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The $10 billion unicorn in INmune Bio: how only INMB uses the recipe behind big pharma’s recent successes with anti-amyloid antibodies

Writer's picture: Carl KestensCarl Kestens

Updated: 6 days ago


Historical failure rate of therapies targeting amyloid


Alzheimer’s is characterized by aggregation of anti-amyloid antibodies and phosphorylated tau. Although the idea behind the development of anti-amyloid antibodies dates back to the mid-1980s, the amyloid cascade hypothesis was proposed in a 1992 paper by J. Hardy and G. Higgins, entitled ‘Alzheimer's disease: the amyloid cascade hypothesis’.


The paper posited that beta-amyloid was the causative agent of AD, and that other changes, such as the accumulation of tau protein neurofibrillary tangles, were downstream consequences. The amyloid cascade hypothesis has been the prevailing idea in the field for about 30 years and attracted the lions’ share of the billions of research dollars.


That includes numerous failures, spread out over a couple of mechanistically different approaches. Without going too much into detail as to how these work or trying to be exhaustive, here are some of the failed therapies targeting anti-amyloid:


  • Beta-Secretase (BACE) Inhibitors - BACE inhibitors: designed to block the enzyme beta-secretase, which is involved in amyloid-beta production: Verubecestat (MK-8931) by Merck, Lanabecestat (AZD3293) by AstraZeneca/Eli Lilly, Atabecestat (JNJ-54861911) by Janssen/Johnson & Johnson, LY2886721 by Eli Lilly, CNP520 (Umibecestat) by Novartis/Amgen.


  • Gamma-Secretase Inhibitors and Modulators

    Gamma-secretase inhibitors aimed to block another key enzyme involved in amyloid production but led to off-target effects and toxicity: failures include among others Semagacestat (LY450139) by Eli Lilly, and Avagacestat (BMS-708163) – Bristol-Myers Squibb.


  • Amyloid-Beta Monoclonal Antibodies

    Monoclonal antibodies targeted amyloid-beta plaques or soluble amyloid-beta, but many failed to show efficacy or had adverse effects, such as: Bapineuzumab by Pfizer/Johnson & Johnson, Solanezumab by Eli Lilly, Crenezumab by Roche/Genentech, Gantenerumab by Roche/Genentech, Ponezumab (PF-04360365) by Pfizer, and AAB-001 by Elan/Wyeth.


  • Amyloid-Beta Aggregation Inhibitors

    These drugs aimed to prevent amyloid-beta proteins from aggregating into plaques. Failures include Tarenflurbil (Flurizan) by  Myriad Genetics and Scyllo-Inositol (ELND005) by Elan.


  • Immunotherapy Approaches

    Active immunotherapies aimed to stimulate the immune system to attack amyloid-beta. This was an interesting development, in that they were trying to modulate an already overactive immune system. One of the failures was AN1792 by Elan Pharmaceuticals, which was discontinued due to severe side effects  such meningoencephalitis.

 

The reason behind recent successes of anti-amyloid trials


Introduction


Unlike earlier Alzheimer's disease trials, the clinical studies for anti-amyloid antibodies lecanemab (Leqembi) and donanemab (Kisunla) specifically enrolled patients who were confirmed to be amyloid-positive. Amyloid-positivity was typically determined through advanced imaging techniques like positron emission tomography (PET) scans or cerebrospinal fluid (CSF) analysis.


For instance, the Clarity AD trial for lecanemab (Biogen / Eisai) demonstrated that the drug reduced markers of amyloid in early Alzheimer's disease and resulted in moderately less decline on measures of cognition and function than placebo at 18 months. Similarly, the TRAILBLAZER-ALZ trial for donanemab (Eli Lilly) showed that treatment slowed clinical decline by 35% compared to placebo and resulted in 40% less decline in the ability to perform activities of daily living.  


Rationale behind selecting patients with amyloid positivity


By selecting participants with confirmed amyloid pathology, these trials were considered to more accurately assess the efficacy of treatments in individuals most likely to benefit. 

This also means that treatment, as approved by the FDA, is reserved for patients with amyloid positivity.


However, an additional element is often overlooked. The altered patient selection also changed the course of dementia in patients.  Scientific literature has established several times that MCI patients without amyloid burden have a much lower chance of conversion to dementia than those with amyloid positivity. In other words, patients with amyloid decline faster. Or still in other words, big pharma altered its placebo to a faster-declining placebo by changing the trial’s inclusion criteria. I had not figured that out when I drafted this blog post on fast progressors in AD in October 2022, mentioning: “APOE4 carriers in Alzheimer’s disease show earlier Aβ deposition and clinical disease onset. They also show faster disease progression, heavier Aβ plaque burden and increased brain atrophy.” Biogen/Eisai had just released their first-ever positive results a month before.


To become successful, big pharma had to change both the treated and placebo group for its trials. That element appears essential to success.


So there are two parts to this success, by one change, namely by having altered the trials’ inclusion criteria.


