Hope, Hype, Consent and Alzheimer’s

By Johanna Ryan

A recent New York Times article told the troubling story of two women who died in a clinical trial of a new Alzheimer’s drug.

Jean and Genna

One in particular stayed on my mind.  Her name was Jean Terrien, and she was just about my age.  Like me, she lived in the Chicago area, perhaps a dozen miles up the road, and had been retired for just about a year.

Jean’s story had a lot to say about a topic much discussed on RxISK:  Informed consent—or the lack of it—when starting a new drug.

Jean did not have Alzheimer’s, but she was concerned about the disease, like lots of women our age.  She had more reasons to worry than most: She had already lost close relatives to Alzheimer’s.  It seemed to run in her family.  Now she was noticing some memory loss herself, enough to qualify as “mild cognitive impairment.”   So she volunteered as a research subject for a new drug called lecanemab, or Leqembi.  The study was run by the US biotech firm Biogen and Eisai Pharmaceuticals of Japan.

Before the study began, Biogen/Eisai gave Jean a few tests.  As it turned out, she had an inherited risk for Alzheimer’s: a gene called ApoE4.  One copy of that gene raises your chances of developing Alzheimer’s.  Jean had two copies, making her risk even higher.  But that’s not all:  People like her also face an increased risk of serious side effects on drugs like Leqembi.  It can cause brain bleeding and swelling which can be disabling and even fatal.

Thanks to their testing, Biogen/Eisai knew that.  But they didn’t tell Jean.  In September 2022, after her third infusion of Leqembi, she suffered an apparent stroke and was taken to a local emergency room.  The staff administered tPA, an anti-clotting drug commonly given as initial therapy for stroke.  Jean began screaming, and it took eight people to hold her down.  She was rushed to intensive care and placed on a ventilator.  Three days later she died.  She was 65.

Genna Lane, also a double-ApoE4 carrier, died that month under very similar circumstances, also after her third Leqembi infusion. Genna was enrolled at the Charter Research trial center in The Villages, the large Florida retirement community where she lived. Dozens of other subjects suffered severe brain bleeds and swelling.

Leqembi and Kisunla

In a similar Alzheimer’s drug trial, pharma giant Eli Lilly made the same choice to test subjects for ApoE4 without telling them their results or the extra risks they faced on its drug donanemab (Kisunla). In all, 274 double-carriers were enrolled in the Leqembi trial, and 289 in Lilly’s trial of Kisunla.

Leqembi was granted “accelerated approval” by the FDA in January 2023, and full approval in July 2023.  In July 2024, FDA granted similar approval to Kisunla.  The Prescribing Information listed the potential serious adverse effects and known risk factors, but left the final decision to each doctor’s judgment.  There was no exclusion for double-carriers like Jean and Genna.

How did these two drug companies get away with such an arrangement?

Alzheimer’s

Alzheimer’s is definitely a brain disease.  And it’s a fearsome one: unlike some forms of dementia, it is progressive and eventually fatal.  Left to run its course, it can steal everything you value—your reason, your personality and your closest relationships—before it ends your life.

However, we still don’t know what causes it.  A definitive diagnosis can only be made after death, based on a history of dementia and a finding of plaques in the brain formed by a protein called beta-amyloid.  For over 20 years, the search for a cause—and a potential cure—has centered on those plaques.   Leqembi is the latest in a series of monoclonal antibodies which bind to and remove amyloid plaques from the brain.

But while the drugs succeed in removing the plaques, none have been able to stop the disease, much less reverse it.  At most they’ve demonstrated only a slight decline in the rate at which patients go downhill.  Leqembi has been more successful than most.  While virtually all patients in the trial saw their scores on cognitive assessments decline after eighteen months, that decline was 27% slower for patients on Leqembi than in the placebo group.

Drug companies have touted those extremely modest results as buying precious time for patients—perhaps up to six months’ freedom from further decline.  But in fact it represents a mere 1.5 point advantage on an 18-point rating scale of cognitive abilities. It’s not at all clear this effect is big enough to make a real difference in daily lives—prolonging an ability to live at home or maintain relationships with loved ones, for example.

And after 20+ years of anti-amyloid drug development, a broader question remains:  Are the plaques the cause of the disease, or are they just a form of collateral damage?   Many older people have beta-amyloid plaques without showing any signs of Alzheimer’s—and some Alzheimer’s patients don’t have plaques.

After all, the association between falling leaves and the onset of winter in Chicago is pretty robust, too.  But no one claims that clearing the fallen leaves from our streets (or spraying trees with glue to keep the leaves in place) will delay the onset of winter.  The link between plaques and Alzheimer’s may be just that illusory—or at best only one of many factors.

In other words, Biogen/Eisai/Eli Lilly cannot promise (or even suggest) that their drugs will hold you together long enough to celebrate your grandchild’s graduation.  Nor can they warn you that without “treatment” you will be too impaired by that time to recognize your grandchildren.

A Dreadful Gamble

Arrayed against that faint hope of reprieve are the drugs’ potentially catastrophic side effects.  The worst are brain hemorrhages and swelling, re-branded by drug companies as  “ARIA” (or amyloid-associated imaging abnormalities).  ARIA may cause only mild symptoms or none at all, at least in the short run—but it can also be crippling or even deadly.  In recent trials 41% of patients on Leqembi experienced ARIA in some form.

