The $10 billion unicorn in INMB: on allostatic load, and why all the others may have non-responders

Summary

Allostatic load is the cumulative burden of stressors one encounters throughout life.

The underlying causes/triggers for any neurodegenerative disease may be different for anyone.

A personalized approach to any of these neurodegenerative diseases is logical.

In the absence of a right diagnosis and personalized approach, any drug candidate in this field may fail for a number of people.

I believe that companies claiming they can solve any kind of neurodegenerative disease entirely may mislead the public and their investors.

The necessity of a patient-oriented approach in treating Alzheimer’s

INmune Bio’s is issuing a series of short videos ahead of the AAIC 2022. The video published on July 29, 2022 is entitled: ‘The INmune Bio approach to Alzheimer’s disease’.

For me, this is the most important one by far. It essentially states two ideas. The first one will be the object of the current article. The second one is the utterly important consequence of what I wrote on microglia, and I will cover that idea a bit more in a later article.

- Contrary to others who have used an all-comers approach in their trials, INmune Bio is only targeting patients whose biology is most likely to benefit from XPro;

- INmune Bio is targeting neurodegeneration in a way that stops the excessive inflammation in the central nervous system, and allows its immune system to facilitate repair.

The idea of only targeting patients whose biology matches the mechanism of action of XPro has a consequence; INmune Bio is not targeting those whose biology is likely not to respond to treatment, allowing those patients to register for other therapies that do match their biology. I’m adding immediately that I believe that any person or company claiming Alzheimer’s in its entirety can be treated with one drug, or any other neurodegenerative disease for that sake, is essentially lying, misleading, or ignorant. That idea is the result of progressing insight; I wasn’t there yet a year ago, and I’m happy I am now. Does it mean that any trial that targets the entire Alzheimer’s population is destined to fail, in the sense that a randomized placebo-controlled trial will always lead to a statistically insignificant result? No, I wouldn’t go so far, I would even say that if INmune Bio would target the entire Alzheimer’s population, their results would probably turn out to be statistically significant. Yet, they may have a certain percentage of non-responders, just like Cassava Sciences does – a quite significant number even. And who wants to receive a drug that claims to solve Alzheimer’s only to find out it doesn’t work in an undefined set of patients? Nobody.

The recent exceptions confirm the rule

The idea of INmune Bio is almost unique, I would say, in the sense that over 95% of all persons/companies involved in the space have an all-comers approach. But there are a few exceptions. For example, Cortexyme/Quince Therapeutics as of August 1, 2022, is now following that path after having failed an earlier trial targeting the entire Alzheimer’s population. But even beforehand, Dale Bredesen, MD, has written a book about it entitled ‘The End of Alzheimer’s, The First Program to Prevent and Reverse Cognitive Decline’.

In that book, the author claims that the Alzheimer’s disease can be treated by way of a personalized approach, where patient’s stressors and Alzheimer’s triggers are first identified in a so-called cognoscopy, after which the patient should follow an extremely rigorous personalized program designed to compensate for these stressors. Dr. Bredesen identifies three types of Alzheimer’s: (i) the inflammatory type where he sees the genetic predisposition play the most prominent role, (ii) an atrophic type and (iii) a toxic type. Dr. Bredesen already states that types (i) and (ii) can overlap.

Was it really the End of Alzheimer’s?

Has Dale Bredesen’s protocol to treat Alzheimer’s worked? Dale Bredesen claims it has reversed cognitive decline, quite a number of times, and alleges he has the patients to back it up.

Has it been criticized? Yes, it has, and some have also claimed the protocol did not work.

As for my personal opinion; where I appreciate the book for some good insights, I also disagree with its approach. I’ll elaborate on this below.

