Updated: Mar 17
What most investors seem to forget is diving into scientific literature
The trials and tribulations of the stock market seem, to me, in large part due to the extreme disconnect between the state of scientific literature and the companies to invest in. That’s where one can make a difference. Investors, I feel, often approach the exercise in a reverse way; first they buy, then to search confirmation of their thesis. Or, they buy on a hunch or on the basis of a bullish article. And once a purchase has been made, some seem extremely hard to shake in their beliefs. One should always be open to revisiting the thesis, I feel. I will give my thoughts below on some interesting companies in the AD space that I have been analyzing prior to my investment in INmune Bio.
The curious case of Cortexyme
I have always believed Cortexyme was an interesting company because its scientific foundation, in my eyes, in essence confirmed the thesis that INmune Bio was on the right track, and I saw that thesis confirmed when Cortexyme brought results in October 2021.
What is Cortexyme’s thesis, put simply:
- scientific literature supports that there is a link between gingipains, a gum disease caused by P. Gingivalis, and Alzheimer’s disease;
- if one could make a drug against P. Gingivalis infection, and could solve Alzheimer’s disease.
Cortexyme referred to just four scientific articles showing the link between gingipains and Alzheimer’s disease. That, already, is not convincing to me, but others do even worse. Having studied that literature, I was not convinced that the causal link between gingipains and Alzheimer’s disease was fully proven, i.e. perhaps there was no 100% link, or perhaps even there was no causal connection.
Coming from the broader scientific literature that, in abundance - contrary to some articles - considers that neuroinflammation is a hallmark of Alzheimer’s disease, and assuming on the basis of the Cortexyme theory that gum disease adds to / leads to neuroinflammation, I tended to consider that Cortexyme’s trial with COR388, which went for the entirety of the Alzheimer’s population, was doomed not to have a 100% response rate, or even more, that the drug may not even have a significant effect. That ended up being the case, and besides, the drug caused liver issues and led to an FDA-imposed clinical hold, in my eyes because management did not set the trial up for success from the start (they went at it blindly). In comparison, INmune Bio’s management does not even go for 100% of the Alzheimer’s population; they go for 100% response rate, and their trial should address 50% of the Alzheimer’s population. This view on trial design originates from a webinar of 2019 where the man behind the acetylcholinesterase inhibitor Donepezil was interviewed. It’s such a more prudent way to look at things, and in the end, the addressable population may be larger, but trying to treat the entire AD population at once may lie at the basis of systematic failures of AD trials in the past. Alzheimer’s disease may be the end-stage of a disease with multiple pathways. Neuroinflammation may be a vital one of these pathways, but perhaps not the primary one in each of the patients; fact is, we still don’t understand the disease fully, and anyone claiming he does is discarded from the start.
In spite of the failed trial, Cortexyme claimed there was a significant effect of COR388 in a subpopulation of AD patients with gingipains, and hence, a second drug, COR588, should solve the safety issue, and a new trial could be designed with more focus. Months after the fallout, with Cortexyme years away from any meaningful result in clinical trials, Cortexyme’s market cap has now at last fallen below INmune Bio’s market cap, and its enterprise value has been reduced to 17 million. So, in short: investors have all lost their money, knowing the market cap was above $ 2 billion in September 2021. Has Cortexyme learned from this? I don’t think so. Their anticipated 2022 milestones now mention: “Cortexyme is announcing a potential new indication for its lysine gingipain inhibitor, atuzaginstat (COR388), to prevent the development of oral/head and neck squamous cell carcinoma (O/HNSCC). P. gingivalis infection is associated with the development of O/HNSCC, and also with a significantly worse overall survival in patients with P. gingivalis positive O/HNSCC.” So, basically, they make the same mistake all over again; seeing an association is not enough for a causal link, and besides, the drug is toxic and has already led to a clinical hold.
Cortexyme also didn’t take the effort to inform its investors that more than one infection has been mentioned in literature as possibly being a trigger for Alzheimer’s disease. In fact, a 2020 article in Nature listed at least six infections linked to the development of Alzheimer’s:
“Several microbes have been proposed as triggers of Alzheimer’s, including three human herpes viruses and three bacteria: Chlamydia pneumoniae, a cause of lung infections; Borrelia burgdorferi, the agent of Lyme disease; and, most recently, Porphyromonas gingivalis, which leads to gum disease. In theory, any infectious agent that can invade the brain could have this trigger role (there’s no good evidence, however, that SARS-CoV-2, the virus behind COVID-19, has this ability).“
Interesting in that framework is, too, that two years later, the position on SARS-CoV-2 may have changed or is about to change.
What does that say to me? Not the infections, but their inflammatory consequences, trigger AD pathogenesis, or advance it faster. The COR388 trials was therefore, in my eyes, majorly misleading. Yet, many investors including funds had been convinced COR388 stood a chance of bringing a positive result. Cortexyme was part of the reason I decided to make this website; to inform people and insofar as necessary caution them that this may happen again.
What I learned from the rise and fall of Cortexyme
There was something very interesting in following the rise and fall of Cortexyme. After the bad results, the claim by Cortexyme that they had something, namely a subgroup of AD patients with gingipains who responded to treatment, in my eyes confirmed the thesis supported by abundant recent literature on AD and other neurodegenerative diseases, namely that neuroinflammation may lead to these diseases; take away the neuroinflammation and one should note an effect on neurodegeneration, remyelination and eventually cognition. INmune Bio has proven that XPro actually goes so far as to restore nerve cells and synapses, in other words, regeneration and remyelination both steadily moving up to about 15% over the course of 12 months, with inflammation continuously going down about 50% over that same time period. Those results, though fully ignored by the market, prove that neuroinflammation is not just a but probably thé main driving force behind neurodegeneration and loss of myelin in AD and possibly further neurodegenerative diseases.
Surely the entire diseases pathogenesis will always be an interplay between nature and nurture, where food, lifestyle and environmental factors will influence genetic predisposition together with the natural process of aging and rising inflammation. The same goes for cancer and many other diseases. Surely factors that belong to the food, lifestyle and environmental factors can be influenced, and could as such lead to reduction of risk to develop AD or the tempo by which it develops.
Gum disease and the inflammation it provokes, surely may add to neuroinflammation. So yes, there may be a link. And treating gum disease in inflamed patients, if that can be done safely with a drug – which unfortunately wasn’t properly tested in advance - should help those patients. However, probably the same can be achieved by reducing neuroinflammation in another way, and probably this other way takes away the entire burden of neuroinflammation instead of only the one caused by gum disease.
What were those results? Prespecified subcohorts that represented up to half of the GAIN trial participants showed a trend of approximately 50% slowing of cognitive decline over 12 months.
That mentioning of ‘up to half of the GAIN trial participants’ is interesting as well, as it happens that INmune Bio claims that it will go for about half of the AD population.“Enrichments means that the use of biomarkers to select patients for a clinical trial to match their disease with the drug therapy. Basically you're slanting the trial to success. Our CNS trials are enriched for patients who have neuroinflammation. This distinct ADi subset equals about half of the Alzheimer's disease patient population.
Hence my thesis: Cortexyme’s results corroborate INmune Bio’s. Even more, XPro reduces a whole panel of biomarkers of neuroinflammation at a steadily improving rate over the course of 12 months, and this has consequences on remyelination and neuroregeneration, steadily improving over that same time period with no sign of stabilization, and will likely lead to a much stronger effect than the effect generated by Cortexyme in its COR388 in the subgroup with gingipains.
Companies like Anavex and Annovis will be covered in upcoming blogs.