For decades, attempts to treat or slow Alzheimer's disease (AD) — a brain disorder that causes dementia through damage to brain cells and other changes in the brain — have been dispiriting failures. America's aging baby boom population, among other demographic and historical factors, is expected to increase the number of Americans with the disease. Currently, around 55 million people worldwide have the condition — roughly the population of Colombia — while 500,000 new cases are diagnosed in the U.S. each year.
But two new and one potential U.S. Food and Drug Administration (FDA) approvals of drugs might be a sign that the dominant theory of the disease, long disappointing, is panning out at last. The drugs work by removing a substance found in the brains of people with the disease, but it remains to be seen whether this is the answer to AD's devastating and ultimately fatal symptoms of cognitive decline.
"Our hope is that these are firsts for our field," Dr. Maria Carrillo, chief science officer of the Alzheimer's Association, told Salon in a video call about the new and upcoming medication approvals.
First there was aducanumab (sold as Aduhelm by Biogen), approved by the FDA in June 2021. The first new drug for Alzheimer's in twenty years, it's a monoclonal antibody given as an infusion once a month to patients with mild cognitive impairment or dementia. Aducanumab targets beta-amyloid plaques — hard accumulations of the protein between neurons — a phenomenon found in the brains of people with AD, as well as in people who died without ever exhibiting signs of the disease.
Despite this seeming breakthrough, a big question remains: how well does the drug actually work? Although aducanumab breaks up these clumps of protein, there isn't evidence that it changes the course of the disease, nor that it slows cognitive decline in a clinically significant way. But it's the first drug to target the processes that are believed to lead to Alzheimer's.
Controversies around this approval included the resignation of three members of the FDA committee that advised in November of 2020 against authorizing the drug without further study.
Two phase III trials for aducanumab were halted in March 2019 following a "futility analysis," meaning it didn't seem likely that continuing the trials would find it worked any better than placebo. But by October of that year, researchers reported a small cognitive benefit from higher doses in reducing the formation of beta-amyloid plaques in one of the studies, which allowed the drug to receive FDA fast-track approval.
This means full approval will only come after successful post-approval studies conducted by Biogen. Controversies around this approval included the resignation of three members of the FDA committee that advised in November of 2020 against authorizing the drug without further study, after the agency went ahead and approved it the following year.
Rob Howard, a professor of old age psychiatry at University College London, told MedPage Today at the time that "Regrettably, the FDA has ignored high quality scientific evidence of non-efficacy provided by the large and carefully conducted phase III studies. They've effectively approved an expensive placebo with unpleasant side effects on the basis of action against brain amyloid levels, an action that has already been shown to have little or no effect on cognitive and functional decline with this and earlier agents."
To this day, critics remain unhappy about the FDA approvals for reasons of effectiveness, risk and its extremely high cost. But there are other options for Alzheimer's.
Next there's lecanemab (sold as Leqembi), approved just this spring, the first Alzheimer's drug to show an impact on disease progression. However, the benefit this confers, on average, is slight, and in fact it might be hard to say if an individual patient was experiencing benefit or not.
Like its predecessor, lecanemab has proven controversial. Of the 1,795 participants in the clinical trial that led to accelerated approval for the drug, some thirteen percent experienced dangerous brain swelling or bleeding, with two deaths linked to brain bleeds. This makes it extremely hard to weigh unquantifiable benefits against a real risk of harm. Even worse, those who are genetically predisposed to Alzheimer's or who are taking blood-thinning medications are at greater risk.
Other processes that seem to be involved in AD include insulin resistance, immune dysfunction, neurovascular problems, hypertension (which can cause beta-amyloid build-up in the brain) and inflammation. Repurposed drug candidates targeting these processes that are being studied by scientists range from Viagra to the diabetes medication metformin. Carrillo also notes that her organization is involved in other areas of research, including lifestyle prevention.
Of the 1,795 participants in the clinical trial, some thirteen percent experienced dangerous brain swelling or bleeding.
Still, the association, which is the main research-involved Alzheimer's organization in the United States, sees amyloid plaques and misfolded neurofibrillary proteins (called tau tangles) as not just associated with AD, but as early markers of future disease. The goal of course is to prevent Alzheimer's before it starts, but failing that, to turn it from a terminal disease to a manageable condition.
"The core underlying biology are beta-amyloid and tau tangles," Carrillo asserted.
Hence their excitement about the third new medication, Eli Lilly's donanemab, which has no brand name yet. Like the others, donanemab targets specific parts of the process of beta-amyloid forming clumps or plaques in the brain. Trial results published in July in the journal JAMA showed significant impact on clinical progression of the disease after 76 weeks in patients who already showed both mild Alzheimer's symptoms and the characteristic accumulation of amyloid plaques and tau tangles.
For this reason, the Alzheimer's Association is advocating for the same speedy approval and access to the drug. But again, critics urge greater caution and diligence in not letting approvals run ahead of the evidence for efficacy and safety (it caused brain swelling in nearly a quarter of patients who received it, and many stopped due to nausea).
Expensive antibody-driven therapies like Leqembi allow drug companies to recoup their investment in the short term — even if the drugs later prove essentially useless.
One such critic is Gregg Gonsalves, an associate professor of both epidemiology and law at Yale and a researcher on public health and health equity (not, he stresses, an Alzheimer's researcher like his fellow critics of the beta-amyloid clearing drugs). Gonsalves argues that expensive antibody-driven therapies like Leqembi allow drug companies to recoup their investment in the short term — even if the drugs later prove essentially useless. It's a strategy that promotes the idea that any drug is better than no drug (if only for companies' bottom lines), something most patients facing eroding cognition would be likely to support, if only out of desperation.
Gonsalves is a veteran of the '80s struggle of patients to secure access to new, still-experimental drugs for AIDS — while ensuring they actually worked and carried low risks. Back then, that involved a parallel track process. Interestingly, it was proposed by then National Institute of Allergy and Infectious Disease director Anthony Fauci, who many now recognize for his work during the COVID-19 pandemic, and pushed for by activists like Gonsalves. It allowed certain AIDS patients to be given access to experimental drugs without interrupting the ongoing clinical trials process.
"What we have now is companies saying the only way you're gonna get these drugs is if you push the FDA to approve them. So basically, they're holding patients hostage."
From the point of view of activists like Gonsalves, this represented a bargain: "we would get drugs not on the market that showed potential clinical benefit with the caveat that within the very short term you can tell us that the drugs actually had clinical effect."
By contrast, "What we have now is companies saying the only way you're gonna get these drugs is if you push the FDA to approve them. So basically, they're holding patients hostage," Gonsalves said.
Dr. Carrillo doesn't see it that way at all, noting that the drugs have met endpoints established years earlier in the process through negotiation between the FDA and the drug companies. And she points out that even the possibility of a few months of delayed progression of the disease as a result of being able to access this medication — even though in an individual patient it might be hard to know if it can be attributed to it or not — may be incredibly meaningful.
We need your help to stay independent
Critics also point to the long history of beta-amyloid research failures, and even to fraudulent work, including tampering with and cut-and-pasting of images in an important and highly-cited 2006 paper to make the results — which showed one type of beta-amyloid protein as causing Alzheimer's in rats — appear stronger. Still, although this and other data irregularities and conflicts of interest don't mean that beta-amyloid plaques and tau protein tangles are irrelevant. Not at all — still the question remains what exactly is going on, and whether or not they are driving the development of AD.
And for that, despite patients' and families' natural eagerness for treatments, we may need far more basic research — something everyone in the field agrees on.
"We don't need hope," said Gonsalves. "We need drugs that work."
