In histories written about Alzheimer’s disease, 2019 will turn up as a landmark year, one in which researchers, clinicians, patients, and their families were whipsawed from crushing despair to giddy optimism.

The year unfolded with a string of disappointments. One of the biggest came on March 21 when Boston-based Biogen announced it had pulled the plug on two clinical trials of aducanumab, a promising treatment for individuals with Alzheimer’s disease. The drug had failed a “futility analysis,” meaning it would not be able to achieve its objectives. More bad news came in the weeks and months to follow. An entire class of drugs called BACE inhibitors (pronounced “base” as in baseball) had failed.

By the annual international meeting of Alzheimer’s investigators in Los Angeles in July, a pervasive disappointment was enmeshed with embarrassment, heightened by the meeting’s timing on the 50th anniversary of the successful Apollo mission to the moon. A half a century ago, we were able to send someone to the moon, have him walk about, and return home but, despite all our time and effort and money since then, despite all the advances in genomics, proteomics, and other “omics,” despite precision medicine, we haven’t been able to make a dent in this disease.

advertisement

Five months later, at the Clinical Trials in Alzheimer’s Disease (CtAD) conference on Thursday, December 5, I and other Alzheimer’s researchers gathered once again in California. This time the mood was giddy. The crowd in the Indigo ballroom at the San Diego Bayfront Hilton behaved more like a gathering at an awards ceremony than an early morning session at a scientific meeting. There were hugs, laughter, and backslaps.

Why the change? Biogen had somehow flipped the switch on aducanumab. According to its reanalysis of the clinical trial data, aducanumab wasn’t a flop but a success, and the company had decided to ask the FDA to approve aducanumab for the treatment of Alzheimer’s disease.

advertisement

Samantha Budd Haeberlein, who heads late stage clinical development for Alzheimer’s disease at Biogen, spent 45 minutes explaining the complicated events leading up to and following the futility analysis. One key message was that the company had gathered more data in the three months between the start of the futility analysis and the decision to end the trial, but that data hadn’t been part of the analysis. After adding it into the analysis, a different picture emerged: The highest dose of aducanumab just might slow down the cognitive and functional decline caused by Alzheimer’s disease.

The much-used phrase “a shot heard ’round the world” comes from the dawn of the American Revolution. It evokes when war first broke out in and around Boston between British troops and American rebels. It sent a message to Britain’s George III and every other monarch and the aristocracies they sustained: Your days are numbered.

Biogen’s reinterpretation of its data must still be subjected to FDA and peer review, of course. But if it holds up, I believe that aducanumab will be a shot heard round the world: the beginning of the end of Alzheimer’s disease.

It won’t end Alzheimer’s because it cures the disease. It doesn’t do that. Aducanumab appears to slow, but does not stop, and certainly does not reverse, patients’ cognitive and functional declines. Given the past disputes over the effects of earlier Alzheimer’s drugs, experts will vigorously debate aducanumab’s benefits.

But as long as the benefits are judged to outweigh the risks, aducanumab won’t just treat individuals with Alzheimer’s disease. It will treat our Alzheimer’s culture.

When a disease is common, has unknown causes, and no effective treatments, stigma flourishes. The stigmas of Alzheimer’s are intense. They cause people to avoid seeking a diagnosis. They nudge some clinicians to hide the diagnosis. Patients who do learn their diagnosis experience self-stigma. They start to doubt their abilities and worth to others. Friends disappear. Caregivers worry about the future.

Stigma causes all kinds of language games. When Ronald Reagan announced his diagnosis of Alzheimer’s disease, he in fact didn’t say he had it. In a handwritten letter to his fellow Americans in 1994, the Great Communicator explained, “I have recently been told that I am one of the millions of Americans who will be afflicted with Alzheimer’s disease.” The “will be” stands out. It distanced him from his diagnosis.

What makes aducanumab so powerful is that it targets one of the pathologies of Alzheimer’s disease, and it does so in persons who are not yet diagnosed with dementia. A bit of history is needed to explain this novel way of labeling people with Alzheimer’s disease and why it is so significant.

For much of the 20th century, Alzheimer’s disease and dementia were enmeshed. A person had to have dementia to be diagnosed with Alzheimer’s disease. This made sense. You have to be ill to have a disease.

Most of the participants in Biogen’s trials, however, did not have dementia. They had what’s called mild cognitive impairment, known widely as MCI. Characterized in 1999 by researchers at the Mayo Clinic, MCI describes changes in individuals’ cognitive abilities that, while noticeable and often annoying, are not disabling. They don’t have dementia, nor do they have normal aging. They’re sort of in between.

