New FDA-approved Alzheimer's drugs shrink your brain (and may kill you)
Thank you for the (human) sacrifice
When Eli Lilly’s new drug Kisunla, for the treatment of Alzheimer’s disease, was approved by the FDA in July of this year, the company put out a news release thanking all those who had participated in the drug trials:
Our deepest thanks to the patients and their loved ones for participating in our clinical programs and to Lilly scientists and collaborators persevering over decades of research. Each year, more and more people are at risk for this disease, and we are determined to make life better for them.
Lilly indeed had a lot to be grateful for in terms of the sacrifices made by those participants, given that at least 26 people died during Kisunla’s clinical trials. 16 of the deaths occurred in the drug cohort and 10 in the placebo cohort. However, the researchers running the trials determined that only 3 of the 16 deaths in the Kisunla cohort were related to the drug.
Might this have something to do with that determination?
This is the list of researchers who conducted the clinical trials for Kisunla. While it is not uncommon for a clinical study to be conducted by internal researchers, Kisunla was not only researched but also recommended for FDA approval by "experts" with strong ties to Eli Lilly. Two investigative journalists, writing in the British Medical Journal (BMJ), believe there is a connection between those approving the drug and money pouring in to them from the drug’s manufacturer. Their article, titled, “Conflicts of interest found in FDA committee that approved new Alzheimer’s drug,” sheds light on the machinations of the federal agency that is supposed to protect consumers from dangerous products. In fact, the FDA initially refused to authorize Kisunla, for very good reasons, but eventually changed its mind.
Why?
New, exciting, and deadly
The BMJ article’s opening paragraph sums up the concerns swirling around Kisunla very succinctly:
A new drug for Alzheimer’s disease is causing excitement despite excess deaths, missing safety data, questionable efficacy, and financial conflicts of interest among the “independent” advisory panelists who recommended approval.
Why the excitement, given the excess deaths? The answer is that Kisunla is one of a new class of drugs designed to slow down the decline of Alzheimer’s patients. These drugs are anti-amyloid monoclonal antibodies which target amyloid plaques that, in Eli Lilly’s words, “may lead to memory and thinking issues associated with Alzheimer’s disease.”
The key word here is “may,” because it is not proven that reducing the amount of amyloid plaques is in fact beneficial to Alzheimer’s patients.Nonetheless, given that there are no proven pharmacological treatments for curing the disease, many are inclined to grasp at even flimsy and sometimes dangerous straws in the hope of at least some relief.
Where do inconvenient data go to die?
The path to Kisunla’s approval has been long and winding. In early 2023, the FDA declined to approve it, citing a “high rate” of missing data and insufficient evidence of safety when the drug is used in the long-term (which is how it is designed to be used).
Among their concerns, the FDA pointed out that many more people in the drug arm of the trial withdrew due to experiencing adverse events than did those in the placebo arm. Instead of incorporating these numbers into the trial results, however, the researchers simply removed the data entirely from the final analysis. The FDA noted that it was impossible from the published results to determine whether or not those who withdrew were still alive, or had passed away perhaps due to the adverse events they experienced.
The main dangers of the drug that emerged were brain hemorrhage and swelling, which is (in the trial) collectively referred to as amyloid related imaging abnormalities (ARIA). ARIA of various kinds occurred in 36.8% of patients taking Kisunla (a.k.a. donanemab) versus 14.9% of placebo patients.
The numbers of deaths appeared alarming, but the trial researchers concluded that almost none of them were related to the drug — in fact, they acknowledged a link between Kisunla and death in only 3 trial participants, who died due to complications from ARIA.
However, the FDA remained unconvinced and told Lilly that if it wanted the drug approved, the firm would have to come up with the “lost” data on all the missing trial participants. There were a great many of them — 221 out of an initial 1,074 in the Kisunla cohort and 170 out of an initial 1,048 in the placebo cohort.
