one that people could live with for many years, the same way people live 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 may cure Alzheimer’s disease, may be correct. But many of us began to doubt this theory, as trial after trial showed that amyloid could be cleared from the brain but the clinical progression of the disease was not altered.

So, does the drug work?

I attended the one-day FDA hearing on November 6, 2020 and also independently reviewed all publicly available data on aducanumab. There has been one small clinical trial (phase 2) to assess efficacy and side effects, and two large clinical trials (phase 3) to assess efficacy, side effects, safety, and how the drug is could be used in clinical practice. The small phase 2 study and one of the large phase 3 studies were positive, meaning the drug helped slow the decline in thinking, memory and function that is usually not possible to control. ‘stop in Alzheimer’s disease. The other big study was negative. Hmm… are two out of three positive studies enough? The Biogen science team had many plausible explanations as to why this study was negative.

The advisory committee, however, was not convinced. They pointed out that phase 2 studies are always positive because otherwise you wouldn’t go to phase 3 so this study doesn’t count. They also pointed out that while you can think of the positive Phase 3 study as the ‘real’ and try to understand why the negative failed (which Biogen did), you can also regard the negative study as the ‘true’. true, and try to understand why the other has given positive results.

The advisory board was concerned about the “functional blindness” in both studies, as a large number of participants in the treatment group needed additional MRIs and physical exams to deal with side effects. that did not occur in the placebo group. Therefore, if you were asked to come in for an additional MRI, you knew you were taking the real medicine. This knowledge may have influenced the responses subjects and their family members gave about how they were doing, which were the main findings of the study.

Should the FDA approve it?

In determining whether a drug should be approved, many factors must be taken into account. The first is whether it works and, as noted above, questions arise as to its effectiveness. You also need to consider side effects and other burdens on patients, families, and society.

You first need an amyloid PET scan to make sure you have Alzheimer’s amyloid plaques. Then, 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 10% had tiny bleeding from the brain. These side effects should be monitored closely by a team of neurology / radiology experts who understand how to monitor these events and know when to pause or stop the medication.

Another factor to consider is the size of the benefit. Here it was quite small. Looking at the two objective measurements, in the positive trial the high dose made a 0.6 point change on the Mini-Mental State Examination (MMSE) to 30 points. On the 85-point Alzheimer’s Disease Rating Scale – Cognitive-13 subscale (ADAS-Cog-13), the high dose made a change of 1.4 points. In the negative trial, analogous results were -0.1 (worsening) for MMSE and 0.6 for ADAS-Cog-13.

The cost must also be taken into account; for aducanumab, this is estimated at $ 50,000 per year per patient. There are over two million people with Alzheimer’s disease in the stages of mild cognitive impairment and mild dementia. If a quarter of those decide to take the drug, that’s $ 25 billion each year – not including the cost of PET scans and neurology / radiology teams to monitor side effects. Since most people with Alzheimer’s disease have Medicare, we’ll all share that cost.

Additionally, Dr. Joel Perlmutter, a neurologist at Washington University in St. Louis and a member of the FDA advisory board, argued that if the FDA approves aducanumab, fewer people would want to participate in a trial. a new drug – and that would probably delay approval of better drugs.

If not approved, what other treatments are there?

There are many other treatments for Alzheimer’s disease that are also in development. Drugs that remove tau – the tangles of Alzheimer’s disease – are being tested. Treatments that use flashing lights to induce specific brain rhythms can protect the brain. Other treatments change the microbiome in the gut or other parts of the body. Drugs are being developed that modify nitric oxide – a gas that has essential functions for brain health. Finally, in my lab, we’re developing strategies to help people with mild Alzheimer’s disease and mild cognitive impairment remember things better, because, in the end, that’s what matters most.

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Jothi Venkat

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