The $10 billion unicorn in INmune Bio: where fraud and arrogance aren’t, solutions to AD are (C. Piller book coverage)

 Introduction

Science journalist Charles Piller wrote a book, called ‘Doctored: fraud, arrogance, and tragedy in the quest to cure Alzheimer’s. The book is written with a focus on Cassava Sciences as well as on the mishaps (fraud stories) that have happened in the anti-amyloid space.

As usual, I will focus on what this book adds with regards to due diligence on INmune Bio and its potential competitors. I have changed the order of some ideas expressed in the book to that purpose. In fact, as the story of Cassava Sciences has also been written, and covered by me here, there was no need to repeat all of that. As for the essential failures of Alzheimer’s research in the past, I have discussed those in my coverage of Karl Herrup’s ‘Alzheimer’s, how not to study a disease’. Insofar as that relates to potential fraud, I have not, and that will be discussed here.

The book is a good read because it conveys the message that the Alzheimer’s space has attracted too much low-quality science. Some persons have cast a bad name on the space as a whole, and that needed to change as soon as possible. It is a wake-up call that should perhaps already have been published years ago, to divert the field’s eyes from a non-living target that only covers a target that concerns a rather small amount of the brain volume of only some patients with dementia, as compared to targets such glial cells which are living targets that are more abundant then neurons in the brain.

The anti-amyloid hypothesis - The “Amyloid Mafia”

Aside from Cassava Sciences, this is Charles Piller’s main body of work.

The story of anti-amyloid therapies in Alzheimer’s research has been marked by controversy, regulatory lapses, and scientific disputes. The development and approval of drugs like Aduhelm, Leqembi, and Donanemab reflect broader concerns about the amyloid hypothesis and its dominance in the field. I will discuss all three below, but will get first into the development of the amyloid hypothesis as seen by Charles Piller.

The Amyloid Hypothesis

For decades, proponents of the amyloid hypothesis have held a powerful grip on Alzheimer’s research funding, sidelining alternative approaches. A key moment in amyloid research came with the discovery of Aβ56, an amyloid-beta oligomer purportedly linked to cognitive decline. This work, led by Karen Ashe and Sylvain Lesné, helped cement the amyloid cascade hypothesis. However, questions arose when inconsistencies in immunostaining images suggested data manipulation. A peer reviewer flagged concerns, prompting further scrutiny. Ultimately, the 2006 Nature paper that introduced Aβ56 was retracted in 2024. Ashe initially sought to protect her legacy, arguing that the findings remained valid. However, her lab faced financial fallout as funding sources withdrew support. The revised version of her research, published in iScience, attempted to salvage credibility but failed to dispel skepticism. The retraction marked a critical turning point, reinforcing doubts about the amyloid hypothesis and the integrity of Alzheimer’s research.

The amyloid hypothesis is also flawed because, while beta-amyloid is abundant in Alzheimer’s patients’ brains, many individuals with significant amyloid buildup retain normal cognition. Biology suggests a more complex disease mechanism beyond amyloid accumulation alone.

The tight grip of the Alzheimer’s proponents has had its consequences for the entire field. The National Institutes of Health (NIH), the world’s largest biomedical funder, allocated around $3.7 billion to Alzheimer’s research in 2022, much of it directed toward amyloid-based studies. An informal so-called “amyloid mafia” has discouraged exploration of other promising avenues.

Yet the FDA bought the amyloid hypothesis in full.

Biogen’s Aduhelm and the FDA’s Controversial Approval

Biogen’s Aduhelm initially faced failure when clinical trial results did not show cognitive improvement. However, after a reassessment of the data, Biogen revived the drug’s prospects. Despite a damning vote by an FDA advisory committee—ten against, one uncertain—the agency granted accelerated approval. This decision led to resignations among FDA advisors who criticized the approval as an improper use of the fast-track process. Internal Biogen documents revealed a close engagement strategy with regulators, raising concerns about undue influence. Biogen’s lobbying efforts played a critical role in Aduhelm’s approval. The company funneled money into patient advocacy groups, which then pressured the FDA and Congress. STAT News uncovered a particularly close relationship between Biogen and the FDA’s Billy Dunn, the top regulator for Alzheimer’s drugs, who maintained a direct backchannel with the company to ensure the drug’s approval. These connections highlight how industry influence can compromise regulatory oversight.

That’s a troublesome start for anti-amyloid antibodies.

Biogen/Eisai’s Leqembi: no tangible effects

Leqembi, another amyloid-targeting drug, was heralded as a breakthrough but ultimately offered minimal benefit. While it slowed cognitive decline slightly, many experts argued that patients and doctors might not notice any tangible effects.