The reason why the field cared about MCI was that the Mayo team showed it was a risk factor for developing Alzheimer’s disease, like smoking or obesity. The Mayo investigators reported that an individual with MCI had about a 15% per year chance of declining from MCI to dementia.

One other event is important. In 2002, investigators at the University of Pittsburgh stunned the Alzheimer’s field when they announced the discovery of a radiotracer they called Pittsburgh compound B that could visualize amyloid in the brain of a living person. Before this, the only way to see this characteristic pathology of Alzheimer’s disease was with a brain autopsy. A person with dementia had to die so their caregivers could learn the cause of their dementia. Amyloid imaging ended that Gothic horror story.

Which brings me back to Biogen’s trials. Eighty percent of the participants did not have dementia. They had MCI and PET scans that showed elevated amounts of amyloid in their brains. Some Alzheimer’s experts label this as “prodromal Alzheimer’s disease,” others as “MCI caused by Alzheimer’s disease.” Still others prefer the blunt label “Alzheimer’s disease.”

Patients will reject each of these labels. There’s maddening ambiguity around what MCI actually is. It’s like a semi-boneless ham. The term Alzheimer’s disease is unacceptable to individuals with MCI. It is hidebound to dementia, which they do not have.

Alzheimer’s is the senility of the 21st century. Patients and their families will give their own names to what they have and why they are getting treated. Perhaps they’ll say they have abnormal amyloid or, in a word, amyloidosis.

This renaming is sensible. A drug that targets a pathology targets stigma. It offers some explanation for what’s wrong, the hope of treatment, and a means to rethink and even rename a disease.

The statin drugs that reduced cholesterol, first tested in the 1980s, recast heart disease into a test for “good” and “bad” cholesterol. After fluoxetine was baptized Prozac and psychiatrist and author Peter Kramer counselled America to listen to it, antidepressants recast depression. Prozac and its many cousins didn’t just treat American depression and anxiety. Being on Prozac transformed depression into a problem of serotonin balance. A stigmatizing mental illness became a near universal experience.

So too shall be the recasting of Alzheimer’s disease. Because aducanumab isn’t just a drug — it’s also an idea. Just like the American Revolution and the shot heard ’round the world.

Jason Karlawish, M.D., is a professor of medicine, medical ethics and health policy, and neurology at the University of Pennsylvania and co-director of the Penn Memory Center. He reports receiving grant support for Alzheimer’s clinical trials from Eli Lilly and Co. and Novartis.

  • To amplify on my previous comment. Aducanumab’s targets are patient with neurodegenertion (Loss Neurons) resulting from Tau fibrils and tangles. Once Tau becomes involved, amyloid is no longer an influence in decline progression (See evidence in the AN-1792 “Alzheimer Vaccine Trial – Halted in 2002) Aducanumab’s only effectivity might be for Asymptomatic Candidates before neurodegeneration begins.

    See more-visit
    https://alzheimersabcs.com

  • My wife suffering Alzimas. Taking Donitaz sr 23 and Qution 100 m. g. Can ensure better drug invention ?

  • I think that the possibility that this could work if? If they first flush the brain with anti blood clotting solution. Because from the very beginning this have been a cause and effect disease. Somewhere along the way, studies have shown that white cell blood clotting have been shown in some models and studies. The clotting of the white cells created blood flow problems. Think of it in the form of a fire hoes being turned into a garden hoes. Causing the once Tau and Beta=amyloid to be flushed from the system and out as waste. But, now because of the lack of the proper blood flow not all of the Tau and beta-Amyloid is flushed and away and over time accumulates of the Tau and BA. But that is not the only problems With late of proper blood flow, vessels begin to shrink that can be seen in the eyes and can cause brain shrinkage over time. over this same time the aging of time and the bodies of the older fight infection more causing the increase of the white cells being flooding the system causing more clotting. The reason most of these drugs don’t meet bench marks because they are trying to cure the effect and not the cause.

  • I have volunteered with dementia, Alz patients for 20 years. I would never take a medicine that prolongs Alzheimers…..i have seen people last 15 years with Alz….unable to live alone, needing constant supervision, then a slow long death. I would rather have cancer than Alzheimers. I am just being honest.

  • Great idea, and proper focus. Until we understand the cause, we can’t find the cure. And the other ethical concern that no one is addressing is that people with dementia should NOT be guinea pigs for drugs that target the brain.

