Obscuring harms with sweet-sounding words?

And how the acronym "ARIA" may point to more insidious motives from Alzheimer's pharmaceutical companies.

This post has reached the “Post too long for email” bandwidth, so please continue reading the article on the Substack website or app if it is unavailable through email.

Also, note that several of the links were found through Petersen’s article in the LA Times. This helped to find some of the available information on ARIA which I appreciate.

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Readers who have read my prior postings on Alzheimer’s immunotherapies should be privy to the acronym “ARIA”, short for Amyloid Related Imaging Abnormalities. ARIA is a possible side effect of these immunotherapies seeing rapid approval by the FDA and is broadly categorized into two groups based upon imaging findings related to brain swelling (ARIA-E for “edema”) and ones related to brain microbleeds (ARIA-H for “hemorrhage”).

Now, in my typical ignorant fashion I realized that the word “aria” sounded familiar but didn’t think much of it.

Of course, more cultured readers would be aware that aria refers to a piece in opera usually involving a single voice. It’s a word that usually signals a beautiful, expressive piece of art.

A collection of some ARIA I randomly found on YouTube as some examples:

So, it would be rather shocking to associate such a word with something as terrible as brain bleeds or brain swelling.

That is, unless one is trying to obscure side effects of a drug through conflation…

A few months ago, an article published in the Los Angeles Times caught my attention for raising this concern.

The author of this piece Melody Petersen (an ironic name tbh) notes an incident in which an elderly woman named Genevieve Lane died from a seizure days after her third dose of the immunotherapy Leqembi:

Infusions of the drug gave her headaches so severe they sent her to bed. A week after the third dose, she was at a restaurant with her best friend when her speech slurred and she had a seizure. Five days later she was dead.

Seemingly unknown to Lane and those around her was the risk of developing ARIA while taking Leqembi, and it’s likely this lack of knowledge that caused many of the signs of ARIA development to have been missed, leading to the unfortunate passing of Lane:

“Mom believed the drug would help slow progression of her memory problems or do nothing,” said Lane’s daughter, Yvonne Battaglia. “She didn’t know it might kill her.”

Those who have been keeping up with the Alzheimer’s immunotherapy debacle should recognize how much obfuscation is occurring with respect to these side effects. It’s not difficult to find comments that would simultaneously warn of serious complications on these medications that are also paired with the idea that these events of ARIA are “transient” or “resolve without issues”.

A brochure produced by the pharmaceutical company Eisai, the developers of Leqembi, even downplays these concerning side effects:

Things can be “usually asymptomatic” … until the one time that it isn’t… Unfortunately for Lane she seems to have been one of those instances in which her ARIA was not “asymptomatic” and did not “resolved over time”.

Remember that the FDA has sought fast-tracked approval of these medications under the guise that having some sort of treatment is better than having nothing- after all, you need to give people whose loved ones have Alzheimer’s some bit of hope (even if that hope comes with serious side effects…). This comes with the other fact that those on the FDA’s approval committee argued that the benefits of these medications greatly outweigh the risk.

In contrast to the latter point, remember that European drug regulators have recently rejected Leqembi’s approval in European markets arguing that the benefits of the immunotherapy did not in fact outweigh the risks associated with it.

Nonetheless, many people seem to continue to downplay these concerning side effects while touting the actual efficacy of these medications, which can be noted in an article from UC Irvine which rebuts Petersen’s concerns regarding ARIA [context included]:

What was largely missing from the [LA Times] article was a balanced review of lecanemab and other anti-amyloid monoclonal antibodies, which are the product of decades of research progress and are the first ever approved treatments that directly target the biology of Alzheimer’s disease. Around 13% of patients treated with lecanemab in a large phase 3 clinical trial experienced ARIA-E, though the risk was higher in patients of particular genotypes. Most cases of ARIA do not cause symptoms and therefore require routine imaging to be detected (and thus accounted for the naming of the of the phenomenon).

The rebuttal goes on to further note that most patients should not actually notice changes in their loved one’s memory loss as no change would be indicative of the drug working. After all, these medications are intended to slow down the progression of the disease rather than lead to improved memory and cognition:

The article downplayed the efficacy of these treatments, noting that patients and families wouldn’t notice the difference. In fact, the goal with these medications is to slow disease progression, which would be largely imperceptible to patients and families. This is a key point of education when we enroll patients and families in these clinical trials—not noticing a change could be the best sign that the drugs are working.

It's ironic to see such a comment that people shouldn’t see any difference. For anyone who read my post on the FDA’s committee meeting over Leqembi’s approval I noted that several testimonials were provided by loved ones of Leqembi patients in which they said the opposite- they commented that their loved ones were “returning back to their old selves” or at least made comments along those lines. Of course, no one who is for the drugs approval (certainly not Eisai) would dare to make such a comment that loved ones on Leqembi shouldn’t see any improvement- they should just see their loved ones not getting any worse.

(The following post is one that may not have garnered much attention, but it’s important in order to contextualize the actual “meaningfulness” of these products.)

