Alzheimer’s drug approved Monday by FDA raises questions for journalists

About Liz Seegert and Tara Haelle

Liz Seegert (@lseegert) is AHCJ’s topic leader on aging. Her work has appeared in NextAvenue.com, Journal of Active Aging, Cancer Today and other outlets. Tara Haelle (@TaraHaelle) is medical studies core topic leader, helping journalists translate evidence into accurate information.

Beakers

Photo: Knowing Roger via Flickr

Part two of two parts; the first ran Thursday, June 10.

There’s still a great deal we don’t yet understand about aducanumab (brand name Aduhelm) or its longer-term effects. If early-stage Alzheimer’s disease is diagnosed in time for someone to begin taking the drug, are the potential adverse effects cumulative? Could long-term toxicity build up over time? How long might the drug stave off development of the plaque, and how long might it slow down the process of cognitive decline, if at all, and how will clinicians assess its benefit in patients?

Since Biogen has argued that longer follow-up was necessary to show its benefit, the question is how long is long enough to determine whether someone taking aducanumab is receiving clinical benefit—or whether someone is taking a very expensive drug they don’t need. Other questions include:

  • Can the plaque adapt to grow despite the antibody’s presence?
  •  Will those with mild disease need to be on this expensive drug for years, or possibly the rest of their lives?
  •  What might happen if a patient stops the drug? Could stopping treatment with aducanumab lead the plaques to redouble their growth, much as ending steroid therapy can sometimes cause a flare of certain rheumatic conditions that the steroids are designed to control?

But the precedent this approval sets for future Alzheimer’s therapeutic candidates raises other important questions. To determine whether a drug offers enough benefit to make a noticeable difference in patients’ lives (clinical significance), it’s necessary to identify the minimum clinically important difference (MCID)—the least amount of improvement needed to justify claims of a benefit.

“There is no consensus on MCIDs for outcomes in Alzheimer’s disease trials, but the U.S. Food and Drug Administration’s consideration of aducanumab clinical trials data has exposed the uncertainty of the clinical meaning of statistically significant but small improvements,” wrote three researchers in a recent Lancet Psychiatry review. “Without MCIDs, sponsors are motivated to power trials to detect statistical significance for only small and potentially inconsequential effects on clinical outcomes.”

In other words, if sponsors, such as Biogen, are not beholden to show a prespecified minimum benefit for their drug, they may design trials that only result in the smallest statistically significant difference possible, without regard to whether the improvement makes a real difference in patients’ lives.

Some are wondering why the FDA went against its own advisory panel, as well as outside experts’ recommendations. Did they cave to pressure from desperate families or lobbying from the Alzheimer’s Association and other advocacy groups? Or, as Caleb Alexander, an internist and professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health and Michael Greicius, a professor of neurology at Stanford and director of the Stanford Center for Memory Disorders pointed out in a New York Times opinion piece, was there “an unusually close collaboration between the F.D.A. and Biogen before and during the agency’s review?”

So many questions remain for reporters to explore and perhaps for those with the investigative resources to dig deep. Currently, neither of the studies appear to have been published in full, so the only data available is what’s been shared by press release — never a reliable source for data — and the slides from the FDA’s clinical review of efficacy.

“One has to fully empathize with people with Alzheimer’s and their families, desperately looking for treatment,” said Dilip Jeste, MD, a neuroscientist and director of the Sam and Rose Stein Institute for Research on Aging at UC San Diego. “At the same time, we have to be careful that we don’t offer false hope.”

As Douglas Scharre, MD, a neurologist and director of the division of Cognitive Neurology at Ohio State Wexner Medical Center pointed out, aducanumab is only one step along the path to discovering how to prevent or slow down progression of Alzheimer’s.  Biotech startup Alztheon has  just started phase 3 trials on its ALZ-801 drug, which targets people with the apoE4 gene — another risk factor for the disease (more on this soon).

For more on reporting about aducanumab, and Alzheimer’s Disease:

  • STAT’s Elizabeth Cooney has put together a terrific FAQ on aducanumab.
  • The National Institute on Aging has wealth of information about Alzheimer’s Disease — from the basic biology to current research.
  • The new federal Alzheimer’s disease web site has backgrounders about the disease, information on clinical trials, resources for families and caregivers and a list of national research centers.
  • The Alzheimer’s Association issued a reaction statement on aducanumab approval; their website is a good source for finding current data on Alzheimer’s disease and related dementias.

