On The Possible, part 2: Review of Martin Shkreli’s Live Stream On INmune Bio
- Carl Kestens
- May 7
- 29 min read
Introduction
INmune Bio (INMB) is developing a novel therapy targeting neurodegenerative diseases, particularly Alzheimer’s disease (AD). Placebo-controlled results are expected for June 2025.
Most INmune Bio shorts are institutional, without a concrete bear thesis. A large part of the short thesis appears to hinge on XPro not being brain-penetrant and being identical to non-selective TNF inhibitors. That thesis defies science. Another thing stands out: a scientific battle that took place years ago between the proponents of the amyloid thesis and those that believe Alzheimer’s may be an immunologic disease, now finds its way to the investor world, though the academic field has meanwhile moved on. I saw it in On The Impossible and Paurana Capital’s coverage mostly. My next blog post – including excerpts of a KOL interview – should go into that a bit deeper.
In my previous post, I reviewed Martin Shkreli’s bearish arguments on Cassava Sciences and have concluded that the thesis for INmune Bio should be: On The Possible.
As expected – we saw bearish arguments the past weeks from retail shorts who don’t seem to fully comprehend the story – Martin Shkreli would eventually take a small short position, which appears to have been short-lived. At the time, he posted on his X account that INmune Bio would be ‘one of the shadiest companies in biotech’, and that ‘it’s a zero’. This is the link to the coverage, as of h. 5.57: https://www.youtube.com/live/uz7y-ZejRTU It looked like he was discovering the company on the go, and in the end there wasn’t much that could qualify as even potentially ‘shady’ that was discussed during that coverage. All of the points that were addressed were mistaken. There is no fraud. I understand that an attempt to bring the stock down could be mentioning that you’re looking at one of the shadiest companies in biotech, and that worked – for a short while – but that statement had no basis so the attempt ultimately failed. The average retail INmune investor is knowledgeable, and many INmune investors have shorted Cassava Sciences on the basis of their knowledge.
This is the summary of that stream and my answers below.
Topic | Claims | Rebuttal |
Brain Penetration (1) | M: XPro is too large (50–80 kDa) to cross the BBB. Claims of brain penetration seem unlikely. (6:04:00) | - Data shows brain penetration: 99.9% of soluble TNF blocked at 1 mg/kg dose (Day 6).- Biomarkers (CSF) confirm CNS activity.- BBB dysfunction in Alzheimer’s may facilitate entry.- Peripheral-crosstalk possible (e.g., non-penetrant TNF inhibitors show cognitive benefits in studies). |
Brain Penetration (2) | A/M: Pegylation increases size; no evidence systemic XPro reaches brain. Parkinson’s study showed only local CNS administration worked. Dosing is fine(6:08:50–6:15:00) | - Prior studies confirm penetration: 2014 animal data. - INmune’s biomarker results show brain penetration.- BBB is dysfunctional in AD.- XPro’s design allows efficacy. - Dosing is fine. |
Mechanism of Action (1) | M: TNF isn’t a ‘brain-operating system’; microglia are primary. Why not use Humira/Enbrel? (6:15:00) | - TNF’s role in neuroinflammation is established: Glial polarization (microglia/astrocytes) drives inflammation and neurodegeneration.- XPro’s selectivity: Inhibits only soluble TNF (pro-inflammatory), sparing transmembrane TNF (remyelination/repair). Non-selective drugs (Humira/Enbrel) lack this precision and lead to demyelinating events. |
Mechanism of Action (2) | M/A: TNF receptor 1 vs. 2 distinction is handwaving. No clinical proof. (6:15:00–6:39:05) | - Academic consensus: TNFR1 (inflammatory) vs. TNFR2 (remyelination) is well-documented.- Preclinical/clinical data: XPro promotes remyelination (multiple studies: 2022–2024 PRs, white matter imaging). Non-selective inhibitors cause demyelination. |
Trial Design | M: EMACC endpoint is sketchy; might be data manipulation. (6:21:00) | - EMACC aligns with FDA guidance: Designed for mild AD/MCI sensitivity (unlike ADAS-Cog).- Webinar/publications explain rationale. No evidence of manipulation. |
Due Diligence (1) | M: Only one small Phase 1 trial; US clinical hold = red flag. (6:39:05) | - Hold lifted (2024): Manufacturing issue resolved; trials continued outside US (Australia/Canada/Europe).- Phase 1 biomarkers: Robust CSF cytokine reductions (e.g., TNF-shadow CCL7 ↓47%) and best-in-class biomarker evidence. |
Biomarkers (1) | M: Chart fraud suspected in inflammation composite. (6:54:00) | - No evidence of fraud. - Olink assay: Gold-standard for cytokine quantification. TNF reduction (-15%). |
Biomarkers (2) | M: “pTau-217/181 changes meaningless without placebo, hard to understand.” (6:55:00) | - pTau-217: FDA-recognized biomarker (Breakthrough Designation, 2025). Strong confirmation by academic field as biomarker of excellence for AD.- Phase 1 wasn’t placebo-controlled, but that wasn’t the goal. Current trial (MINDful) is placebo-controlled. |
Mouse Models | A/M: Alzheimer’s mouse models rarely translate. (6:48:24) | - Translation was seen in Phase 1, and XPro has independent academic validation across multiple models/diseases (MS, AD, Parkinson’s). Consistent results increase confidence. |
Financing | M: Raised $5M? Boca Raton = suboptimal location. (6:55:57) | - No financing occurred. Location is irrelevant (by the way, ADMA Biologics succeeded in FL). |
I add a word on Vinay Prasad being appointed head of CBER. Though not directly relevant as XPro would fall under the authority of the CDER, Mr. Prasad He has repeatedly been vocal about Aducanumab’s approval not being supported by the data, which showed no efficacy. We know the FDA’s accelerated approval was based on reduction of amyloid, but that approval had three FDA-advisers resign, and some of them had been vocal too. Since more than a year now, Aduhelm has been taken off the market. Biogen/Eisai never showed efficacy in a confirmatory trial. If XPro shows efficacy, without safety issues, it’s a totally different ball game, without the risk of big pharma influence. And there will be academic support.