The doctor who performed Jean’s autopsy found brain bleeding unlike any he’d previously seen. He explained that beta-amyloid had invaded the blood vessels in her brain, a condition called CAA – cerebral amyloid angiopathy.  Her initial stroke likely occurred when those vessels were inflamed and weakened by Leqembi’s amyloid-stripping action.  When the clot-busting treatment, tPA, was added, they simply burst.

“It was a one-two punch,” he told Science magazine.  “There’s zero doubt in my mind that this is a treatment-caused illness and death. If the patient hadn’t been on lecanemab she would be alive today.”

Such risks are by no means confined to double ApoE4 carriers like Jean and Genna.  CAA is fairly common in elders with dementia-related symptoms, and it can’t be reliably spotted even with sophisticated imaging studies.  As for anti-clotting drugs, they are widely prescribed to prevent stroke in seniors with common heart-rhythm abnormalities.

A still more common effect of plaque-stripping drugs is brain shrinkage or atrophy, which occurs faster on the drugs than on placebo.  No one can predict the exact impact of this atrophy on patients’ future decline—but no one has argued that brain atrophy is a good thing.

In short, some unlucky patients like Jean and Genna will die long before the disease itself would have robbed their lives of meaning or pleasure.  A far larger number could find their cognitive abilities fade faster rather than slower in the long run.  For them the drugs may steal time rather than buying it. Others may benefit—but not by much.  It’s a dreadful gamble.

Profits Galore

It’s also a business opportunity.  Leqembi’s US price is $26,500 per year, according to CBS News HealthWatch.   Additional charges for genetic tests, repeat MRI scans and regular monitoring to manage its risks could boost that to $82,500.  One million Americans may qualify for the drug.  (Medicare will cover 80% of the costs of this care; results may vary for the 50% of seniors in privately managed Medicare Advantage plans.)

This makes Leqembi “a money center for infusion centers and MRI operators.”  Ditto for Eli Lilly’s Kisunla which will cost $32,000 per year and will require even more follow-up.  This might explain why the bulk of the research for both drugs was managed by private for-profit enterprises backed by private equity funds.

The ethical oversight for these studies was also managed by a private company – Advarra. Advarra is a private-equity owned company that owns and operates the Institutional Review Board that approved both studies.   Advarra is involved in multiple branches of the clinical research business, from study design and software to recruiting staff.  In signing off on the plan not to inform the double-carriers of their extra risks, Advarra may have been grading its own homework.

Peter Selley brought Advarra to our attention investigating company studies of maternal vaccinations for RSV – Women, Pregnancy and Clinical Trials.  One of the big players behind Advarra, perhaps the driving force, is Mark Barnes – a lawyer working for Harvard, Pfizer and Ropes and Gray, a law firm who defend GSK and Pfizer.  Mark’s influence on our atrophying abilities to detect ‘Side Effects’ is outlined in Harmatology.

“Hope Starts Here”

For a research subject to give Informed Consent, she must first be told the possible risks and benefits of participation.  Secondly, she must understand the study is not being done for her benefit, and is not “treatment.”   Clearly Jean and Genna were denied the first.  They may also have been denied the second, as private research centers sought to blur the distinction between research and “care.”

Jean’s last dreadful days were spent at a top-ranked university hospital—but she received her Leqembi at Great Lakes Clinical Research, a private for-profit clinical trial center on Chicago’s north side.   In January 2022 Great Lakes was acquired by Flourish Research, a multi-state chain backed by NMS Capital.

Charter Research, the company that enrolled Genna Lane in Florida, is a similar private research chain. Charter’s ads in The Villages offered “free memory screens” and lab tests, along with a steady stream of free activities from luncheons to karaoke parties.  Residents like Genna could easily believe Charter’s slogan that “Hope Starts Here” – not just for science, but their own worrisome symptoms.  (Some West Coast clinical-research chains have gone farther, branding their recruitment centers as “Memory Clinics” according to a report by the Los Angeles Times.)

Meanwhile, back in Chicago, here’s what Flourish’s website offers potential subjects:  Free memory consults.  Diagnostic scans, genetic testing and other advanced services at no cost.  Not to mention “one-on-one care” from board certified physicians “without having to wait months for an appointment.”  Even an educated patient like Jean, who had worked as a lawyer and a psychotherapist, might come to see the clinical-trial center as the best “care option” in town—and miss the fact that its first loyalty was to Biogen, not her.

In the end, Jean (recent photo above) and Genna never had a chance for Informed Consent.  The term Alzheimer’s Disease conjures up a very different image to Jean’s here.  She was just like many of us.  She did not have Alzheimer’s. As new Alzheimer’s drugs move from research to approval and promotion, what happened to her and Genna may become a problem for millions of the rest of us.

In the Background

Jean and Genna’s stories transform a worrying background into a truly shocking story.

Before Leqembi, there was Aduhelm – another monoclonal antibody aducanamab, which like Leqembi caused catastrophic brain bleeds. What to Know about Aduhelm.  An advisory panel of academics and clinicians looked at this for FDA and recommended turning it down. FDA dissolved the panel, brought the drug back for review 6 months later and approved it. Several FDA reviewers resigned.

Consilium Scientific has run an excellent debate on the growing controversies surrounding this and other drugs for Alzheimer’s – See Is the FDA Failing the Public chaired by Peter Whitehouse.

But for anyone who reads the BMJ and likely other major journals – it’s impossible at the moment to avoid Lilly adverts offering to teach us more about biomarkers for Alzheimer’s.