3 thoughts on “Alzheimer’s drug approved Monday by FDA raises questions for journalists

  1. Ruth Taber

    The Kefauver amendment in 1962 was supposed to take care of problems like Biogen.
    Preying on families with dementia problems is pathetic. As a full time caregiver for my 94 year old former physician (and author of the 1969 book Proving New Drugs) now suffering from dementia I put Biogen in a class of snake oil hucksters. $56,000 annually for a drug that hasn’t been proven safe/effective? And the Biogen CEO says it’s a “fair” price!
    No different than the stuff marketed every night on tv – lovely couples smiling saying that they’ve taken these “magic potion” for years and their memory is great. And their control group? Money, money, money…….makes the world go round.

  2. Edward Blonz

    Excellent work on these articles.

    Some additional perspective on Aduhelm (aducanumab). Brain scans found that it is effective at reducing amyloid beta (A-beta) in the brain. However, it is essential to appreciate that a drug that can provide a non-selective quantitative reduction in A-beta does not necessarily translate to a qualitative – a functional improvement – to cognition.

    For perspective, consider neuroplasticity, the ability of the brain to utilize different pathways to store and retrieve information.

    One application associated with neuroplasticity is the situational adjustment to use an alternate retrieval pathway when the habitual route is no longer available (sort of like having to use a different way to get to your destination if there is an accident blocking your usual route).

    Functional neuroplasticity can allow an individual to not be aware that anything is wrong during the initial stages of Alzheimer’s disease (AD), a disease that can take decades before clinical symptoms manifest. It is an insidious process given that memory lapses are common in aging, and, for most, this is not an indication that AD is on the horizon. One typical manifestation is a frustrating delay in recalling information “we know we know.“ We all have experienced not being able to remember something “we should,” but at a later time that info pops into our consciousness. It is an example of how the brain continuing its assignment to locate the sought-after information – and elevate it to awareness even after we stop conscious recall efforts.

    If it is AD pathogenesis at play, memory lapses continue and become more widespread. By the time cognitive impairment becomes too extensive to deny, there will usually be a significant presence of A-Beta, (typically with another manifestation, tau tangles) in the CNS. At this point, neuroplasticity has already done all it can to retrieve around the impairments.

    Can aducanumab help at this point?

    Computer analogy: When you erase a file or folder by name, it wipes out the detailed entries in the drive directory that lists where all information can be found. That information is still there, but the loss of the directory makes it that it cannot be retrieved. (There are programs that can retrieve and reassemble info without a directory, which is a key reason you should format any drive containing secure information before they are discarded.)

    Consider our memory as having a directory system, perhaps similar to a locator road map, that makes an entry when information is stored, and provides guidance when recall is desired. The uneven clinical findings relating to aducanumab may be explained because its generic reduction of A-beta has limited ability to improve information handling and retrieval.

    But perhaps most critical, aducanumab does not address the reason why the A-beta has been forming in the first place. There is also the possibility that a quantitative reduction of A-beta could stimulate beta-secretase (BACE1) – the enzyme that makes A-beta – to produce more. There have been experimental drugs to inhibit BACE1, but these never proved effective – likely because the body will make more BACE1 to meet the drive to make A-beta.

    It has long been my take that the evidence suggests A-beta begins to form as a result of the chronic, progressive, neuroenergetic deficit; this can be facilitated by a variety of genetic factors and co-morbidities, getting misread as resulting from microbial action in the CNS (with A-beta being the endogenous antimicrobial that gets the call to make things better). This is the kindling for AD pathogenesis, and until the neuroenergetic deficit is sated, the best we can do is slow things a bit. (See my paper at: https://blonz.org/96z3e)

  3. Liz Seegert

    Hi Ed,
    Thanks for your thoughtful and insightful comments. I like your analogies. There is still so much we don’t know about this drug, about Alzheimer’s disease in general and about brain function. As you know, these are only a few reasons it’s taken so long to get to this point. The drug may work for some people, sometimes, but one has to wonder about the potential risks vs benefits vs costs. We also don’t know yet about Medicare coverage, which could put this drug out of reach for many people if a 20% copay becomes the norm. Insurance topic leader Joe Burns is on top of this question. ”

    Another huge concern (one of many) is that desperate patients/families will insist on using this drug, although it may not be right for their situation. Then, they will be even more devastated if it doesn’t work. As Dr. Jeste said, it’s up to health reporters (and other experts) to put this in perspective as best we can, and not to offer false hope. I understand the desire to try something, anything, to make the situation better. I just fear that a lot of money will be spent on something offering marginal benefit, at best.

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