Review of the live-stream
I include only the relevant excerpts addressing XPro’s potential failure and my comments, having tried to skip the filler words, and several inconclusive thoughts, and have rearranged some arguments for purposes of easy reading. Martin Shkreli = M. Caller Anthony = A.
1. On brain-penetration (1)
M.: “Why doesn't BBB play. It's a large molecule It's hard to get in the brain. They say it's brain penetrant but that seems unlikely.” (6:04:00)
XPro is brain penetrant in sufficient amounts.
This slide shows that more than 99.9% of the soluble TNF is blocked by the 1 mg/kg dose.
Many of the brain biomarkers INmune has used look in the brain specifically. It is impossible that these results were obtained without the drug passing the blood-brain-barrier.
Additionally, there may be beneficial interaction with the periphery. Crosstalk between immune cells of the CNS and those of the periphery has been established. That may explain the meta-analyses showing reducing dementia risk in patients on TNF inhibitors, which are non-brain-penetrant. That may also explain the recently published study (April 2025) showing statistically significant cognitive improvement from TNF inhibitors in patients with mild cognitive impairment.
Finally, the blood-brain-barrier is dysfunctional / broken down in Alzheimer’s disease, which could also explain the quick efficacy.
2. On brain-penetration (2)
- M. “So how did Xencor make it?” [6:08:50]
- A. “I was actually reading the original paper, it's called this dominant negative domain or something, so they engineered a few point mutations into soluble TNF to basically break
- M. “Oh my God, yes, I remember this.”
- A. “because it's a homotrimer in its native soluble form, and they try to make the heterotrimer that if one of the three domains is a part of the you know complex then it doesn't bind to the TNF receptor anymore. And they pegylated it too.”
- M.: […] so it's like a stoichiometric inhibitor.
- A. Yeah.
- M. It’s probably still not small enough to get into the brain.
- A. No, I've been doing a lot of work on that as well. And I don't think it does. And there are there are other studies which have looked at this precise drug in other neuroindications like we found a paper of people trying to use it in Parkinson's, and they found that local administration like to the CNS could get some kind of an effect going, but systemic administration did not. So that right there, I mean like, kind of proved the point.”
See above. XPro is brain penetrant in sufficient amounts to inhibit 99.9% of soluble TNF at day 6 after administration. Brain penetration in therapeutically relevant amounts had also been confirmed in a 2014 previous animal study.
3. On the Moa (1)
M. “I mean I think you know it's not totally crazy that you know lowering inflammation and lowering immune activity wouldn't help Alzheimer's. In fact, that's you know it's a pretty prominent hypothesis now. One of the problems there is that you’re dealing with a very different immune system in the brain, that’s mostly microglia-mediated.
And TNF is not generally thought to be sort of a brain operating kind of system. But at the same time I'd like to be somewhat you know somewhat careful before I prejudge it.”
Correct on the microglia - see my blog post from April 2022 on the subject - incorrect on TNF levels in the brain.
4. On the MoA (2)
M. “This is going well going way back but like I remember somebody maybe pitching me on this, but it's so long ago, and the problem I had with it then, I was just like, okay we have Enbrel too, we have Humira, what more do you need? And then the other funny hypothesis is, if you have if you have translocation across the blood brain barrier, then you have peripheral sync right, so you know you can just give Humira. Because you would deplete soluble TNF or sequester it or whatever just as easily.”
This touches upon the essence of the short thesis, and the differentiation of XPro. Enbrel and Humira are non-selective TNF inhibitors.
XPro is not inhibiting transmembrane TNF signaling, which is crucial for recovery and remyelination. It is inhibiting only soluble TNF, which is responsible for the pro-inflammatory signaling. That differentiation allows the glial cells in the brain to shift away from their detrimental pro-inflammatory state, without suppressing them altogether, like non-selective inhibitors may (leading to demyelination). Both the inhibition of soluble TNF and the non-inhibition of transmembrane TNF are crucial. There are many papers on that.
