Summary
INmune Bio is making significant strides across multiple programs, positioning itself as a major player in biotech. CORDstrom unexpectedly emerged as a multi-billion-dollar opportunity in recessive dystrophic epidermolysis bullosa (RDEB). Meanwhile, INKmune has advanced to a Phase 2 trial in metastatic castration-resistant prostate cancer (mCRPC), targeting a $15 billion market.
Beyond these developments, with unprecedented biomarkers in Alzheimer's disease, XPro remains the company’s most promising asset.
INmune has repeatedly considered that inflammatory biomarkers correlate with accelerated disease progression. The current blog post covers that topic.
Pre-Introduction: CORDstrom and INKmune
Big big news this week, with INmune suddenly firing on all cylinders.
CORDStrom
First, we saw a sudden addition of CORDStrom to the company’s pipeline as INmune is preparing to file a BLA in the US and will seek marketing authorizations in the European Medicines Agency and the Medicines and Healthcare products Regulatory Agency. This news follows a type C meeting with the FDA, a rare pediatric disease designation for Epidermolysis Bullosa on December 13, 2024, and an orphan drug designation on January 6th, 2025. For valuation purposes, the reference stock here is Krystal Biotech, currently valued at $4.35 billion. Further thoughts on valuation have been, and can be, discussed in the INmune investors discord server prior to my further analysis on this website.
INKmune: Phase 2 in mCRPC
Second, INKmune is now a Phase 2 treatment candidate for metastatic castration-resistant prostate cancer. mCRPC is a huge and growing market, valued at almost $13 billion in 2024. INKmune is unique, safe and efficacious (see my blog posts of 2022 here and here), and I plan to cover it further once INmune releases data which should be in the coming weeks. Clearly, also, enrollment is picking up.
Summary
Both come from the stable of serial entrepreneur Mark Lowdell, and are not to be underestimated. CORDstrom came out of the blue for most investors, and I would go so far as to say that in my opinion it is now the asset that adds to INmune’s drastic undervaluation most.
Now, as for the value driver most investors are here for: XPro for the treatment of Alzheimer’s disease.
Inflammation drives cognitive decline
Introduction
INmune Bio claims it can do a short trial of six months to detect cognitive efficacy, and measures such efficacy with a cognitive rating scale specifically designed to detect cognitive changes in patients with mild cognitive impairment (MCI) and early AD.
The Phase 2 trial modeling has been done on the basis of the ADNI database.
The question then is whether the rate of cognitive decline in patients with Alzheimer’s disease who have higher levels of inflammation is indeed faster than that of those that do not. The question is important to verify that a short trial in patients with inflammation can indeed permit a good outcome.
Let’s take a look.
What did Leqembi and Kisunla do at six months?
Let’s first take a look at how the entirety of patients with Alzheimer’s disease, who are amyloid-positive, progress. As we have learned (see my blog post: “How only INMB uses the recipe behind big pharma’s recent successes with anti-amyloid antibodies.”), the reason behind the success of Leqembi (lecanemab) and Kisunla (donanemab) is the trial design adaptation, which only allows inclusion of amyloid-positive patients. In other words: trial design is aligned with patient biology. INmune does the same: XPro targets inflammation, so only patients with biomarkers of inflammation are enrolled. That’s essential.
But Biogen/Eisai and Eli Lilly did long 18-month trials. Were they necessary?
These are the cognitive charts for Leqembi and Kisunla. Leqembi’s chart shows months, Kisunla’s shows weeks. INmune’s trial lasts six months, or 24 weeks.
These circles are Biogen’s/Eisai’s. Leqembi’s chart clearly indicates that the cognitive divergence at six months was already there. The stars are interesting here, too. Two stars, at six months, indicates a p-value of <0.01. The threshold for statistical significance is a p-value of 0.05.
Here, the red bars are my own addition. What they indicate is the 24-week time point, i.e. the time point of INmune’s upcoming readout.