Lilly agreed — in an agreement of sorts. What they in fact did was hire an outside company to search “publicly available records and databases, social media, and traditional media” to obtain the missing data. When approached by The BMJ, Lilly explained that data tracking was limited to sites that agreed to follow up and to countries where it was “legally permissible” to seek out patients through public media. Four of the eight countries refused: Japan, Netherlands, the Czech Republic, and Poland.
The BMJ also asked Lilly to reveal the name of the outside company, but Lilly refused.
Inconvenient data resurrected! Or...
After the outside company reported back, Lilly announced that 118 of the 221 missing patients in the Kisunla cohort and 66 of the 170 in the placebo cohort had been located, and of them, 2 people had died in the Kisunla cohort and 5 in the placebo cohort. That meant that there were now a total of 18 deaths in the Kisunla group and 15 in the placebo group.
However, there was still no information on adverse events among the missing people, and among the deaths, no causes were provided, as Dr.Steven Goodman, a professor of epidemiology at Stanford University, told The BMJ:
There was also no information on health outcomes in those patients other than death, or the causes of the deaths. The failure to formally follow patients who stopped treatment was a significant design flaw, particularly when that discontinuation was partly due to adverse drug effects.
The “failure to follow patients who stopped treatment” may have been due to other reasons than “design flaw,” of course. However, the reasons for Lilly’s researchers designing the trial as they did are a matter of conjecture.
Brain shrinkage is a sign you're doing better (says Eli Lilly)...
The FDA remains concerned about ARIA, noting in its “snapshot” of Kisunla’s drug trials that some types of ARIA which cause bleeding in the brain “may not resolve.” Side effects (aside from death) include headache, confusion, dizziness, vision changes, nausea, seizures, and difficulty walking. As can be seen in the table provided above, such events occurred disproportionately to the extreme in the Kisunla group in the trials and one may assume that the same applies to the people whose data was “temporarily lost.”
However, there are also other serious concerns linked to Kisunla (and all the drugs in this new class of anti-amyloid monoclonal antibodies). One of them is “brain shrinkage.”
Alzheimer’s disease is itself associated with brain atrophy leading to cognitive decline, so use of a drug that accelerates that shrinkage would seem to be rather controversial. Eli Lilly, however, claims that the brain shrinkage associated with Kisunla is a very different type of shrinkage from that linked to Alzheimer’s — in fact, they insist it is a sign that the drug is working precisely as it should, because it is reducing the amount of amyloid plaques and the associated inflammation.
The BMJ article’s authors dispute this, pointing out that Kisunla’s trials itself showed that the drug increased the amount of a certain protein that increases together with brain cell death.
... even if you can't see any improvement at all
All the same, perhaps all of the above is a worthwhile price to pay for a drug that has a significantly positive effect on Alzheimer’s patients? While some Alzheimer’s advocacy groups lobbied hard for the drug to be approved (for various reasons), George Perry, editor-in-chief of the Journal of Alzheimer’s Disease, told The BMJ that Kisunla and all the other new drugs in its class have a negligible effect on slowing cognitive decline:
... all demonstrate an imperceptible slowing of dementia in the midst of serious adverse effects, including death. [emphasis added]
Why, then, did the FDA determine that Kisunla’s impact on Alzheimer’s was significant, and approve it?
The most widely accepted scale for measuring cognitive function is the CDR-SB (clinical dementia rating scale-sum of boxes). Eli Lilly began its trials for Kisunla using the CDR-SB scale but, during the course of the trial, switched to another scale called the iADRS (integrated Alzheimer’s disease rating scale). Unlike the CDR-SB, which was developed by a team from the Washington University School of Medicine, the iADRS was created by... Eli Lilly.
Why might they have done that? Possibly it was due to the fact that (as Lilly admitted), Kisunla “failed to show a significant difference” in its phase 2 trials.
The FDA objected to the change, saying they “did not agree” with it. However, the published results showing a mild degree of efficacy for Kisunla were still presented according to the iADRS.