As mentioned on the other coverage, numerous meta-analyses showed some efficacy of broad TNF inhibition in preventing Alzheimer’s. E.g., a study of 8.5 million insured adults, a large, retrospective case-control study from 56 million unique adult patients, a study of 2510 patients with rheumatoid arthritis. See here, here and here are some further meta analyses. Various TNF-blocking agents including etanercept, infliximab and adalimumab have furthermore demonstrated the ability to reduce microgliosis, neuronal loss, tau tangles, and Aβ accumulation. Both pre-clinical and clinical studies have indicated their potential in improving cognitive function.
Recently, a new element to that research has been added. On April 11, 2025, a non-placebo-controlled study was published showing a statistically significant association between cognitive improvement, particularly executive function and memory, and TNF inhibition. The study reported an improvement in cognition by a point on the same scale (p = 0.001). Improvements in the MoCA were associated with average CRP, the standard biomarker for levels of inflammation in the blood, and one of four selection biomarkers of INmune’s MINDful trial (hsCRP).
So, yes, there is probably cross talk with the peripheral immune system, but it is unknown what the extent of that would be, and what the conditions for that are. And Humira, like other traditional TNF inhibitors, is not selective. The beneficial function of tmTNF is necessary for glial cell activity and recovery – as proven by external academics numerous times.
INmune Bio’s study will be placebo-controlled, XPro is brain-penetrant and selective for soluble TNF only, allowing the benefits of tmTNF signaling.
5. On the MoA (3)
M. “So it's a 52 kilodalton homotrimer. So divide that by three, right? [6:15:00]
A.: “But they pegylated too, so it's got like 10 or 15 kd for the peg on each subunit.”
M.: “But they're not giving a trimer, they're giving a monomer I assume.”
A. “I think that is correct. But I also think that this thing kind of like self-aggregates into the trimer. I am not 100% on that, but it seems that would be what happens.
M. “Alrighty I'll let that one go.”
A. “I think the total size of like this you know molecule is supposed to be like in the neighborhood of 50 to 80 kD because of the pegylation it's not getting on the brain. Unless it's like somehow there some kind of like a receptor mediated transport there's no way it crosses the brain except for that they were speculating. I heard something, not necessarily with relation to XPro, but that there were speculating about soluble TNF getting into the brain on the basis of inflammation degrading the tight junctions in the blood brain barrier.
M.: “Yeah it's a stretch. It's a stretch.
A.: “And I'm like, I wasn't super, I didn't see a lot of data to support that point yet. So but that was like a theory that I had read and I was like, but otherwise how this thing isn't getting across the blood brain barrier at all? But they do have some data to suggest that something, like, is getting across the blood brain barrier. Like, they had some slides that showed that there was more.”
See above. XPro is brain penetrant in sufficient amounts to inhibit 99.9% of soluble TNF at day 6 after administration.
6. On trial design (1)
A. “What do you think about this Emacc endpoint? [6:21:00]
M. “Oh god. I don't understand that either, and I'm wondering if it's part of some ploy on their part to mess around with the data.”
7. On being humble in the face of science (1)
M. “But let's, like, I mean in in most of these kinds of things I try to give as much benefit of the doubt as possible just because you know, I mean, science is a humility, you know, kind of a requires a lot of humility, and you never know what might work and what might not, and a lot of it is sort of ex-post, ex ante, you know, so I don't know I'm willing to be surprised.
I was, for example, my prejudgment of the psychedelics, you know, was that there's no way there's good data for psilocybin for Compass. And then, you know, just look at Compass's stock price. It's a [ ] show, and one of the Compass guys worked for me a while back and he was an idiot, so I'm like, there's no [ ] way this thing works. And I pull up the Compass not the Compass data, but I pull up some psilocybin data, I'm like it's actually not bad. So you know, it still probably won't meet its primary end point, but the point is, like, you should never prejudge any of these things. Just look at the data, be as objective as you can, because you don't get any points for being snarky or arrogant, or the only points you get is, when your accounts go up in value.”
It's not really the kind of assessment you’d expect with regards to one of the shadiest companies out there, but yes, an objective look at the data helps.
8. On being humble in the face of science (2)
A. “I've been talking to a couple people about it, and I think the idea the rationale if you will behind it was that it could try to offer, like, basically a more dynamic range to the mild moderate patient population in Alzheimer's disease. I guess they were arguing that ADAS-Cog just like doesn't pick up any differences at some point early stage patients.” M. “Well Aducanumab, somebody who writes Aducanumab, Aducanumab pulled it off. Maybe this can. Aducanumab has, you know… there's some relevance to the disease. You know, it's like causal basically, of the disease, so that's pretty good. So that's a big, slight, you know, big difference.”
The idea that inflammation would not be relevant to the disease is wrong. Neuroinflammation is linked to the pro-inflammatory phenotype of the glia, the brain’s immune cells composed mostly of microglia and astrocytes, as seen in neurodegenerative diseases. “Neuroinflammation is a shared feature of different CNS pathologies, which is regulated mainly by specialized brain immune and inflammatory cells, including astrocytes and microglia.” “Glial cells play a central role in orchestrating these neuroinflammation processes in both deleterious and beneficial ways.”