Teachings from the Leqembi and Kisunla trials
Cognitive efficacy seen at the six-month timepoint
In both trials, the cognitive difference between treated patients and patients on placebo was already clear at six months. The trials could have ended there. But big pharma chose to overpower them (enormously).
What these results indicate is that, with the right drug, in the right targeted patient population, cognitive efficacy does not require an 18-month trial. Any regulatory authority should understand that too, seeing these examples. The FDA approved these drugs on the basis of cognitive efficacy and aligned biomarkers.
Imperfect traditional rating scales
Furthermore, the cognitive rating scales used in these trials are imperfect, some of them even inappropriate, to measure cognitive change specifically in patients with MCI or early AD. A look at the divergence between what Kisunla reported on different rating scales already indicates that. I had covered this briefly in my blog post “On fast-progressors in AD, APOE4, TREM2 and EMACC”, but will revert to this much more extensively in light of the insights gained from INmune’s highly insightful webinar on EMACC. This webinar is a must-view in my eyes, as it is part of the innovation that INmune brings. I also think this area is probably where the shorts– if they have done their homework, and not just shooting from the hip – may be too confident and could be behind the curve; Alzheimer’s has been littered with trial failures mostly because of wrong drugs, misunderstanding of the disease, imperfect trial design, ánd because the used measuring scales may not have detected all cognitive changes. ADAS-Cog, if you will, is not carved in stone, because it simply can’t guarantee detection of cognitive changes, even with all of its variants (see here for an article on that). Using that scale is setting a company up for failure, if you will, even if it were to have a drug that could work in a prespecified patient population. CDR-SB is a bit better, but or any other rating scale are not much better. In fact, the FDA wants companies to use more precise rating scales, particularly in earlier stages of the disease – which is where we want to intervene. But I will cover that one day more in-depth.
Cognitive efficacy of anti-amyloid antibodies: a non-noticeable 30%
The cognitive efficacy seen in trials with Kisunla and Leqembi is only about 30% and therefore not noticeable for the average patient and family. This fact alone indicates that Alzheimer’s disease may, to a large extent (the remaining ~70% or more, in case cognitive improvement as seen with XPro would indeed belong to the realm of the possible), be caused by other factors.
We know that amyloid-beta plaques alone are insufficient to cause the cognitive decline associated with AD. In fact, amyloid burden is frequently seen in elderly patients without cognitive decline (also see my blog post: “Alzheimer’s, How Not To Study A Disease”). Many individuals with significant amyloid deposition do not exhibit clinical dementia. The presence of amyloid does raise the risk of either developing dementia, or continuing to decline if already diagnosed, by 1.9-2.6 times respectively compared to individuals without amyloid burden.
The fact that cognitively unimpaired individuals may have amyloid burden, but are still at higher risk of developing dementia, suggests that additional factors, such as neuroinflammation, contribute to the transition from amyloid pathology to neurodegeneration and dementia.
Could it be inflammation alone? That is unlikely. The answer could lie in genetic predisposition and allostatic load (see my blog post “On allostatic load, and why all the others may have non-responders”). The accumulated (inflammatory) burden may not be the only (other) target in Alzheimer’s disease. There may be other drivers too, some of which I plan to cover one day.
As for amyloid: though more profound research is required, my understanding at this time is that it is a disease driver independent of inflammation. Hence the possible utility of combination therapies, one day. As I understand it, Xpro is being tested preclinically in combination with approved anti-amyloid therapies. We will perhaps see the results of that testing one day.
High correlation between CDR-SB and EMACC in INMB’s Phase 2 trial
In summary, the trials for Leqembi and Kisunla were incredibly overpowered and showed efficacy already at the six-month time point.
