Mired in Controversy over Aducanumab, Biogen reports "positive" results over their new Alzheimer's Immunotherapy Lecanemab
As the public yearns for a solution to Alzheimer's, dementia treatments may be the next frontier for fast-tracked approval.
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Edit 12/5/2022: Apparently one of the headers below had the word “presentences” when the proper word should have been “pretenses”. I will blame this on autocorrect but note that the header has been changed.
The world of Alzheimer’s research has been rattled in recent years due to controversy after controversy.
It’s extremely concerning given the fact that dementia and other age-related diseases are increasing in prevalence as higher numbers of people enter into old age. This has led many endeavors and funding to be funneled towards Alzheimer’s research in order to find ways of reducing and treating dementia as one of the newest frontiers in modern medicine.
Last year I wrote one of my first articles on Substack in regards the FDA’s fast-tracked approval of the first ever anti-amyloid-β immunotherapy named Aducanumab (brand name Adulhelm) from Biogen.
Although this should be deemed as the entryway into the era of dementia therapeutics, the approval became one of the most controversial decisions made by the FDA (aside from the controversies over the COVID vaccines).
I also revisited the topic earlier this year as well with additional context and information. Rather than rehash many of the controversies I suggest people read these two previous posts (the one above and the one linked below to the relevant section. The one below has a concise summary for those with limited time):
In short, the approval of Aducanumab may be considered one of the worst failures of regulatory medicine, as not only did the evidence not support its approval but the adverse reactions and the exorbitant cost associated with the drug raised questions about the extent of malfeasance that may have led to the approval.
All of this comes at a point in which questions and concerns are beginning to sprout over the fraudulent nature of Alzheimer’s research in general.
Alzheimer’s research and the false pretenses of science
The controversies surrounding Aducanumab come on the heels of medical misgivings in Alzheimer’s research.
A few months ago an exposé on Alzheimer’s research published in Science suggested that some of the premiere findings in the field may actually be a farce.
Of note, one of the most widely cited Azheimer’s studies from 2006 led by researcher Sylvain Lesné proposed the idea that Alzheimer’s was associated with a specific amyloid-β protein named Aβ*56 based on research in mice.
These findings would lead many researchers (now seemingly incorrectly) to go down the amyloid hypothesis route of research including finding therapeutics that could target these plaques with the assumption that such treatments may reduce cognitive decline at the cost of hundreds of millions of dollars in funding being directed to these endeavors.
However it appears, as reported in the Science article, that some of the images from these studies may have been either manipulated or fabricated (emphasis mine).
The first author of that influential study, published in Nature in 2006, was an ascending neuroscientist: Sylvain Lesné of the University of Minnesota (UMN), Twin Cities. His work underpins a key element of the dominant yet controversial amyloid hypothesis of Alzheimer’s, which holds that Aβ clumps, known as plaques, in brain tissue are a primary cause of the devastating illness, which afflicts tens of millions globally. In what looked like a smoking gun for the theory and a lead to possible therapies, Lesné and his colleagues discovered an Aβ subtype and seemed to prove it caused dementia in rats. If Schrag’s [lead investigator] doubts are correct, Lesné’s findings were an elaborate mirage.
A 6-month investigation by Science provided strong support for Schrag’s suspicions and raised questions about Lesné’s research. A leading independent image analyst and several top Alzheimer’s researchers—including George Perry of the University of Texas, San Antonio, and John Forsayeth of the University of California, San Francisco (UCSF)—reviewed most of Schrag’s findings at Science’s request. They concurred with his overall conclusions, which cast doubt on hundreds of images, including more than 70 in Lesné’s papers. Some look like “shockingly blatant” examples of image tampering, says Donna Wilcock, an Alzheimer’s expert at the University of Kentucky.
The authors “appeared to have composed figures by piecing together parts of photos from different experiments,” says Elisabeth Bik, a molecular biologist and well-known forensic image consultant. “The obtained experimental results might not have been the desired results, and that data might have been changed to … better fit a hypothesis.”
I would suggest readers of this Substack read the rest of the Science article for more in-depth investigative reporting on these scientific failures. It provides a telling account and provides an example of how some Western Blots may have been manipulated.
In short, the reports here raised doubts on many of the findings in Alzheimer’s research.
More important to our interests in this post, the investigation conducted by Matthew Schrag did not come out of nowhere, and the findings about the images used by Lesné and other researchers were only a downstream consequence of primary research into the pharmaceutical developer Cassava Sciences.
As reported in the Science article, Schrag was first asked to investigate the findings from Cassava Science and their immunotherapy named Simufilam which targeted the amyloid-beta plaques similar to Aducanumab.
Hired by scientists with vested interests in the pharmaceutical developer, Schrag was tasked with assessing the clinical results of Cassava Science’s trials of Simufilam, which Schrag remarked may have used manipulated or duplicated images in dozens of their articles.