Glia are non-neuronal immune cells whose functions are to phagocytose and remove cellular debris and act against invaders, but also to promote neuro-/gliogenesis, angiogenesis, axonal outgrowth, synaptogenesis and synaptic pruning. In neurodegenerative diseases, they degrade toxic proteins, but at a given moment in the course of the disease they polarize towards a pro-inflammatory non-homeostatic phenotype which seems to prohibit them from maintaining their essential nurturing and phagocytic functions, and may lead to an inflammatory loop.
I went deeper into that in the rebuttal to Paurana’s note.
An emerging role is also attributed to oligodendrocyte precursor cells, the predecessors of oligodendrocytes, immune cells whose function it is to provide for myelination. Myelin is the substance that allows for insulation of axons, allowing good connectivity between neurons. Oligodendrocytes myelinate axons after axons have connected with their targets. The result of myelination is increased neurotransmission speed and efficacy.
The chronic prohibition of original function, or lack thereof, may be the cause of neurodegeneration, which makes rebalancing polarized glial cells a therapeutic target for neurodegenerative diseases. Allowing glia to revert to homeostatic functions may be essential in preventing neurodegeneration and promoting neuroregeneration.
There is a continuous stream of information on this. For example, on the day of publication of the first part of this coverage post, the following article came out: The Synergistic Roles of Glial Cells and Non-Coding RNAs in the Pathogenesis of Alzheimer’s Disease and Related Dementias (ADRDs). Excerpts: microglial activation across dementias drives chronic inflammation and neuronal damage. Some excerpts: Microglia release elevated levels of pro-inflammatory cytokines, including TNF, IL-1β, and IL-6, exacerbating neuronal injury, impairing synaptic function, and perpetuating neurotoxic feedback loops with other glial cells. Microglia exhibit molecular mechanisms of impaired Aβ clearance in AD. pro-inflammatory cytokines such as TNF-α and IL-1β, which are elevated in AD, inhibit microglial phagocytic capacity while promoting a neurotoxic phenotype. Oligodendrocytes, responsible for myelinating axons, also play a role in maintaining neuronal integrity and function. Therapeutic strategies that modulate the activation and function of glial cells, while also targeting ncRNAs, may restore the delicate balance required for proper neuroinflammatory responses and neuronal protection. For example, restoring astrocytic function through the inhibition of pro-inflammatory cytokines such as IL-1β and TNF-α, or by enhancing astrocytic glutamate uptake, could help mitigate the neurotoxic environment that promotes neurodegeneration.
9. On the MoA (4)
M. “Okay so there's a 5x fad model here, and that looks like it's some of the authors now affiliated with company. I could be wrong but I think this is out of Emory, and this is a good 15 years after first paper.
A. “I'm like not an expert on neuro stuff, but I've been trying to learn more about these mice models. But I mean it seems to me like mouse models are generally a lot more forgiving.”
M. “It's been a rough field. Any all the Parkinson's, Alzheimer's, Huntington's mice, they're not very useful research models.
A. “Yeah very low translation.”
M. “All right. So there's, I mean, it's been somewhat studied at least preclinically.”
A. “They had a bunch of mouse models.
M. “A lot of little pieces of data here.”
Agreed, we’ve cured Alzheimer’s in mice many times, the translation to the clinic in AD in general is low. Eventually we will get there though, and it will be with a drug that also showed benefits in animal models. As Martin Shkreli also discovered, there is an abundance of research on XPro in many different models of disease, and much of that research is from independent academics. If the drug was thought to be worthless by them, there wouldn't be so much, and many of these papers show clear benefits. I’ve covered some of that research more extensively in this blog from 2021. Since then, some useful additional papers have been published, some of which are not shown yet on INmune Bio’s website. I’m also sharing this slide.
10. On the MoA (5)
M. “But getting back to the point which is why not use an antibody. I don't understand the transmembrane soluble thing a long time ago when TNS came out this was a subject, and that's why Etanercept was a soluble receptor, but to this day I don't think anybody ever cared whether or not you're like binding to the transmembrane that gets cleaved anyway by like some caspase or whatever that releases it. So it doesn't really make a [ __ ] difference. They try to make a big deal of that in their filings.
A. “The argument they seemed to put forth was that it's the difference between activating TNF receptor 1 and TNF receptor 2 and that they are selectively like hitting TNFR1 and that this is best because it reduces inflammation but that if you also stimulate TNFR you like prevent remyelination in these Alzheimer's disease patients, which is a pretty wild assertion to me.“
M. “Well, you know, the problem you would have seen that TNF in general isn't very potent to begin with, right. All the TNF drugs have been replaced by stronger counterparts. Like, people moved away from TNF, so it's one thing I'd sort of point out.
But I think the TNF receptor one versus two thing, I mean, you can always handwave and point at stuff, but I think there's. It's just not, you know, until you have the data, it's just not there. So let's look, do they have any data?”
The ‘soluble versus transmembrane thing’ and their respective binding receptors is well established in research. See, for example: here, here, here, here, here, here, here, here or here (just a quick selection after a Google search). INmune is not trying to make a big deal out of that, many academic researchers have. The difference to non-selective TNF inhibitors is equally well established. Many researchers have cared whether TNF inhibition is selective or not.