  • I’m afraid this is just another example of how it is more profitable to develop treatments to manage disease than to develop a cure. Slowing the progress of Alzheimers to some undefined extent in some patients is hardly revolutionary. I have great respect for the biotech industry, but they do tend to exhibit group think once a disease target like amyloid is discovered despite evidence that amyloid is at best one factor among many in this disease. Perhaps incentivizing the biotech firms to focus on cures rather than disease management would break this bandwagon approach. For example, we could establish a policy that any firm that develops an actual cure for one of the top 10 most costly diseases gets to sell that treatment tax free whereas treatments that are not cures are taxed at the prevailing corporate tax rate. This would encourage more effort on a wider variety of R&D approaches.

    • This is another common myth about the pharmaceutical industry, that they secretly “know” the cure for cancer or the “cure” for alzheimer’s. This makes no sense. Potential targets are first elucidated in government-funded public research, and those are then followed up when pharmaceutical companies develop molecules to activate/inactivate those targets. It is a conspiracy theory of the largest scale ever to believe that research has been done, trials taken place, but a cure has been hidden. These diseases affect the researchers out there too, you think they would stay silent in order to help their company? There aren’t even very useful treatments of Alzheimer’s out there, so most companies are missing the boat on this “profitability of not curing the disease” entirely. Competition means that anyone who developed a cure would take away ALL the business from someone else whose drug merely slows progression. Not to mention, they would surely charge big bucks for a patent-protected, actual cure. Just look at the pricing for Solvaldi, a recent hepatitis cure (about $1000/pill, taken for 12 weeks).

  • I find many comment encouraging as to discouraging FDA approval of Aducanumab as a slowing treatment. However, I contend MABs have a role in prevention. Amyloid is not the killer of neuron. That is the role of Tau fibrils and tangles. Treating symptomatic patients to slow or delay AD needs an intervention For Tau fibrils and tangles, not amyloid. Biogen should approach the FDA with seeking approval for prevention of candidates who have not demonstrated Tau fibrils and tangles and inparallel run a trial to prove prevention. These candidates should be 45 to 55 (Asymptomatic and heridity background. Once symptoms appear, the brain has lost too many neurons (See Braak and Braak 1991 along with Teresa Gomex Ise et. al 1996. See my Aducanumab Story on my web site: https://alzheimersabcs.com
    Bruce Bauer
    Eighty Six year old Caregiver –> now in my nineteenth year caring for my wife.
    Author: ABC’S OF ALZHEIMER’S DISEASE: A SHARED REALITY BY ME AND MY SHADOW

  • Your reporting of Biogen’s latest results is alarmingly over-the-top and honestly makes me wonder what you’re reading. I’m a medical researcher and I see this latest move as unethical and not in the best interest of society. Biogen wants people who are showing only mild symptoms to take a heavy-duty drug for YEARS in the hopes that it might provide some relief from SOME relief against progression of the disease. It’s not a new drug, it’s the one that has already failed. It’s certainly not a game-changer, by any stretch. This is an act of financial desperation on Biogen’s part, and it will potentially lead millions of people down an expensive, wrong path, instead of focusing on lifestyle and nutrition, which the evolving science is pointing to as better preventative measures against dementia. I hope your readers do more research before running to the doctor and asking for this drug, and I sincerely hope other doctors don’t prescribe this drug without looking into other options for this vulnerable group of the population.

    • Lorrie B took the words right out of my mouth. Melodramatic analogies made ad nauseam only serve as flapping red flags of malarkey. This dishonest diatribe could have been summed up in one concise sentence: Unable to accept the fact that they held a losing lottery ticket, Biogen decides to alter the numbers and insist on being awarded the billion dollar prize. Their behavior is that of entitled, self-serving rich kids; nothing remotely resembling honorable war heroes.

    • Agreed. We are talking about a 23% DECLINE in the RATE of worsening symptoms, of people at the earliest stages, who likely are not progressing very fast yet. Yes, you can see this difference when analyzing very large groups of people, but an ordinary person taking this would not notice that their decline slowed down after taking this. They WILL notice that they keep getting worse. Until the point that they don’t understand what is going on around them anyway. And then you have to ask the question if they should still be taking a very expensive biological drug. Of course the patient will not even be able to make a decision, so I guess this would be up to whoever holds power of attorney.

Comments are closed.

Sign up to receive a free weekly opinions recap from our community of experts.
Privacy Policy