Here they are:
The difference between Kisunla and placebo here is 2.9 on a scale of 144 points. According to Lilly’s own criteria, a 5-point difference or more indicates a clinically meaningful result (i.e., a result that can be felt in the real world, not just plotted on a graph). Anything below that is “not considered to be perceptible to patients or their carers,” as The BMJ puts it.
Nonetheless, Lilly proudly proclaimed the trials a success and, what’s more, they manipulated the results by dividing the trial participants into several groups according to “tau” level (which may or may not have real-world significance for Alzheimer’s patients), and announced that Kisunla “slows decline by 35 percent.”
35 percent sounds quite impressive (much like the alleged 90+ percent efficacy of the COVID shots). However, it’s only the relative difference between a decline of 6 points and a decline of 9.3 points. That’s a difference of 3.3 points on a 144-point scale.
When one considers that the chances of experiencing dangerous brain bleeding and swelling from the drug appear to be in the region of 25 percent, a positive effect of what works out to just 2.3 percent sounds a little less impressive.
Cherry-picked data, cherry-picked "independent advisers"
And yet the FDA approved Kisunla, shortly after Lilly produced the “missing data.” Why?
In fact, this was just one in a series of questionable approvals of drugs in this anti-amyloid monoclonal class. The other approvals were for Aduhelm and Leqembi. In all three cases, FDA advisory committee members (most of whom were independent academics) voted against approval, almost unanimously. In the case of Aduhelm, the trials failed to show any tangible benefit for the drug and so the researchers instead proclaimed that it reduced the amount of amyloid plaques in the brain, which may or may not be significant for the Alzheimer’s patients themselves.
Nonetheless, the FDA approved Aduhelm and, in protest, 3 of the advisory committee members resigned. When it was Leqembi’s turn, the FDA was taking no chances. It replaced all 11 members of the advisory committee who had criticized the approval of Aduhelm and appointed 6 new physicians to review the drug trials. 4 of them, or their employers, had recent financial ties to manufacturers of Leqembi, while public data on the financial ties of the other 2 are not available.
The new 6-member committee then unanimously approved Leqembi and the FDA authorized it.
Next in line was Kisunla. In early 2024, the FDA expanded its advisory committee to 11 members, including 8 physicians. From the public database OpenPayments, members’ CVs, disclosures in published articles, and the Google patent ownership database, The BMJ found that these advisers received up to $62,000 for consulting and speaking fees and up to $10.5m in research grants from 2017 through to the end of 2023.
Three physician advisers had financial ties to Lilly and two to Roche (Lilly’s development partner in creating a new blood test for Alzheimer’s). Two doctors have patents for amyloid antibodies, while another has received research funding from Janssen for another Alzheimer’s drug. This is also relevant, because approval of one drug in a class makes it more likely that others in that class will also be approved — as the history of Leqembi and Aduhelm shows).
The BMJ points out that “federal law on conflicts of interest prohibits advisory members from having ties to companies that would have a ‘direct and predictable effect on the financial interests of the [adviser] or his employer.’ ” Furthermore, the FDA asks members to declare past financial interests plus “anything that would give an ‘appearance’ of a conflict,” without specifying a timeframe.
However, the FDA can grant waivers if the expertise of the adviser concerned is deemed necessary and outweighs potential bias. The FDA indeed granted a waiver to two of the advisory members; when The BMJ asked the FDA about the “extensive financial conflicts among the physician advisers," it responded: “The FDA does not comment on matters related to individual members of an advisory committee.”
FDA: We'll review the situation in 13 years
But all is not lost, as the FDA has ordered Eli Lilly to keep track of how much harm Kisunla is doing via a post-market “registry based, prospective, observational study” that will document events including deaths, brain hemorrhage, and edema.
Lilly will be required to submit regular reports to the FDA, but the final report is not due until February 2037.
The information contained in this article is for educational and information purposes only and is not intended as health, medical, financial or legal advice. Always consult a physician, lawyer or other qualified professional regarding any questions you may have about a medical condition, health objectives or legal or financial issues.