It also carried significant risks, including brain swelling and bleeding, classified as amyloid-related imaging abnormalities (ARIA). Several trial participants suffered severe side effects, including death, yet the drug moved forward. The FDA continued to embrace the amyloid hypothesis despite mounting concerns.

Eli Lilly’s Donanemab: more of the same

Following the pattern set by Aduhelm and Leqembi, Eli Lilly’s Donanemab demonstrated statistically significant but clinically questionable benefits.

It also posed heightened risks of brain shrinkage and serious adverse events, leading to deaths in clinical trials. Nevertheless, an FDA advisory committee, stacked with supporters of the amyloid hypothesis, endorsed the drug.

Do anti amyloid antibodies lead to brain volume loss and neurodegeneration?

Do anti amyloid antibodies lead to brain volume loss and neurodegeneration? This is a subject still to be uncovered, but if true, it would be yet another indication that big pharma has been minimizing a potential issue with these treatments.

I include a recent article in The Lancet Neurology on the subject of the potential risk of neurodegeneration resulting from the treatment of anti-amyloid antibodies, written by Professor Rob Howard, Scott Howard and Madhav Thambisetty:

I believe this is a serious subject of concern to be looked into.

Cassava Sciences

I will be brief here; Cassava Sciences has meanwhile moved on, and I believe so should we at this time.

The only relevance the company’s history still has at this time is its historical market value, which may indicate that my blog titles may be spot on one day (or, in fact, underestimated, who knows).

In short, Cassava Sciences claimed that its drug simufilam targeted Filamin A to reduce amyloid-beta plaques, a hallmark of Alzheimer’s. However, a citizen petition by researchers Geoffrey Pitt and David Bredt alleged fraud in key studies supporting simufilam. Multiple journals issued retractions and expressions of concern, raising doubts about the drug’s scientific foundation.

Despite these issues, Cassava used the disputed data to justify moving simufilam into Phase 3 trials. The company was later alleged to have cherry-picked cognitive testing results. CEO Barbier and other executives departed with substantial payouts.In September 2024, Cassava agreed to a $40 million SEC settlement for misleading investors. Barbier, Burns, and Wang also faced individual penalties and were barred from corporate leadership roles for several years.

Other targets – “Innovation and optimism”

The heterogeneity of Alzheimer’s disease

As for the complexity of Alzheimer’s disease, Charles Piller quotes Matthew Schraw, who considers that it’s not logical that a disease of aging would have just one cause, and who thinks that the field is moving on away from amyloid and focusing on the causes of inflammation in the brain.

There is an entrenched echo chamber that involves a lot of big names, but I don’t think it’s anywhere near the majority of scientists in this space. I’m hearing from a lot of people, some publicly, but many privately, who are anxious to see us move past the amyloid hypothesis, even if amyloid-beta is part of the story of Alzheimer’s.” A part. Not all of it. “We see a lot of inflammation in the brain with neurodegenerative disorders,” he said. “Looking at why—that’s an area where I expect we’ll get some traction

Other targets Matthew Schrag mentions are cholesterol, blood pressure, and the lysosome.

Viruses and microbes

One of these targets is viruses. Charles Piller mentions Ruth Itzhaki, as she had seen her 1991 alternative explanation showing a link between the herpes virus and Alzheimer’s rejected by several publications. Since her initial work, several thousands of papers have appeared on the subject of viruses and Alzheimer’s, leading to the viral hypothesis to gain credibility. Mr. Piller is hopeful for two clinical trials that target the treatment of herpes among Alzheimer’s patients, with results should come in 2025 or 2026. He also covered Robert Moir who faced headwinds for his thesis on the microbial basis for Alzheimer’s. I plan to cover that angle – the viral hypothesis – in a blog once.

There’s something to say for those hypotheses, and I have covered a bit of that in my older blog post on Cortexyme. Viral infections also have an inflammatory component. There are about six viruses that are related to Alzheimer’s disease, and some microbes as well. Focusing on one or two of them may not yield much effect, unless perhaps in subgroups, so trial design would be of the penultimate essence.

Overactive immune response

Charles Piller then mentions neuroscientist Malú Tansey, developer of XPro, who was shot down as a young scientist for having shown that a hyperactive immune response can kill brain cells and the connections between them instead of focusing on amyloid plaques. He states that Malù is now focusing on Parkinson’s disease, and that if the Michael J. Fox Foundation hadn’t funded her, “we wouldn’t be here.” In fact, the large volume of work academics have produced with regard to amyloid drives out other stuff. For example, a grant proposal based on how immune cells in the brain can affect nerve degeneration in Alzheimer’s would necessarily be based on less research than a proposal on amyloid early in Alzheimer’s development simply because there would be five hundred amyloid references to back it up, overwhelming the reviewers and rank the amyloid-centric proposal highly.

