Introduction
For some time now, INmune Bio has been announcing their trial in treatment resistant depression (TRD). The market, either retail investors or analysts, does not seem to give it a lot of attention. XPro for TRD does not get discussed much, nor is any comparison made with other trials going on in TRD or Major Depressive Disorder (MDD).
However, the potential here is enormous, and I mean this literally, it’s ENORMOUS, and I believe this TRD trial is going to pass by like a freight train.
I believe INmune Bio probably wanted to have the Phase 1 trial in Alzheimer’s finalized and read out before starting this trial, to ensure they understand how the drug works in humans enough. That’s most important. Surely, they also make Alzheimer’s their priority goal.
I personally believe XPro may find its way to market equally successfully and perhaps even with faster approval process in depression. The market is simply enormous, patients suffering from major depressive disorder are often desperate for help, and with all I know, I believe the chances of success in this trial are really pretty high.
So, now that the crucial Phase 2 trial will finally kick off in the second half of this year, and will probably be read out before the larger market properly realizes it is even ongoing, or in other words before XPro blows the roof off, I will share some of my insights in this blog and the upcoming one.
B. TRDi – Treatment Resistant Depression in patients with elevated biomarkers of Inflammation
In the last quarterly call of 5 May 2022, a good call to say the very least, the above has finally been mentioned (as of min. 12.40).
RJ Tesi:
“ADi, that’s capital A, capital D, small I, is the term we use to define AD patients with neuroinflammation that are the target of our clinical programs in Alzheimer’s disease. The design of the Phase 2 ADi trials is based on what we learned from the successful Phase 1 trial. The use of biomarkers helps select dose, duration and endpoints of the trials to de-risk programs.
These biomarkers are relevant beyond ADi, and provide new opportunities for the staging and treatment of CNS diseases. The opportunities to use XPro beyond ADi are real. Alzheimer’s disease is the first of the neurodegenerative diseases we will be treating with XPro.
We have announced a Phase 2 program in treatment resistant depression, that’s TRD, to treat patients with neuroinflammation, something we call TRDi.”
CJ Barnum:
“Now I will turn to treatment resistant depression. There are approximately 7 million patients per year in the U.S. with treatment resistant depression. Approximately one third of those patients will have biomarkers of neuroinflammation that we believe is a cause of their treatment resistant depression. Proof-of-concept studies with non-selective TNF inhibitors have demonstrated a therapeutic benefit for patients with treatment resistant depression and biomarkers of inflammation. We have announced the Phase 2 trial of XPro in treatment resistant patients supported in part by a $ 2.9 million grant from the national institute of health. This study is a six-week blinded placebo-controlled study of XPro in 90 patients with treatment resistant depression and biomarkers of inflammation. Consistent with our AD development strategy, we will select patients with biomarkers of inflammation. The primary endpoint will assess the impact of XPro on the functional activity of the reward pathway in the brain. This functional MRI metric is a well-documented change associated with inflammation and key depressive symptoms including anhedonia and motivation which, alongside with traditional depression scales will be assessed as key secondary endpoints. As with ADi, the enrichment strategy and target engagement for TRD patients with neuroinflammation aligns the pathology of the disease with the mechanism of XPro. More information about this study will be available as we get closer to the start date.”
XPro for TRDi
We have our selected patient group, patients with neuroinflammation who have failed two previous lines of therapy, approximately a 2.3 million patient market in the US alone (and I believe it may be bigger, cfr. infra).
Once we accept that depression is a CNS disease – that’s easy – and once we know that there is a depressed patient population with neuroinflammation, and apparently that population is huge, the neuroinflammation/microglial-related pathway can be repaired and should lead to benefit. Or, to use CJ Barnum’s words (because I can’t say it so well):
“There are plenty of anti-inflammatories on the market, and why are they not effective? The answer is, because how you target the immune system is as important if not more important than just targeting the immune system.
What we have here on the right is a little schematic of immune cells that are supporting the neurons. I actually like to think of neurons as infants. You know, infants can't, you know, they can't feed themselves, they can't socialize themselves, they can't do anything on their own. They require parents. That's what the immune cells in the brain are; they provide all the stuff necessary to communicate. So, by suppressing those, you're putting those neurons at a disadvantage. Of course you want to target what we call the chronic inflammation, the destructive aspects of the immune system, when they become dysfunctional, and so what I'm going to tell you about now is our therapy which we believe is a first in class that is selectively targeting the bad and by default promoting the good.”
In the absence of neuroinflammation, the immune cells, or glia, are the sculptors and architects of the brain. When there is too much chronic neuroinflammation, they do more damage than good. That was covered more deeply in my previous blog. Get rid of the neuroinflammation, and you will allow the parents to treat their children as they should. That’s the thesis, and it’s been proven to work.