As for INmune’s testing of EMACC and CDR-SB, INmune already reported a highly significant correlation (p<0.001) between baseline scores for EMACC and CDR-SB, with a correlation of 0.93 when measured during the screening process and at the first study visit before treatment (cfr. explanatory video), which gives me confidence that EMACC will be very precise and that CDR-SB should detect sufficient changes in cognition even in this early-stage patient population. INmune also reported that a planned blinded interim analysis by a third party confirmed the accuracy of the sample size calculations and statistical power for EMACC, not requiring trial duration or size.
The next question is: could we end up with similar results in patients with inflammation? I think the answer is positive: we could end up with (far) better results. I’ll explain my reasoning.
Inflammation drives cognitive decline
Introduction
INmune had previously designed two separate trials: one in MCI and one in early Alzheimer’s disease. These trials were finally joined together, and I appreciate that INmune did so. Interestingly, though, the MCI trial was designed as a 3-month trial.
The following comment on that was given during the Q1 2021 analyst call:
“Because dementia in patients with ADi progresses both rapidly and reliably, I'll repeat, rapidly and reliably, the clinical trials are shorter and smaller than trials that do not use enrichment strategies. Combining findings from publicly available databases, such as the ADNI database out of the USC, with data from our Phase I trial that showed that the response to XPro happens quickly in patients with mild, we designed the MCI and mild AD trials to last three or six months, respectively.”
The afore-mentioned ADNI database (http://adni.loni.usc.edu/ and www.adni-info.org) was created in 2003 as a public–private partnership with the primary goal of determining whether neuroimaging, other biomarkers, and clinical and neuropsychological assessments could be combined to measure the progression of early AD. ADNI recruited participants between the ages of 55 and 90 years in North America to be followed longitudinally, with testing at regular intervals. A diagnosis of mild AD was determined, as well a score of between 20 and 26 on the MMSE rating scale, a tool frequently used to screen for cognitive impairment in clinical, research, and community settings.
The current corporate presentation shows this slide indicating the faster progression seen in patients with higher levels of inflammation.
Inflammation as a driver of cognitive decline
There is scientific literature suggesting that neuroinflammation plays a significant role in the development of dementia and neurodegeneration, and that individuals with amyloid deposition may be less likely to develop dementia if they do not exhibit neuroinflammation.
In animal models of neurodegeneration, it had already been shown that induced acute systemic inflammation exacerbates neurodegeneration, which resulted in accelerated disease progression.
In 2010, an article was published entitled: “Soluble TNF receptors are associated with Aβ metabolism and conversion to dementia in subjects with mild cognitive impairment.” As a reminder, soluble TNF is the target of XPro. Soluble TNF is the pro-inflammatory or ‘bad’ TNF. The teachings of that article, in patients with mild cognitive impairment who were followed for 4–6 years, was that those who subsequently developed either Alzheimer’s or vascular dementia had higher levels of soluble TNF receptor activity already at baseline when compared to age-matched controls. These levels also correlated with markers of amyloid and tau.
In 2021, another article came out suggesting in its conclusion that neuroinflammation is an independent factor that drives disease progression and cognitive decline in early stage of Alzheimer’s disease.
In 2023, another article was published entitled “Neuroinflammation and amyloid deposition in the progression of mixed Alzheimer and vascular dementia”, which concludes that neuroinflammation, but not Aβ deposition, contributes to white matter hyperintensities (WMH) baseline volume and progression. I quote: “Neuroinflammation, but not pathologic Aβ deposition, was associated with baseline WMH volume and predicted its progression over 11.5 years.” White matter hyperintensities are associated with cognitive impairment, triple the risk of stroke and double the risk of dementia. On white matter, see my blog post: “Could remyelination explain the fast functional/cognitive recovery seen in patients?”
The important part for INmune investors here is that neuroinflammation was again seen to contribute to the progression of dementia.
Faster decline, but by how much?
In 2009, an article was published entitled: “Systemic inflammation and disease progression in Alzheimer disease”, finding that high baseline levels of TNF- were associated with a 4-fold increase in the rate of cognitive decline. Subjects who had low levels of serum TNF- throughout the study showed no cognitive decline over the 6-month period. Acute systemic inflammatory events were associated with a 2-fold increase in the rate of cognitive decline over a 6-month period.
