New Alzheimer's Drug ~ Off Target

 

The newly-approved drug, Aduhelm, is not a treatment or cure for Alzheimer’s Disease [AD]. Scientists do not know whether AD is caused by a virus, infection, genetic, lifestyle, environment, or a combination of these. Or something else entirely.

    Dr. Claudia Kawas, M.D. and chief investigator of the NIH-funded 90+ Study at the University of California, Irvine, was interviewed on 60 Minutes in 2014. It was aired again as an update on Sunday, 6 June 2021, and sections have been excerpted below. She suggests that science is fixated on “one thing” and ignoring factors that are emerging from other studies.

    Kawas and her team examined the brains of participants [named below] and also examine brains post-mortem. In half of the cases, scientists found people with healthy brains despite having been diagnosed with AD. Conversely, they found pathology in the brains of participants who died with their cognitive functioning fully intact. Back in 2003, Dr. David Snowdon, chief investigator of the longitudinal Nun Study, found similar patterns of clinical expression: Plaques and tangles do not always result in cognitive decline. Some older adults who die fully intact show significant plaques and tangles in their brains at autopsy. And vice versa.

    From what I have reviewed, there is no justification for the approval of Aduhelm. Three separate studies with only 3,482 participants are not significant justification for a “treatment” drug for AD. Why? It is preemptive. We do not know the cause of AD, and therefore “treating” plaques and tangles have limited scientific merit. Agedoc

Excerpt from the 60-minute interview:  

Claudia Kawas: We're finding out that if you die without dementia in this age group about half the time you still have plaques and tangles in your head.

Lesley Stahl: No? So you can exhibit Alzheimer's and not have plaques and tangles half the time, and the reverse--

Claudia Kawas: Both directions.

Lesley Stahl: --you're fine and you do have plaques and tangles? So what do you make of that?

Claudia Kawas: I mean one possibility is that plaques and tangles have nothing to do with it. But it might be that plaques and tangles are very, very important, but just a 90-year-old who has them and didn't develop thinking problems has some way of getting around them that maybe all the rest of us would like to know.

So now they're looking at people with no signs of dementia like Ruthy Stahl, Lou Tirado, Sid Shero, and Jane Whistler to see if they have plaques and tangles, but are not affected by them. There's a new type of PET scan that for the first time makes it possible to find plaques during life, so the 90+ study is engaged in the delicate task of putting 99-year-olds like Jane Whistler, into scanners. Sid Shero, at 92, hopped right in.

Claudia Kawas: Jane and Sid both have very, very, very good thinking, as you saw.

Lesley Stahl: Yes. Definitely.

Claudia Kawas: And it turns out that one of their scans is positive, and one is negative.

She showed them to us one on top of the other. Yellow and red indicate the presence of amyloid plaque.

Claudia Kawas: So this is Miss Whistler, and this is Mr. Shero.

Lesley Stahl: Well, I'm surprised--

Claudia Kawas: Sid Shero--

Lesley Stahl: --having talked to him, that I'm seeing yellow and red here. Kind of stunning.

So what does that mean for Sid? The positive scan means statistically he's at greater risk of cognitive decline, but Dr. Kawas says the fact he's doing so well in spite of the plaque in his brain, and his stroke -- means he may have that something protective and special that could help the rest of us. She says they'll be keeping a close watch on him.

Lesley Stahl: If it's unclear that the pathology hooks up with what you're seeing, what does that mean in your mind?

Claudia Kawas: I think we're looking for too simple an answer. I think we want one thing to explain Alzheimer's. Look at something different. Like what makes skin wrinkle. Well, I mean, getting older makes skin wrinkle. Being in the sun too much makes skin wrinkle. Not taking care of your diet and they put them all together and they all contribute. And I think it might turn out to be the same for our thinking, especially in late life, that it's not just Alzheimer's pathology from plaques or not just microinfarcts, but the number of these hits that you take. And after a while you can't withstand them all.