What I like about the book

- The book is very much on board with inflammation being a very important, if not thé most important trigger to Alzheimer’s. Many of the diet and lifestyle changes the doctor’s protocol mentions are supposed to relieve sources of inflammation in the body. Dr. Bredesen claims Alzheimer’s disease is what happens when the brain tries to protect itself from three metabolic and toxic threats:

• inflammation (from infection, diet, or other causes);

• decline and shortage of supportive nutrients, hormones, and other brain-supporting molecules;

• toxic substances such as metals or biotoxins (poisons produced by microbes such as molds).

- I believe Dr. Bredesen’s personalized approach is correct; I think his pricey and utterly hard-to-follow protocol may have worked for a substantial number of patients, and who am I to dispute the reversal of cognitive decline as seen in quite a number of patients?

- Dr. Bredesen wrote his Alzheimer’s protocol out of frustration of seeing many trials targeting the entire Alzheimer’s population with one drug.

- Dr. Bredesen claims Alzheimer’s disease is reversible – and it follows from both the massive preclinical and trial data INmune has shared that that is a well possible scenario.

- The doctor has also taken the effort to identify a large number of stressors that may be involved in the emergence of Alzheimer’s, and the pathways to alleviate them. I have selected a couple of those as one will see targets of different drugs that currently receive some attention across different trials in the Alzheimer’s space: reduce APPβ-cleavage, prevent amyloid-beta oligomerization, increase microglial clearance of Aβ, increase autophagy, increase brain-derived neurotrophic factor, increase nerve growth factor, increase insulin sensitivity, enhance mitochondrial function, reduce oxidative damage and optimize reactive oxygen species, enhance cholinergic neurotransmission, reduce inflammation, reduce NF-κB, reduce glial scarring.

What I don’t like about the book

- I believe Dr. Bredesen is wrong from a scientific perspective when it comes to how Alzheimer’s disease originates and how it evolves.

- The book gives very little attention to the workings of glial cells which, I continue to read on a daily basis these days, seem very much involved with any aspect of Alzheimer’s disease.

- Yet again, the protocol is alleged to help all of Alzheimer’s patients, which risks to be misleading. J. Powell said this week one needs to be nimble in the light of data, and sometimes I ask myself: why aren’t more persons in the Alzheimer’s space saying this? Aren’t they supposed to be so scientifically rigorous, and who to trust if they keep on claiming the solve an entire disease where almost no-one has even had the slightest bit of luck in showing any statistical relevance in randomized trials? There should be no need in medicine to claim you can save everybody, and I believe that if one does, he’s likely to be lying, deceiving or ignorant.

- The differentiation between subtypes feels artificial and insufficiently backed up.

- At times, the book is written in such a borderline scientific manner that it exposes itself to the reproach of being pseudoscientific.

I see from the data having come out of the already existing INmune trials so far that results in patients are noticed both on a biomarker as on a day-to-day level much earlier than those in Dr. Bredesen’s patients.

So, if I believe Dr. Bredesen was right in considering that an approach where all patients are targeted with the same therapy is wrong, I believe he was not nimble in his statements that his protocol would be able to help the entirety of Alzheimer’s patients. And though Dr. Bredesen purports to have seen quite some patients to back up his ideas, no randomized placebo-controlled study has (yet) confirmed the validity of his protocol.

Finally, Dr. Bredesen’s stance is a good example of the concept of allostatic load in the framework of any neurodegenerative disease.

On allostatic load

Allostatic load refers to the cumulative burden of chronic stress and life events. “It involves the interaction of different physiological systems at varying degrees of activity. When environmental challenges exceed the individual ability to cope, then allostatic overload ensues. Allostatic load is identified by the use of biomarkers and clinical criteria.” This includes genetics, environmental stressors, physical and bodily stress and strains put on the body because of one’s diet and level of exercise.

Identifying and using the right biomarkers for diagnosis and treatment follow-up are essential in that regard.

I have read quite some scientific papers claiming that processes involving neurodegeneration start when the central nervous system fails to relieve itself from the allostatic burden it faces.

