Friday, November 13, 2020

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

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 decide by March 2021, based on its own analysis of clinical trial data and an advisory panel’s review of the evidence.

How does the drug work?

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

Will the FDA’s decision be important?

If aducanumab works, it would be the first drug that actually slows down the progression of Alzheimer’s. That means we could possibly turn Alzheimer’s from a fatal disease into one that people could live with for many years, in the same way that people are living with cancer, diabetes, and HIV/AIDS.

For researchers, it means that more than 20 years of scientific work, which suggests that removing amyloid from the brain can cure Alzheimer’s, may be correct. But many of us have begun to doubt this theory, because trial after trial has shown that amyloid could be cleared from the brain but clinical disease progression was not altered.

So, does the drug work?

I attended the day-long FDA hearing on November 6, 2020, and also independently reviewed all the publicly available data for aducanumab. There was one small (phase 2) clinical trial to assess efficacy and side effects, and two large (phase 3) clinical trials to assess effectiveness, side effects, safety, and how the drug might be used in clinical practice. The small phase 2 study and one of the large phase 3 studies were positive, meaning that the drug worked to slow down the decline of thinking, memory, and function that is usually impossible to stop in Alzheimer’s. The other large study was negative. Hmm… Is two out of three positive studies good enough? Biogen’s scientific team had many plausible explanations for why that one study was negative.

The advisory panel, however, was not convinced. They pointed out that phase 2 studies are always positive, because otherwise you wouldn’t move on to phase 3, so that study doesn’t count. They also pointed out that, although you can think of the positive phase 3 study as the “true” one, and try to understand why the negative one failed (which is what Biogen did), you could equally think of the negative study as the true one, and try to understand why the other one showed positive results.

The advisory council was concerned that there was “functional unblinding” in both studies, because large numbers of participants in the treatment group needed additional MRI scans and physical exams to deal with side effects, which did not occur in the placebo group. Hence, if you were asked to come in for an extra MRI scan, you knew that you were on the real drug. This knowledge may have influenced the responses subjects and their family members gave regarding how they were doing, which were the primary outcomes of the study.

Should the FDA approve it?

To determine if a drug should be approved, many factors need to be considered. First is whether it works and, as discussed above, there are questions regarding its efficacy. You also have to consider side effects and other burdens on patients, families, and society.

You first need an amyloid PET scan to be sure you have the amyloid plaques of Alzheimer’s. Then to take the drug, you need an intravenous infusion every four weeks — forever. Thirty percent of those who took the drug had a reversible swelling of the brain, and more than 10% had tiny brain bleeds. These side effects need to be watched closely by an expert neurology/radiology team who understand how to monitor for these events, and know when to pause or stop the drug.

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

Cost also needs to be considered; for aducanumab, this is estimated at $50,000 per year per patient. There are more than two million people with Alzheimer’s in the mild cognitive impairment and mild dementia stages. If one-quarter of those decide to take the drug, that’s $25 billion each year — not including the cost of the PET scans and the neurology/radiology teams to monitor side effects. Since most people with Alzheimer’s disease have Medicare, we will all share this cost.

Moreover, Dr. Joel Perlmutter, a neurologist at Washington University in St. Louis and member of the FDA’s advisory committee, argued that if the FDA approves aducanumab, fewer people would want to participate in a trial of a novel medication — and that would likely delay the approval of better medicines.

If it’s not approved, what other treatments are out there?

There are many other treatments for Alzheimer’s that are also being developed. Drugs that remove tau — the tangles of Alzheimer’s — are being tested. Treatments using flashing lights to induce specific brain rhythms may protect the brain. Other treatments change the microbiome of the gut or other parts of the body. Drugs are being developed which alter nitric oxide — a gas that has critical functions in brain health. Lastly, in my laboratory, we are developing strategies to help individuals with mild Alzheimer’s and mild cognitive impairment to remember things better, because, at the end of the day, that’s what matters most.

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