As for the field having moved on from TNF inhibitors, Humira peaked in 2021 with $21 billion in revenue, having been the top earning in pharma for six years straight, and having about 40% of the TNF inhibitors market. Total revenue for Humira alone was estimated around $208 billion in 2023. But again, XPro is a different drug.
As for the need for selectivity, I recall Paurana’s selective quote on a scientific article that mentioned, among others:
“By comparing the effects of XPro1595, a selective soluble TNF inhibitor, and etanercept, a non-selective TNF inhibitor, we directly demonstrate that transmembrane TNF signalling is necessary for functional recovery, axon preservation and, most importantly, remyelination in a murine model of multiple sclerosis. […]
The inhibition by etanercept of transmembrane TNF signalling on specific cell populations, e.g. dendritic cells, which have tolerogenic potential (Fu and Jiang, 2010), could disrupt cross-talk with effector T cells and prevent the formation of tolerizing T cells, allowing for continued immune attack of oligodendrocyte precursor cells and oligodendrocytes resulting in ongoing demyelination. […] Lastly, it is worth mentioning that, unlike etanercept, XPro1595 does not directly block lymphotoxin (Zalevsky et al., 2007), a cytokine belonging to the tumour necrosis factor superfamily and capable of binding to both TNFR1 and TNFR2. […] Collectively, our data suggest that, in the balance between demyelination and remyelination, it is the positive effect of transmembrane TNF in the remyelination process that ultimately accounts for the observed functional recovery and resolution of EAE. […] Using a pharmacological approach, here we show that soluble TNF is responsible for the damage, whereas transmembrane TNF drives the repair process. XPro1595 maintains the protective properties of TNF and allows remyelination to occur. Therefore, unlike non-selective TNF inhibitors, which are associated with demyelination when administered in human therapy, XPro1595 represents a promising new candidate to be added to the limited repertoire of multiple sclerosis modulating drugs, finally opening the door to the introduction of a TNF inhibitor into multiple sclerosis therapy.” My next blog post should have some additional insights in this regard.
Remyelination, essential to brain functioning, is proven after treatment with XPro, both in animal models and clinically, and it’s an important thing because it is an indicator of the effect on the immune cells of the brain, which are not immunosuppressed. My blog on it can be read here. A recent PR (October 2024) on preclinical data showing remyelination can be found here (Microglia Regulate Cortical Remyelination via ΤNFR1-Dependent Phenotypic Polarization). Another PR from 2023 can be found here. Another PR from May 2022 on remyelination in a preclinical model can be found here, with a quote: “Myelin is a critical component to normal central nervous system function. The myelin sheath, produced by oligodendrocytes, is critical for normal nerve function. When the myelin sheath is damaged, nerve cells cannot transmit signals efficiently and, if the damage persists, the cells undergo neurodegeneration and die. Demyelination is a common feature across many neurodegenerative diseases. A decade ago, Professor Probert’s laboratory showed that in rodent models of MS, XProTM promoted remyelination (the repair of myelin) in white matter whereas currently approved non-selective TNF inhibitors promote demyelination. Her laboratory works to understand why soluble TNF causes demyelination and identifies therapies that promote remyelination.” The combination of that external research shows that remyelination is caused by the involvement oligodendrocytes, microglia ánd astrocytes, the three primary immune cells of the brain. For a video on some of that research, see here. In September 2021, INmune Bio did a webinar on the results of XPro in AD showing improvements in white matter pathology and decrease in PTau. One of the imaging biomarkers mentioned in that study was radial diffusivity, a proxy for remyelination. That biomarker normally goes up in Alzheimer’s disease, but gradually decreased by 16% on 1mg/kg of XPro after 12 months. For an opinion by CEO RJ Tesi on the subject of white matter and myelin, see here.
11. On due diligence (1)
M.: “Do they have any phase 2, or, I'm sorry, do they have any Alzheimer's data?”
A.: “Yeah it's just the phase one, but it's biomarker data.”
M. “So they've done what, one clinical trial?”
A.: “As far as I know, yeah. They had a bunch of preclinical data, and I don't know if they tried in other neuroindications. Seems like other people have studied this drug in other neuroindications.
M. “I don't think so, I don't see any.
A. “Yeah, clinical data, no. But in their deck they do share a few things. I just don't think I saw any papers.”
M. “Okay, let's see if they there's any.” Just look for INmune. [research]
That's a really small n. [6:39:05] It's funny, when you look at the Aducanumab phase two they had a big phase two, like 600 patients, they wanted like 50 plus patients in each arm, and get a big dosing range because otherwise, how do you know what the hell you're getting, and here you know you've got 1.0. Do they not have a US study sites? Oh man, I thought. So they're on clinical hold in the US, I love stocks like this. It’s like Anavex. Did you know that?”