It's further example of how there’s so much obscuring going on with these medications. The public has no idea what these drugs are even supposed to do or what side effects to look out for, and certainly no one invested in getting these drugs approved would contextualize people’s expectations of benefits and risk in a realistic manner.

Unfortunately, this seems to be intentional, and is possibly one of the reasons why the term “ARIA” was provided as alluded to by Pertesen’s writings:

In a recent article, a Stanford neurologist and his colleagues detailed their concerns about ARIA, which they called a “soothing acronym” for brain bleeding and swelling.

“It does certainly have the ring of something that a pharmaceutical company or public relations person would come up with,” Dr. Michael Greicius said in an interview.

Unfortunately, I can’t access the article provided and therefore can’t contextualize the “soothing acronym” phrase, or the exact evidence used to make such an association.

Nonetheless, this claim does make one wonder how exactly one comes to create such an acronym, and why one associate with an otherwise positive, melodious word?

The origins of ARIA appear to have been derived from a 2011 Alzheimer’s Association Research Roundtable Workgroup between FDA advisors, clinicians, pharmaceutical representatives, and members of the Alzheimer’s Association, which published the below article because of the workgroup:

Prior to the workgroup the FDA established strict criteria regarding the exclusion of participants in Alzheimer’s immunotherapy clinical trials. This included researchers excluding patients who had evidence of more than two brain microhemorrhages prior to treatment, increased monitoring of patients for evidence of ARIA, as well as exclusion of participants who develop signs of ARIA during trial participant.

However, these stringent criteria seemed to work against those in the pharmaceutical industry who saw such criteria as a roadblock in drug approval:

Some stakeholders found the original FDA guidance, which was shared with clinical trial sponsors just before AAIC 2010, excessively restrictive. They expressed that these restrictions had the potential to (a) stall progress in evaluating this class of investigational drugs, (b) create a barrier to participant access to clinical studies, and (c) limit the applicability of new therapies in real-world community treatment settings outside research centers.

In response to these remarks the 2011 workgroup was constructed¹, eventually resulting in the nomenclature ARIA to describe these side effects.

This also resulted in far-less stringent exclusionary criteria for trial participants, with new guidelines:

Of note, participants are now allowed nearly double the amount of pre-existing microbleeds to be considered within clinical trials upping the number up to 4, and if ARIA is detected during a trial a participant is allowed to continue so long as the participant does now show worse symptoms.

Now, all of this would appear rather fishy for many readers. It’s almost as if guidelines for trial participants were modified to better fit the needs of pharmaceutical representatives- allow for greater leniency to help push drugs towards quicker approval.

Of course, if the FDA found it wise to allow for more lenient guidelines one would have to wonder what evidence was looked at to make such a claim.

What’s rather striking is that this new set of guidelines, along with the adoption of the acronym “ARIA” seem to be based on highly limited, circumstantial evidence.

The adoption of the term “ARIA” seems to be related to the fact that brain microbleeds have been associated with age as well as progression of AD itself, and therefore the direct link between these immunotherapies and side effects of microbleeds and edema are not one to one (emphasis mine):

The Workgroup was composed of academic and industry representatives identified on the basis of their expertise and interest in this area, and was tasked with the objective of providing expert advice regarding the FDA’s concerns related to MRI abnormalities, including signal changes thought to represent “vasogenic edema” (VE) and microhemorrhages (mH) and the relationship of these MR abnormalities to experimental treatment with amyloid-modifying therapies. As VE and mH are typically detected on different MRI sequences, and appear to represent a spectrum of image abnormalities which may share some common underlying pathophysiological mechanisms, both in the natural history of AD and in the setting of amyloid-modifying therapeutic approaches, the Workgroup suggests referring to this spectrum as Amyloid Related Imaging Abnormalities (ARIA).

If one were to dig a little into the workgroup to figure out what evidence was looked at, you’ll note that hardly any clinical evidence was available, with some of the only available clinical evidence coming from Phase I and Phase II clinical trials of the trial immunotherapy Bapineuzumab:

There are currently very limited publicly available data regarding the clinical course associated with ARIA-E occurring in the setting of clinical trials of amyloid modifying therapies. Thus the Workgroup reviewed the data from bapineuzumab trials, but it is unknown whether ARIA seen in other amyloid-modifying therapies will have similar clinical course.

And this emphasis on limited data is seen near the end of the article as well (emphasis mine):

The Workgroup concluded that there is very limited information thus far regarding ARIA in the natural setting or publicly available information from ongoing clinical trial programs to make conclusive recommendations for clinical trial policies. In particular, there is limited data regarding the relationship between ARIA-H and ARIA-E. Additional information regarding whether the presence of baseline ARIA-H as a potential risk factor for ARIA-E, and ARIA-E as a risk factor for incident ARIA-H is needed to provide guidance for the conduct of these studies. Most importantly, we need information about whether specific components of ARIA have an impact on clinical course and response to treatment.