The higher the inflammatory burden, the steeper the cognitive decline. How high? Increased inflammatory baseline levels were associated with a 4-fold increase in the rate of cognitive decline over the course of only 6 months. Individuals with high levels of TNF at baseline and the presence of systemic inflammatory events over the following 6 months even had a 10-fold increased rate of cognitive decline compared with subjects with low levels of TNF at baseline without such inflammatory events. Those who maintained low levels of TNF showed no cognitive decline at 6 months.
In 2025, an article was published entitled: “Neuroinflammation: A Driving Force in the Onset and Progression of Alzheimer’s Disease” concluding that neuroinflammation can no longer be considered a symptom of AD but rather a driving force in the onset and progression of the disease. Its findings were, among others, that the higher the inflammatory burden measured by either an inflammatory composite or CRP-levels, the steeper the cognitive decline, namely respectively 8% and 12% steeper.
"For each standard deviation (SD) increase in the inflammation composite score, participants’ cognitive composite scores decreased by 0.035 SD at the 20-year mark. Moreover, this effect seemed to have a dose-dependent response, with subjects in the highest quartile of inflammatory composite scores showing nearly an 8% steeper decline than those in the lowest quartile. Specifically, participants with CRP in the highest quartile showed a decline that was nearly 12% steeper than those in the lowest quartile."
MINDful’s trial design
INmune’s Phase 2 trial has been powered to detect cognitive efficacy in Alzheimer’s patients with inflammation based on the CDR-SB rating scale. However, using the primary endpoint EMACC, the effect size difference was substantially larger than for CDR-SB.
When calculating a study that would be 80% powered to detect cognitive efficacy in patients with Alzheimer’s disease with biomarkers of inflammation over the course of 12 months, INmune’s sample size requirements were: 56 patients for EMACC, 126 for CDR, and 130 for ADAS-Cog13.
Statistical power refers to the ability to detect a real cognitive effect, and 80% is the standard power for trials. The trial ended up overenrolled with a total of 208 patients in the trial.
Given the expected much stronger efficacy of EMACC, the study should be well overpowered to detect cognitive efficacy on this primary endpoint.
In conclusion, higher inflammatory markers indeed lead to faster cognitive deterioration. That, in turn, should allow for a shorter trial design.
Though all of that may not be as Leqembi and Kisunla’s trial results at six months already detected efficacy. And Leqembi and Kisunla’s biomarkers are far from those seen in INmune’s Phase 1 trial, suggesting XPro’s much higher efficacy potential.
Conclusion
INmune is firing on all cylinders.
CORDstrom, an asset no investor was focused on, turned into a multi-billion opportunity in RDEB.
INKmune is now a Phase 2 asset in mCRPC, a market valued at close to $15 billion.
As for XPro, we know its biomarker results are outstanding and unlike anything ever reported. We also know that the trials for Leqembi and Kisunla, the biomarkers of which are far less compelling than XPro’s, detected cognitive efficacy already at the six-month timepoint. INmune’s intention with XPro is to stabilize cognition.
INmune has repeatedly considered that patients with biomarkers of inflammation progress much faster than other patients with Alzheimer’s disease. That finding is confirmed by scientific literature; patients with higher levels of inflammation indeed progress faster, and the rate of faster progression is significant. INmune’s trial assumptions are therefore externally validated.
The Phase 2 trial is furthermore overpowered to detect cognitive efficacy, as EMACC is its primary endpoint although trial design was based on CDR-SB.
In conclusion, if XPro does what it has done in the past, I believe chances are reasonable we will see cognitive efficacy in June 2025.
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This blog post came early as next week's, which I am looking forward to, may also.
Discord ‘INmune investors server’: https://discord.gg/JEA8r7wCGY
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