A. “I did not know that.”
As mentioned above, the clinical hold which was manufacturing-related has been lifted for more than a year. Australia sites never stopped enrolling. As meanwhile other sites had opened outside of the US, such as in Canada and different European countries, enrollment took place there. So not having clinical sites in the US is related to a hold uniquely imposed by the FDA, which the other regulators apparently did not see issues with, and then later the FDA did not either. In practice, as the trial was open, that meant patients have been enrolled in venues outside of the US. The similarity with Anavex is incorrect.
12. On brain penetration
M. “Okay, so this this is a weird thing. Okay so you got 1.0 milligrams per kilogram. Do you know what the KD is for something like this? Because that seems like.” [6:40:00]
A. “I feel like it's a couple weeks, but I'm not sure.
M. “Not half-life, kD.
A. “Sorry. No I don't and that was actually one question that I had.”
M. “Ok, how much soluble TNF? This is going to be funny. Let's ask my friend ChatGPT: how much soluble TNF exists in the human body or in circulation? Any paper result would be helpful. I don't know that you're going to get enough stoichiometrically.”
A. “Yeah they did look at this question. Know. We were talking about it. I think it's in their 10K.
M. “So it's one mg per kg weekly.
A. “They did an old, you know, the Olink assay?”
M. “No.”
A. “Olink is this like really sensitive assay that basically combines antibodies and NGS in to measure quantities of things. It's a pretty good assay. Like I know this company pretty well, they're really quite good, they’re owned by Thermo Fisher now. So they have a panel for tight kinds and they actually have one for TNF and they have been able to quantify TNF, soluble TNF, from patient samples and basically INmune is claiming that some insanely small amount of penetration like 101% [?] of circulating supply is into the brain, and this is enough to literally clear all the soluble out of the brain and trying to take up that data because they're basically making this pretty wild assertion that an extremely small amount almost imperceptible is enough to clear all of the soluble TNF.
M. “Yeah, I mean according to this paper it's an extremely small number. But …… [6:48:24] the thing though is if you're giving one mg per kg and you're saying it's 60 70 kDA?
A. “I think the indigenous hormone timer is 50 but then they have pegylation that kicks it up to closer to 80, a little over 80.
M. “We're assuming they're delivering it as the trimer?
A. “I assume, yeah, I think that's just the safest.
M. “Well we can do both, we can look at both ways, and I administer a drug that weighs 70 kDa at a volume, except that volume, how many, I guess I could do how many grams I only do milligrams maybe nanograms per milliliter, am I administering, Okay, ChatGPT is upset at me.
It's kind of hard to do anything in in 23 weeks or whatever in Alzheimer's, but never say never. Oh is it two to one dosing randomization. It was 23 weeks I thought I saw that right. So what is that: eight months? No, seven months, six months. So there it says concentration would be 14,000 nanogs per milliliter which you know doesn't, relative to TNF, only 1.6 picograms per milliliter. So this thing is like arguably overdosed. Even at low affinity that should be enough to cover all the soluble with TNF. Right?”
A. “Allegedly.”
M. “It depends on the affinity because I mean if the trimers form immediately, you can't dissociate existing trimers, right?
A. “You mean like swap?”
M. “Yeah.
A. “They say they can. They say that you can. Okay.
M. “But you'd have to overcome mass action pretty, it's a tough gradient.”
A. “Yeah, I agree. Okay, if and then even one subunit switching out it renders it inactive and that is like literally the…
M. “Yeah, but it's a hydrogen bond, right. So unless it's the…. Yeah, I suppose, I guess I don't know. And you need to activate receptor.”
A. “Yeah. I don't know, if it's like a part of the engineering of this domain negative thing. Like it's the engineer the receptor binding domain of the unit to not bind to the receptor.”
M. “I'm a little confused though because if you have if it's being administered as a trimer, okay, and presumably it's not dissociating itself, although most hydrogen bond agents do..and then ,if it's dissociating from itself, it's probably also dissociating from a heterotrimer. So if the homotrimer dissociates, the heterotrimer should dissociate, and if the heterotrimer and the homotrimer don't bind TNF, only the homotrimer of the native does. It says will it generally will interrupt already formed TNF trimers? No. They're usually highly stable tightly bound structures. That does make sense. Yeah, I'm not, I'm not sure you get the saturation you need, but it certainly seems like the dosing is fine. So all right.”
I’m going to assume that Martin Shkreli came to the conclusion that dosing was fine.
I refer to the earlier coverage and above, showing that XPro closed the blood-brain-barrier in sufficient amounts to eliminate 99.9 of soluble TNF after six days. Again, the research on the relevance of inhibiting only soluble TNF in the CNS is abundant.
13. On trial design (3)
M. “Alright so, EMACC. So this is like half Adas-Cog. Basically It's like half an Adas-Cog. It's like a modified Adas-Cog. It's kind of the same [ __ ] right, I mean, it's just like a battery of brain teasers.”
14. On due diligence (2)
M. “The question is what does the phase one look like. I think you're mentioning their deck.
A. “Yeah, their deck has some of that data.”
M. “Did you see the financing?”
A. “Did they announce something today? I couldn't find it on Goodell.”
M. “I couldn't find it on there either at first. I saw it. It's on their website. I'm going to ask my engineers why, but oh did they take it down? It's not there anymore. This morning, yeah, okay, yeah that's [ __ ] weird. That's so weird. What the hell? That's why the stock was up too. Who does that? Whatever. I mean okay so assume that'll come out tonight. They raised like five million bucks.”