In that sense, allostatic load may not be a little concept to consider, and it could even explain quite a bit as to why the neurodegenerative space can be accessed in such a difficult manner, all the more if companies are proclaiming to have found thé one solution to Alzheimer’s in a molecular target which hadn’t even been discovered as a target before.

On bacterial or infectious load and the correlation to Alzheimer’s

The entire gingipains/P.Gingivalis idea as the cause of Alzheimer’s, which was hot last year until Cortexyme's trial did not meet its primary endpoint, could soon be replaced by Covid-19. In fact, science is now establishing relationships between Alzheimer’s-like neurodegeneration and a heavy Covid-infection-related burden in the central nervous system even more than all the articles I read on the relationship between gingipains and Alzheimer’s disease. And there are similar articles on Epstein-Barr virus, or HIV, or herpes. All of the afore-mentioned infections seem to bring a heavy inflammatory burden, and there are clear correlations with neurodegeneration. Does it mean these diseases are the cause of Alzheimer’s alone? Probably not, but they may add to the allostatic/inflammatory load to a point where the detrimental actions of glial cells in the immune system of the central nervous system outweigh the beneficial ones.

A part of the solution, not the entire solution, and the risk of non-responders

One must wonder at times how to understand all these companies that claim they have a solution to Alzheimer’s disease, or any neurodegenerative disease for that matter, seeing that almost all of them have a very different take on things. The idea that Alzheimer’s requires one treatment seems so engrained in scientific trials that it almost seems most clever to be short whenever a readout of a randomized placebo-controlled trial comes along.

It is my opinion that many of these companies may be right to a certain extent – and that even includes all those targeting amyloid oligomers, or perhaps even Anavex, Cyclo Therapeutics or Synaptogenix – but that the solutions they propose may only relieve a certain amount – small or big - of the load leading up to the point where neurodegeneration starts. Hence, if they target the entire Alzheimer’s population, the risk is they may fail in randomized placebo-controlled studies, and it is even more likely there will be a substantial number of non-responders. That also means I am not in the camp of those saying that INmune Bio will bring the only solution to Alzheimer’s disease – in fact neither is INmune Bio itself, and I find that comforting. RJ Tesi, INmune Bio’s CEO, has repeatedly stated the golden era of the central nervous system has arrived. That includes more than one approach. As an investor, that may mean that other solutions may be forthcoming, and an investment in INmune Bio does not exclude another one, but any investment is risky when randomized trials may lead to non-responders.

I do infer from my research and the extensive data shared by INmune both preclinically as from the Phase I trial, however, that insofar as XPro targets patients with the biology it addresses, it is likely to be the best treatment by far, and may not require any additional one.

Conclusion

It is my understanding that any neurodegenerative disease is the result of genetic predisposition combined with a number of stressors which may be different to each person. Hence, the underlying cause for any given form of neurodegeneration may be different for any person. Personalized approaches and individualized treatment may be required. Biomarkers are essential in that regard, just as they are in any other disease.

In the absence of a right diagnosis and personalized approach, I believe that any drug candidate in this field is likely to fail for a certain number of people. Randomized placebo-controlled trials may also fail, or at least lead to results which are tainted or less powered than they can be because they will include a number of non-responders.

I believe that companies that claim their treatment can solve the entire population of the neurodegenerative disease they are targeting may be lying, misleading their investors and the public, or ignorant. Progressing insight leads me to believe one should be watchful when it comes to these companies.

I believe neurodegeneration is reversible. It is still unclear to me how many patients this belief can apply to, and how long the reversal can last. INmune Bio is my best pick in the space, and the only one giving me full comfort in my investment because it remains nimble in light of the data. Yet, I do believe many more drugs may be helpful to further relieve the overload of stressors that leads the body to start its process of neurodegeneration. Solutions may even be found in relieving other stressors without directly targeting inflammation, though I have yet to find a company or suggested treatment that would be able to do that.

Disclaimer: This is a blog. It expresses my personal opinions as an investor. Though I read medical articles on a daily basis, I am not a doctor. Please do not take the above as financial advice either.