The results of this investigation led to a petition filed to the FDA in order to halt the Phase III clinical trials of Simufilam based on these worrisome findings, which the FDA appears to have disregarded (read the sidebar on the bottom of the Science article for further details).
But aside from this work Schrag was also one of the most public critics of the Aducanumab clinical trials and criticized its approval.
In short, the investigation into pharmaceutical malfeasance by Schrag not only raised questions about the veracity of investigatory drugs, but also the basis of many Alzhemier’s research.
With such controversies surrounding the field of Alzheimer’s, one would assume that we should raise some rightful concerns on any Alzheimer’s therapy.
The “positive” results of Lecanemab
Biogen, embroiled with the controversies surrounding the fast-tracked approval of Aducanumab, probably shouldn’t be the first company to try to push another Alzheimer’s immunotherapeutic.
However last week Biogen, in partnership with another pharmaceutical company Eisai, released the initial findings from another one of their immunotherapies intended to target the amyloid-beta plaque formation in the early stages of Alzheimer’s named Lecanemab.
Of course, given what we have covered so far one would be right in being reticent of such findings.
These findings were released in a press release which touts that:
Lecanemab met the primary endpoint (CDR-SB: Clinical Dementia Rating-Sum of Boxes*) and all key secondary endpoints with highly statistically significant results.
Remember that the two trials for Aducanumab (ENGAGE and EMERGE) never met their preliminary primary endpoints, and only after retroactive examination of one study was conducted did Biogen find evidence of reduced cognitive decline among the treatment group relative to the placebo group (i.e. the treatment group didn’t show cognitive decline to the same degree as the placebo group).
A BMJ article from Walsh, et al.1 provides the following summary ([context included]:
Both[ ENGAGE and EMERGE] were stopped after preplanned early analyses on data up to December 2018 determined that the trials were “futile” (<20% chance of overall trial returning a positive finding).4 However, Biogen, which funded the trial, continued collecting data until the announcement of termination in March 2019. Reanalysis of data up to March 2019 confirmed the drug’s ineffectiveness in one study, but the other suggested cognitive benefit.
Biogen submitted its reanalysis to the FDA, and together they ran several retrospective analyses to explore the discrepancy between the two trials.4 Despite extensive evidence of ineffectiveness of other anti-amyloid agents,5 6 the new analyses focused on explaining why one of the trials had returned a negative result, rather than exploring why the other one had not. None of these analyses found anything more persuasive than a chance result that would have “regressed to the mean” (averaged out as ineffective) had the trials continued to completion.4 7
So this raises questions as to this supposedly new and improved Aducanumab given the fact that Aducanumab was not able to meet its primary endpoints.
Even more interesting, the results for Lecanemab’s primary endpoint, which was based on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score2 suggested that the treatment group showed less reduction in cognitive decline by a very small margin:
Lecanemab treatment met the primary endpoint and reduced clinical decline on the global cognitive and functional scale, CDR-SB, compared with placebo at 18 months by 27%, which represents a treatment difference in the score change of -0.45 (p=0.00005) in the analysis of Intent-to-treat (ITT) population.
There’s been some contention over the -0.45 value as some researchers argue that this is a marginal difference in cognition between the groups, while some may argue that improvement in any ways is remarkable.
But to put this into perspective, the retroactive analysis of Aducanumab showed a score change on CDR-SB to be -0.39 among the highest treatment group and the placebo group.
Without a frame of reference it’s hard to argue exactly what these numbers would mean in the clinical sense, but it’s also hard to argue that there would be a striking difference between a score of -0.45 and -0.39.
To put this into context, this summary from Tampi et al.3 provides this insight into the relevance of Aducanumab's results (emphasis and context included):
Liu et al. indicate that, on post-hoc analysis in the EMERGE (302) trial, high-dose aducanumab was shown to be better than placebo on the following scales: −0.39 points on the CDR-SB, 0.6 points on the MMSE, −1.4 points on the ADAS-Cog13 and 1.7 points on the ADCS-ADL-MCI.17 […] The authors question whether the small mean differences on these scales favouring aducanumab in the EMERGE trial and the negligible effect in the ENGAGE trial should raise queries as to whether these statistically significant outcomes provide any clinically meaningful effects for the drug. Additionally, they state that the application of the FDA’s own guidance, namely that “one positive well-controlled trial that is supported by confirmatory evidence [is] substantial evidence of effectiveness without considering mean difference or effect size”18, to the above-mentioned trials has created considerable controversy.
In essence, we don’t have any proper measure of the true effectiveness of Lecanemab, but given the facts over Aducanumab we should raise doubt to the actual significance of these findings.
Of course, the full release of the Clarity AD findings should help shed some light, but I’m also rather pessimistic on whether the full results would change any of the public’s perception based on the positive coverage of these findings as reported in mainstream outlets.
It’s just a little brain swelling
Immunotherapies targeting these plaques must travel to the central nervous system including the brain which may cause unique set of adverse reactions to take place.