As for lead Alzheimer’s scientist Dennis Selkoe, which Charles Piller portrays as an amyloid proponent, Mr. Selkoe informed Charles Piller that he had branched out, applying for grants on tau proteins and the possibility that microglia-derived nerve cell inflammation was part of the root cause of Alzheimer’s.  Selkoe is quoted stating that he favors allocating about a third of future basic research funds to amyloids, and equal amounts to brain inflammation and novel ideas, and that anti-inflammatory rheumatoid arthritis drugs show promise.

The standard Alzheimer’s cognitive rating scales are flawed

At different places in his book, Charles Piller discusses Cassava’s and Biogen’s trials and their respective endpoints.

As for Cassava Sciences and their use of MMSE and ADAS-Cog, he quotes scientist Matthew Schrag’s worry about the rigor of the trial. Some experts saw Cassava’s screening criteria as suspect because it relied on the Mini-Mental State Examination (MMSE), widely considered imprecise and easily susceptible to coaching. The MMSE is indeed imprecise. With regards to the ADAS-Cog rating scale as well, Charles Piller considers that although widely accepted, bias can infect the scoring, results, and interpretation of that test. He refers to Suzanne Hendrix of Pentara Corp., an expert statistician who coauthored an article that described the unreliability of ADAS-Cog, and debunked the idea that it is an accurate test for patients with mild Alzheimer’s.

As for Biogen and the CDR-SB test they used, Charles Piller provides the insight that subjectivity makes CDR-SB sensitive to bias, as it relies on interviews with patients and caregivers on subjects that are partly subjective as well. The CDR-SB also cannot give a clear picture of a patient’s cognitive status as that status tends to fluctuate on a daily basis.

In conclusion, Charles Piller gets it. Biogen doesn’t get it. But Piller gets it. Matthew Schrag gets it. INmune gets it. We need better, more precise, rating scales, certainly for early AD, and that’s exactly what the FDA has been saying. I considered in 2022 that ADAS-Cog and the other cognitive scales were too imprecise. Doing trials with the traditional cognitive rating scales includes huge risk in your trials. Using them puts your goal of reaching statistical significance at risk. Yet, I have seen no one on the Cassava Sciences side complain about that.

On this point, I believe Charles Piller conveyes what INmune have been saying all along. Go ahead and look at that webinar INmune made on EMACC before I cover it more in-depth, it has only 365 views, and this is where the science is, as it relates to older cognitive rating scales (min. 7-15): https://www.youtube.com/watch?v=3-J3nx_uxMc&t=3321s

I include a slide:

The academic field’s view on this book

If the scientific field speaks out as a whole with regards to this book, and that is exactly what has happened over the past weeks, then it means they feel they have something to say. Here is their view:

What this tells me is: take the contents of the book with a grain of salt if you want to get a view on the space as a whole. As does its provocative title, the book portrays an image of the Alzheimer’s space that does not correspond to reality.

With such a powerful title, clickbait may become potentially misleading and misguiding, there may be a problem, and I think that’s what the academics tried to convey in the above letter. To each his fortune, I guess.

Malù Tansey, Professor, developer of XPro, and consultant to INmune Bio, did sign that letter as well.

In conclusion, thank you, Charles Piller – now looking ahead

Charles Piller’s book did a good job exposing the fraud behind some of the work in the Alzheimer’s space. It focused on Cassava Sciences – one company that got the spotlight of retail investors for some years – and some academics in the anti-amyloid field.

In focusing on the past mishaps or fraud of these few academics, I believe the book may fail to bring a comprehensive story of the entire anti-amyloid story, let alone the Alzheimer’s space. These mishaps do exist, and they should be eradicated.

The approvals of two anti-amyloid antibodies that have led to similar results both on a cognitive as biomarker level have proven that amyloid is indeed a valid target in Alzheimer’s disease. If these therapies could get safer and perhaps less inflammatory, better results could perhaps be yielded. The science behind them is, therefore, not entirely flawed. Without it, humanity would be a step behind, I believe.

The typical cognitive rating scales used in other trials are blunt and inappropriate. Charles Piller and Matthew Schrag confirm that. That is added value and insight few people have, and confirms INmune Bio's approach with EMACC.

The space needs therapies from another angle, and though briefly, Charles Piller does discuss them. Neuroinflammation is a valid target. He discusses that, and mentions Malù Tansey in that regard. Other targets could be of a viral, microbial or other nature.

In conclusion: thank you, Charles Piller, for your time and efforts. Now let’s turn the page. Given the dramatic outperformance of XPro versus anti-amyloid antibodies on biomarkers, I believe the future looks bright.

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Link to INMB discord server: https://discord.gg/JEA8r7wCGY