In short, these new research guidelines seem to have been developed based upon very limited data from clinical trials for one immunotherapy drug, and unsurprisingly it’s a drug which several members of the workgroup have a tie to.

That is, Bapineuzumab was developed jointly between both Pfizer and J&J, with Irish pharmaceutical company Elan helping to fund the R&D as well.

If you look at the PubMed article, you’ll find that 4 of the 7 pharmaceutical representatives in the roundtable workgroup were from these companies (3 from Pfizer and 1 from J&J).

And aside from members of the Alzheimer’s Association all the clinicians included in the workgroup had conflicts of interest, with some serving as site investigators for clinical trials, receiving grant funding from pharmaceutical companies, having stock in some of these companies, as well as receiving awards.

Usually, such conflicts of interest are not worth mentioning since nearly any bit of research that gets conducted is likely to be funding by the government or pharma.

But in this case, it’s quite pertinent since the purpose of this roundtable was to consider greater leniency in clinical trial guidelines, which would work to the benefit of pharma and researchers who help to conduct clinical trials. Thus, it’s not without reason to assume that there was a perverse incentive to create such a workgroup and push for more drug trials and faster approval.

It’s important to note that Bapineuzumab went on to fail two Phase III clinical trials as it was seen as not faring any better compared to placebo, resulting in the halting of the drug and even comments criticizing the amyloid hypothesis as a whole:

The article from Forbes mentions that Elan, as well as Eli Lilly (with 1 member on the ARIA workgroup) had their own blow ups with their immunotherapies failing to show any clinical benefit in further clinical trials.

Again, not only is ARIA being defined by limited clinical data, it’s being derived from companies who failed to produce any drug with clear clinical efficacy.

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The purpose of this article was to provide a quick glance at the LA Times article, mostly as it raised an interesting question regarding the influence pharmaceutical companies have on drug marketing. In this case, it would be rather insidious of companies to create acronyms to try and hide serious side effects.

In the case of ARIA it seems that this association may be circumstantial. There isn’t anything aside from speculation to suggest that the acronym ARIA was intended to hide harms by associating it with an otherwise innocuous music term.

However, that doesn’t make the situation seem like coincidence.

Also, this doesn’t mean that patients may not understand ARIA, especially if not provided any information from clinicians. If patients and loved ones are not properly briefed on medical terms then they may become confused when trying to search for ARIA online and come across operas and other music-related articles. ARIA related to Alzheimer’s is highly unlikely to be at the top of any search engine.

In that sense it’s not necessarily the fact that patients may underestimate their side effects, but rather that they may not be able to access any information regarding the side effects online unless they know where to look. In the case of Lane it’s possible that her scenario is a culmination of many factors, and I wouldn’t be surprised if lack of information on ARIA symptoms and lack of observation from clinicians is included in that list.

That being said, what I find more compelling may be the fact that ARIA is representative of the nefarious influence that pharmaceutical companies can have on drug regulation and approval.

Consider the fact that:

1. The roundtable workgroup was put together because stakeholder and pharmaceutical representatives believed that the FDA guidelines on clinical trials was too stringent.

2. Many of the people in the workgroup were from pharma or had ties to pharma, all of whom had an incentive for allowing more clinical trials and drug approvals.

3. Hardly any clinical evidence was examined to construct ARIA and create more lenient guidelines, and the one drug that was examined would go on to fail further clinical trials, with meta-analysis reporting clear evidence of increased risk of developing adverse events based on clinical trial data.²

4. The term ARIA gets adopted as “established nomenclature”, resulting in confusion among clinicians and patients regarding the actual safety and efficacy of these therapies, with the most egregious consequence being the loss of life as has happened to Lane and several others who participated in clinical trials.

So the coining of the “ARIA” acronym may not be as interesting as the circumstances surrounding its creation, in which we can recognize a long list of issues regarding the nature of Alzheimer’s research that have come to surface in recent years.

It highlights one of many failures in how drugs are brought to market, where regulatory bodies are captured by those in the pharmaceutical industry to direct guidelines and practices that work against the betterment of the public.

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1. Sperling, R. A., Jack, C. R., Jr, Black, S. E., Frosch, M. P., Greenberg, S. M., Hyman, B. T., Scheltens, P., Carrillo, M. C., Thies, W., Bednar, M. M., Black, R. S., Brashear, H. R., Grundman, M., Siemers, E. R., Feldman, H. H., & Schindler, R. J. (2011). Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup. Alzheimer's & dementia : the journal of the Alzheimer's Association, 7(4), 367–385. https://doi.org/10.1016/j.jalz.2011.05.2351

2. Abushouk, A. I., Elmaraezy, A., Aglan, A., Salama, R., Fouda, S., Fouda, R., & AlSafadi, A. M. (2017). Bapineuzumab for mild to moderate Alzheimer's disease: a meta-analysis of randomized controlled trials. BMC neurology, 17(1), 66. https://doi.org/10.1186/s12883-017-0850-1