Treatment with anti-amyloid immunotherapies is associated with the phenomenon amyloid-related imaging abnormalities-edema/effusion (ARIA-E), which are a myriad of adverse reactions including brain swelling, bleeding, and other issues. ARIA-H refers specifically to hemorrhages.
This phenomenon has created serious controversies over the safety of these immunotherapies, especially given the fact that the actual effectiveness is up for debate.
For instance, Aducanumab only showed relatively minor effectiveness at higher doses based on the original clinical findings. However, this came at a cost of a spike in ARIA-E events among participants with 1/3 of patients within the highest dosage group showing evidence of ARIA-E compared to around 3% of the placebo group.
And as I reported in my second article above Biogen and the FDA were investigating the death of one elderly women who died from brain swelling after being provided Aducanumab.
But not only are there concerns over safety, but the monitoring for safety signals raises many concerns over feasibility. Findings of ARIA can only occur through routine imaging, so to the extent that such routine imaging can occur among the public is one that should raise questions as to the practicality of monitoring and surveying for ARIA events if such immunotherapies were to be widely prescribed.
So that brings us to Lecanemab and the reports of ARIA, which at least raises some concerning safety signals similar to Aducanumab:
The incidence of amyloid-related imaging abnormalities-edema/effusion (ARIA-E), an adverse event associated with anti-amyloid antibodies, was 12.5% in the lecanemab group and 1.7% in the placebo group. The incidence of symptomatic ARIA-E was 2.8% in the lecanemab group and 0.0% in the placebo group. The ARIA-H (ARIA cerebral microhemorrhages, cerebral macrohemorrhages, and superficial siderosis) rate was 17.0% in the lecanemab group and 8.7% in the placebo group. The incidence of symptomatic ARIA-H was 0.7% in the lecanemab group and 0.2% in the placebo group. There was no imbalance in isolated ARIA-H (i.e., ARIA-H in patients who did not also experience ARIA-E) between lecanemab (8.8%) and placebo (7.6%). The total incidence of ARIA (ARIA-E and/or ARIA-H) was 21.3% in the lecanemab group and 9.3% in the placebo group. Overall, lecanemab’s ARIA incidence profile was within expectations.
The wording above is rather interesting. It raises questions as to what level of ARIA would be expected, and whether these values should actually be considered acceptable.
However, by all accounts such safety signals with spurious results on effectiveness should raise questions as to the real clinical significance of these findings.
It appears to me that the criteria for both safety and efficacy have not been met similar to Aducanumab. But again, this wouldn’t appear to be the case if one looked at coverage of this drug.
The era of fast-tracked therapeutics
At this time Eisai is using the preliminary results from their Phase III trial to push for accelerated approval of Lecanemab, with the FDA expecting to make a decision in early January 2023.
It should also come as no surprise that Eisai’s stock prices jumped after the release of their press release. There’s even this article from Nasdaq published today wondering if people should buy stocks in Eli Lilly which appears to have their own Alzheimer’s immunotherapy being investigated as well called Donanemab.
One wonders exactly what is going on right now.
The revelations from the Science article casts doubt on the field of Alzheimer’s research, with many arguing that the field either needs an overhaul or a “redo”.
At the same time these controversial therapeutics continue to be pushed through.
While we raise concerns about the fast tracking of COVID vaccines we should remember that the landscape for regulatory approval of therapeutics has forever changed.
The approval of Aducanumab shows us that other drugs are likely to be pushed through even when the evidence doesn’t argue in favor of such approvals.
If we are to look at what types of drugs will seek quick approval, all one needs to do is look at where the wind blows for emerging health crises.
Concerns over a growing elderly population provides the initial spark for the public to push pharmaceutical manufacturers and regulatory bodies to find solutions and to find them quick. As such, the FDA, NIH, and Big Pharma may respond by providing these expensive drugs with extremely concerning safety and efficacy profiles.
Remember that the research that gets funded are ones in which the public pushes for. The drugs and therapeutics that get approved are ones that the public pushes for.
Keep that in mind when we look to what may come in the future, and what we may expect from both science and the pharmaceutical industry.
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Walsh, S., Merrick, R., Milne, R., & Brayne, C. (2021). Aducanumab for Alzheimer's disease?. BMJ (Clinical research ed.), 374, n1682. https://doi.org/10.1136/bmj.n1682
Biogen provides this description of CDR-SB:
CDR-SB is a numeric scale used to quantify the various severity of symptoms of dementia. Based on interviews of people living with AD and family/caregivers, qualified healthcare professionals assess cognitive and functional performance in six areas: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The total score of the six areas is the score of CDR-SB, and CDR-SB is also used as an appropriate item for evaluating the effectiveness of therapeutic drugs targeting the early stages of AD.
Tampi, R. R., Forester, B. P., & Agronin, M. (2021). Aducanumab: evidence from clinical trial data and controversies. Drugs in context, 10, 2021-7-3. https://doi.org/10.7573/dic.2021-7-3