Not a clinically relevant benefit, in my opinion


The benefit of these therapies is not clinically relevant in my eyes (the patients will not remark the difference, as their cognition will still continue to decline). In that sense, unless combination therapies can improve efficacy, I believe these treatments will one day be for the history books. But meanwhile they generate income for big pharma, and prove those supporting the amyloid cascade hypothesis at least a little bit right.

Although these therapies have been approved in the U.S. and other territories, the European Medicines Agency has so far taken another position, considering that ‘the observed effect on delaying cognitive decline does not counterbalance the risk of serious side events associated with the medicine, in particular the frequent occurrence of amyloid-related imaging abnormalities (ARIA), involving swelling and potential bleedings in the brain of patients.


A piece of the puzzle – not a guarantee for success for anti-amyloid therapies


To be clear, not each anti-amyloid antibody in trials that enrolled only amyloid-positive patients has shown cognitive benefit. Biogen’s Aducanumab did not, despite accelerated approval based on reduction of amyloid, nor did Roche’s gantenerumab.


However, aducanumab’s (Aduhelm) controversial approval was also based on a subgroup analysis which suggested benefits in patients with early-stage AD and high amyloid burden.


The above could indicate that within the anti-amyloid MoA’s, there is still a differentiation that needs to be made before a therapy can be successful. For example, lecanemab has a high selectivity for amyloid protofibrils, which are neither the smallest nor the largest types of amyloid aggregates, and donanemab binds to insoluble amyloid plaque. There is also a treatment difference: whereas patients can continue to be on Leqembi, treatment with Kisunla can be ended once amyloid levels fall below the amyloid positivity threshold – indicating that there is no further amyloid burden in the brain, and also indicating – to me that there the maximal amount of that particular amyloid antibody therapy has been reached.


Based on biomarker comparisons, I expect efficacy for XPro to considerably outperform that of the above-mentioned anti-amyloid antibodies.


Why the others did not follow suit...yet


Seeing the above, it is hard to understand why other biotech companies have not followed suit.


In 2021, while I was looking into INmune Bio at a time when there was considerable optimism about Cassava Sciences and Annovis’ drug, amyloid antibodies had not yet reported successes on cognition. That could be an explanation.


Contrary to others, INmune Bio was already designing its Phase 2 trial with the inclusion of patients with one or more markers of neuroinflammation, namely one of the below. That underscores the seriousness and high quality of company management, in my eyes.


Patients with markers of neuroinflammation also progress faster. I refer to my October 2022 blog post in that respect, where I quoted INmune Bio stating, among other things:

“So patients with neuroinflammation have more rapidly progressive cognitive decline. Secondly, that rapid progression occurs in a way that has less variance. And what I mean by variance is mean there’s less statistical noise around that decline. And that is what gives us the third advantage. It provides us with an ability to model the response compared to the treatment group in a way that allowed us to do both the shorter trials and the smaller trials.”

“If they have the biomarker of inflammation and you look over the course of the next six months, 12 months or however you want to look at it, their disease progresses faster and the most important part is that the variance in disease progression between patients is low.”

As a result, taking into account the above: by enriching the trial with patients that have markers of neuroinflammation, like big pharma did for amyloid-positivity, INmune Bio has ensured that it enrolls the right patients, and has altered the trajectory of its placebo controls. Those are two essential safeguards for a successful trial in my eyes.

In other words: had INmune Bio not enriched its trials in such a way, the investment thesis would not be as sound.


For a perfect investment in the space, not only would one want to ensure that right patients are enrolled, but also that the trial design takes into account the typical disease trajectory of the enrolled patients.

 

Further proof

I believe there is further proof  - non exhaustive - which can corroborate the above.

  • When Athira reported results, it mentioned that efficacy was noted “in pre-specified subgroups of patients with moderate Alzheimer’s disease or who are APOE4 carriers”, which are “characterized by more rapid disease progression”.

  • Cortexyme’s failed results for a drug targeting (inflammatory) p.gingivalis infection showed a 30% to 50% slowing of cognitive decline in the participants with high P. gingivalis load. The drug also had side effects, so development was stopped, but those are actually good results compared to anti-amyloid antibodies (Cortexyme – now Quince – also had a $2 billion market cap before its fall).

  • Anavex reported greater efficacy in patients with the SIGMAR1 wild-type gene, which is the target of Anavex’s drug.

 

Conclusion


The nuanced successes of anti-amyloid antibody therapies suggest that while targeting amyloid may play a role, it is not the ultimate solution to Alzheimer’s disease.


More importantly, these successes are based on an modified trial designs which may be key to success. By enrolling patients with confirmed amyloid positivity, big pharma has changed both the patients who could benefit from therapy as the progression of placebo patients in trials.


Contrary to its competitors, INmune Bio already included the recipe for success of big pharma into the design of its Phase 2 trial. Here also, there are two advantages: ensuring the trial enrolls patients that will benefit from therapy, and faster progressors affecting placebo decline. That double guarantee is essential to my investment thesis.

 


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