There was no financing.
15. On due diligence (3)
M. “Where's the? Oh, Boca Raton, Florida. Oh my god. Classic. Does it get any worse than Boca Raton, Florida, for biotech? Has there ever been a Florida biotech that's ever not been a screaming zero?”
There is no relevance here. As already pointed out with ADMA by a person following the stream, it is wrong too and there are other examples.
16. On biomarkers (1) [6:54:00]
M. “Okay, the chances of this working are like less than 1%. What is this CSF inflammation composite, that's like very, here's all the markers for inflammation. I'm struggling here because these dots. Okay, all right. So yeah this is the one. Tell me this isn't clear and obvious chart fraud. Okay, again, I'm no scientist but these individual dots are typically. Circle them in green so they're obvious. These are typically individual patients, right. This is what it's supposed to be. These are the four five. No that's… Oh, here's one, two, that's five. There, one, two, three, four, five, and whatever six or something here. Right, okay. So the mean seems to maybe even go up over here and then I don't know where it is, here, but these are like they're almost like candles. So …
I don't worry about the clinical hole too much.
So I'm not sure there's a dose response. In fact if you believe this thing let's say you throw this guy out, the dose response is actually like this. So I don't know that this is, you know, until you publish this, I'm not sure this is going to tell us anything.”
There is a clear dose response. If the allegation is that INmune Bio has committed chart fraud, with no evidence to back that up, that obviously incorrect. If the statement is that, if you remove persons from results, you should see the real results, that would be chart fraud.
17. On biomarkers (2)
M. “48 cytokines. Okay, this looks like something. What is this ptau-217 over 181, or ptau-217 and 181?”
Ptau-217 is the most predictable biomarker of disease, which is why the FDA granted Quanterix Breakthrough Device Designation to a pTau 217 blood test for Alzheimer disease four months ago (January 2025).
Also see here:
18. On biomarkers (3) [6:55:00]
M. “And what, okay, here's more chart fraud. What dose is it? Is there a placebo?
A. “One mg per kg?”
M. “Where does it say that?“
A. “I don't know what you're looking at, but I sent you a deck, and they have that specific slide on.”
M. “I'm on slide nine. I'm on YouTube.”
A. “No, I'm looking at your YouTube. I'm saying I don't know where you pulled this deck from.
M. “Cap Edge. Oh that wasn't you That was Z55. My Bad.”
A. “I think the deck you're looking at is maybe a little bit older.”
M. “May be better. Simpler time but they actually tell the truth. Here's the, here's your deck.”
A. “Then go to slide 16. They're looking at that CNS inflammation composite. They break it down. […]
M. “I met people that believe in this hypothesis, specifically the TNF hypothesis.”
A. “I mean I got a handful of drugs that we can look at that have already been tried and
tested on this indication that haven't done well.”
M. “TNF related?”
A. “Yep.”
M. “Like what?”
A. “Oh let's spoil the list.
M. “I mean I cut my teeth on TNF growing up on Wall Street. Like TNF was be all end all. It says here the mean is actually -15% CSF inflammation composite. “
A. “Look at TNF specifically. It's somewhere in there. Oh there it is.”
M. “It's about 15%. Got to be kidding me with this [ __ ]. You giving me a TNF blocker, no come on, man, stop bullshitting me. The TNF blocker is literally here though? Is this expression?
A. “Okay, this is measuring cytokines.“
M. “Like I said, the assay it’s like an antibody based assay but it amplifies the signal using NGM.”
A. “There's TNF soluble fragment.”
A. “Like, the company alleges that you can't tell the difference between soluble TNF like endogenous and the drug disassociated version, which may be the case but, it's hard, it's hard to say, totally not, it's…
M. “They're different mass spectrometry right?”
A. “It's not, it's not. But it's not mass spec. It's, I guess it's an antibody and it's a weird new diagnostic, It's a pseudolyaser essentially. So you'd have to have the antibody binding soluble TNF and maybe it binds to the endogenous form only and then not the drug form as well. But again it's like this kind of heterotrimer thing, I don't know if the epitopes will work or if it'll bind one of the domains, you know, that doesn't have XPro in it.”
The -15% reduction of detectable cytokines using the Olink assay is meaningful.
It’s an overall figure of cytokine reduction, showing that inhibition of soluble TNF has a broad anti-inflammatory effect, in the brain (because the Olink assay was a CSF – cerebral spinal fluid – inflammation composite).
The most meaningful reduction is a ~-47 reduction of CCL7. CCL7 is considered to increase or decrease rapidly and in close relationship to TNF-signaling. Seeing that reduction points to strong inhibition of TNF, in the brain (taking into account that XPro only inhibits solTNF-, not tmTNF-signaling).
Apart from going back to the same point of XPro potentially not working – which has been abundantly proven – the rest of the conversation does not really amount to much.