Resources:

Begley, S. Their brains had the telltale signs of Alzheimer’s. So why did they still have nimble minds, 11/14/2016. Stat. https://www.statnews.com/2016/11/14/alzheimers-brain-amyloid-plaque/

George, J. Controversial Alzheimer’s Drug Wins FDA Approval, 6/7/21.  MedPage Today. Retrieved from https://www.medpagetoday.com/neurology/alzheimersdisease/92960?xid=NL_breakingnewsalert_2021-06-07&eun=g1613630d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=AducanumabFDAAlert_060721&utm_term=NL_Daily_Breaking_News_Active

New insights from the Study of People Age 90 and Above, 11/23/2020. UCI Mind. Retrieved from https://www.mind.uci.edu/new-insights-from-study-of-people-age-90-and-above/

Snowdon, D.A. (2003). Healthy aging and dementia: findings from the Nun Study. Annals of Internal Medicine. Retrieved from https://pubmed.ncbi.nlm.nih.gov/12965975/

 

Why some people with brain markers of Alzheimer’s have no dementia, 8/17/2018. Science News. https://www.sciencedaily.com/releases/2018/08/180817093810.htm

 

U.S. Food & Drug Administration. FDA Grants Accelerated Approval for Alzheimer’s Drug, 6/7/2021. https://www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-alzheimers-drug

 

For Immediate Release:

June 07, 2021

Today, the U.S. Food and Drug Administration approved Aduhelm (aducanumab) for the treatment of Alzheimer’s, a debilitating disease affecting 6.2 million Americans. Aduhelm was approved using the accelerated approval pathway, which can be used for a drug for a serious or life-threatening illness that provides a meaningful therapeutic advantage over existing treatments. Accelerated approval can be based on the drug’s effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients, with a required post-approval trial to verify that the drug provides the expected clinical benefit. 

“Alzheimer’s disease is a devastating illness that can have a profound impact on the lives of people diagnosed with the disease as well as their loved ones,” said Patrizia Cavazzoni, M.D., director of the FDA’s Center for Drug Evaluation and Research. “Currently available therapies only treat symptoms of the disease; this treatment option is the first therapy to target and affect the underlying disease process of Alzheimer’s. As we have learned from the fight against cancer, the accelerated approval pathway can bring therapies to patients faster while spurring more research and innovation.”

Alzheimer’s is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually, the ability to carry out simple tasks. While the specific causes of Alzheimer’s disease are not fully known, it is characterized by changes in the brain—including amyloid plaques and neurofibrillary, or tau, tangles—that result in loss of neurons and their connections. These changes affect a person’s ability to remember and think. Aduhelm represents a first-of-its-kind treatment approved for Alzheimer’s disease. It is the first new treatment approved for Alzheimer’s since 2003 and is the first therapy that targets the fundamental pathophysiology of the disease.

Researchers evaluated Aduhelm’s efficacy in three separate studies representing a total of 3,482 patients. The studies consisted of double-blind, randomized, placebo-controlled dose-ranging studies in patients with Alzheimer’s disease. Patients receiving the treatment had significant dose-and time-dependent reduction of amyloid beta plaque, while patients in the control arm of the studies had no reduction of amyloid beta plaque.

These results support the accelerated approval of Aduhelm, which is based on the surrogate endpoint of reduction of amyloid beta plaque in the brain—a hallmark of Alzheimer’s disease. Amyloid beta plaque was quantified using positron emission tomography (PET) imaging to estimate the brain levels of amyloid beta plaque in a composite of brain regions expected to be widely affected by Alzheimer’s disease pathology compared to a brain region expected to be spared of such pathology. 

The prescribing information for Aduhelm includes a warning for amyloid-related imaging abnormalities (ARIA), which most commonly presents as temporary swelling in areas of the brain that usually resolves over time and does not cause symptoms, though some people may have symptoms such as headache, confusion, dizziness, vision changes, or nausea. Another warning for Aduhelm is for a risk of hypersensitivity reactions, including angioedema and urticaria. The most common side effects of Aduhelm were ARIA, headache, fall, diarrhea, and confusion/delirium/altered mental status/disorientation.  

Under the accelerated approval provisions, which provide patients suffering from the disease earlier access to the treatment, the FDA is requiring the company, Biogen, to conduct a new randomized, controlled clinical trial to verify the drug’s clinical benefit. If the trial fails to verify clinical benefit, the FDA may initiate proceedings to withdraw approval of the drug.

Aduhelm was granted Fast Track designation, which seeks to expedite the development and review of drugs that are intended to treat serious conditions where initial evidence showed the potential to address an unmet medical need. 

Aduhelm is made by Biogen of Cambridge, Massachusetts.