19. On due diligence (3)
M. “They're doing EB now too?” [6:55:57]
A. “Uh, yeah. There's some other asset in that indication.
M. “Yeah that that space is pretty competitive, I know it fairly well from Krystal. I met people that believe in the this hypothesis specifically the TNF hypothesis. So yeah I mean I got a handful of drugs that we can look at that uh have already been tracked and tested on this indication that haven't been well TNF related.”
Yes, CORDstrom for RDEB is furthest-progressed, as shown since some months now at the beginning of INmune Bio’s corporate deck.
This is not a TNF-based therapy. It’s a mesenchymal stromal cell-based therapy.
20. On biomarkers (4)
M. “Um this is curious to me, because again, baseline week 12, great, but what about the other doses? And what about placebo? And this, is this log ratio thing. So you're telling me that CSF phosphor-tau 217 went down. What is that?
Roughly a log, and then this other one went down. Roughly, I mean, it's basically no change, that 181, it is a log chart. Okay, so, whatever, I don't know what this is, this looks stupid.
A. “Yeah, I read some articles saying they just love this ptau-217 thing instead of ptau-181.”
M. “I mean the synaptic function cancel and alpha waves, this doesn't look like it's different either. I don't know what this is.”
See above: the FDA and academics like ptau-217 because it’s much more specific than any other biomarker. INmune reported on this back in 2022, before the articles were published that showed that ptau-217 was the best biomarker to track disease progression. See above for further info.
The Phase 1 was not placebo-controlled so questioning where the placebo is means a misunderstanding of the Phase 1 trial.
In that regard, the idea – expressed later – that Phase 1 trials should be placebo-controlled is wrong.
21. On the MoA (6)
M. “I mean we've been looking at a lot, there's a trial and it failed. No, there was data. It was it was stat sig not, or, sorry not stat sig, it failed. Like 0.2 the p value at the end.
That was in the right direction at least.
I have to look at it again
Yeah, I mean Etanercept is like the apples to apples comparison. And I mean, you know, the company's trying to say, like: "Oh, we're not Etanercept because we preferentially, yeah yeah yeah TFR1 not TFR 2." They were smart enough to turn off comments for the video. No conclusions about this drug can be drawn.”
This again touches upon the essence of the short thesis, and the differentiation of XPro. Enbrel and Humira are non-selective TNF inhibitors.
XPro is not inhibiting transmembrane TNF signaling, which is crucial for recovery and remyelination. It is inhibiting only soluble TNF, which is responsible for the pro-inflammatory signaling. That differentiation allows the glial cells in the brain to shift away from their detrimental pro-inflammatory state, without suppressing them altogether, like non-selective inhibitors may (leading to demyelination). Both the inhibition of soluble TNF and the non-inhibition of transmembrane TNF are crucial. There are many papers on that.
Some additional comments follow on the involvement of Harris Kupperman’s Praetorian Capital, Xencor and the video of one of the Phase 1 patients. As for the anecdotal evidence, it’s anecdotal, but the story of recovery from AD already existed when the treating clinician reported on these patients in July 2020. An update on these patients came in April 2024.
Conclusion: On The Possible, part II
This coverage consisted of two parts. In part I, I concluded that all nine conditions considered necessary for a drug to be effective in Alzheimer’s disease are overcome. A combined conditional probability of efficacy should therefore be high.
That conclusion followed from a probability analysis on the basis of the following elements: (i) Xpro binds to soluble TNF with high affinity; (ii) XPro accesses the brain in sufficient amounts to inhibit 99.9% of its target; (iii) XPro is a pegylated selective TNF inhibitor; (iv) inhibition of soluble TNF is relevant to Alzheimer’s disease, as is non-inhibition of transmembrane TNF; (v) the efficacy seen in Phase 1 is relevant given the amount of impressive and consistent biomarkers, including those approved by the field; (vi) efficacy seen in Phase 1 aligns with that seen in preclinical research, confirmed and peer-reviewed by external academia; (vii) MCI and mild AD is the right patient population to target; (viii) there was no lack of efficacy in any clinical trial to data with XPro, contrary to Cassava Sciences trials, the MINDful trial is designed well, and it is early enough in the disease to intervene.
After review and correction of information contained in the live coverage of INmune Bio, no elements put the above into question. In fact, XPro’s data show brain penetration, TNF’s bivalent role in neuroinflammation and neurodegeneration is well established, XPro’s selectivity spares tmTNF allowing remyelination and repair which is in line with academic research and preclinical data, biomarkers confirm CNS efficacy and are in line with preclinical findings, ptau-217 and NfL reportings are relevant, the best ever reported and in line with other biomarker findings, and EMACC is the desired endpoint for MCI/mild AD.
As I stated above, the short thesis hinges on the idea that traditional TNF inhibitors have failed. XPro is not a traditional TNF inhibitors, and a recent study showed improvement of cognition in patients with MCI. XPro’s mechanism of action differs largely from non-selective TNF inhibitors. Furthermore, the short thesis seems to reflect the older academic idea on Alzheimer’s being primarily and amyloid-driven disease, contrary to newer scientific insights.
Therefore, the conclusion on INmune Bio should again be: on the possible.
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