I would also add: TRD is not a subform of depression, it’s just depression that other anti-depressants have failed to treat. This means that, if the drug is successful in the long run, the addressable market may be bigger, once XPro becomes a first line therapy. That would allow for predictive precision-treatment, in patients who are these days still given drugs in the hopes that some weeks later, the patient’s mood lifts (and more than often it does not). But that’s the farther future.
The title of a previous blog was that identifying subpopulations in CNS diseases makes sense. I should have phrased that much stronger. The identification of the right subgroup is probably the biggest key to success in this trial, and probably any trial with XPro. Talk about the right team with the right drug at the right time. I still see so many trials either in CNS diseases or in depression just targeting the entire population, and then crossing fingers the drug will work for that entire population.
It's not hard to imagine that already depressed patients may become even more hopeless finding that the drugs they are prescribed by their psychiatrists simply don’t do much, if anything. It’s essential that as much patients as possible be given the right drug, if there is one, the first time round.
The Andy Miller study as the pièce de ‘résistance’
Similar to AD, where a beneficial preventative effect of traditional TNF inhibitors had been established, INmune Bio can rely on previous external studies to show the likelihood of efficacy of XPro as a selective TNF inhibitor, only neutralizing soluble TNF.
That’s where Professor Andrew (Andy) Miller, professor of psychiatry and behavioral sciences at Emory University, steps in. His biography on the website of Emory University reads (excerpt):
“Dr. Miller is an internationally recognized leader in the area of brain-immune interactions as they relate to depression in medically healthy as well as medically ill patients including patients with cancer. His work has demonstrated that during immune activation, inflammatory cytokines can access the brain and interact with the metabolism of dopamine and glutamate, while altering neurocircuits in the brain relevant to motivation and reward as well as anxiety and alarm. Dr. Miller has also studied the impact of cytokines on neuroendocrine regulation and sleep including the study of the specific signal transduction pathways involved. Additionally, Dr. Miller and his group conducted the first clinical trial examining the efficacy of a cytokine antagonist for the treatment of depression, providing a template for current clinical trials using immunotherapeutic strategies to treat mood disorders.”
Once again, the right team. Malu Tansey’s on board for AD, Andy Miller’s on board for TRD.
The study he did together with Charles Raison, and this one is widely quoted in neuropsychiatric scientific circles, put 60 depressed patients on either a traditional TNF inhibitor, infliximab or Remicade, or placebo.
It showed no significant treatment effect, and this was very much to the surprise of Andy Miller and Charles Raison:
“You know we were about two-thirds of the way in, and we were seeing all these miraclecures. Man I mean, these people failed multiple antidepressants, and they were saying oh my god this is a miracle cure. You know, I'm going back to work, I've never felt better, so we were utterly convinced that we were going to, you know, become world famous as discoverers of a new general purpose antidepressant agent because there was no way that salt water could have that kind of effect. When broke the blind and looked at the data, in fact, we found that saltwater had exactly that kind of effect, that in the population as a whole, there was absolutely no difference between infliximab and saltwater and that numerically in fact, saltwater was a little bit better.
Yet, when the subgroups with elevated neuroinflammation and those without elevated neuroinflammation were separated, the results were totally different:
“Blue is infliximab, orange is placebo, the bars on the right that I've circled are people that have elevated inflammation. […] And what you can see is that, in that group, the blue bar is way better than the orange bar, and it is much better than the orange bar as regular antidepressants are compared to placebo. So if your inflammation is elevated and you're depressed, and you block inflammation, you get a specific antidepressant response. So why were the groups so equal to each other in the entire population? Well, this is also an argument for the specificity of this immune inflammatory blocking effect. Look at the bars over on the left these in fact are the two thirds of patients that had, you know, lower levels of inflammation. The lower the levels, the less of a benefit they got from infliximab, and the more of a benefit they got from placebo, such that those guys did way better with salt water, and you don't want to block their inflammation, so you know, look at the orange bars, as your inflammation goes up, your placebo response drops. So there's two fascinating things here; it suggests that, if you use an inflammatory biomarker and you use a powerful anti-inflammatory agent, not only do you get a specific effect in that elevated inflammation population, but you get less of a placebo response rate which has been the, you know, the devil of antidepressant studies because it tends to wash out specific effects. So it's a perfect marriage, in these high-inflammation individuals you win on both counts.”
A study in Canada in people with bipolar depression was done subsequently, where Infliximab was shown to have a huge benefit in patients with early childhood abuse, knowing that early life adversity sets people up for inflammation in later life.
Now, these effects of Remicade are remarkable, but XPro is not Remicade, it does not lead to demyelination or loss of synaptic function, to the contrary, it has been shown to lead to remyelination, neuroregeneration and synaptic repair.
Logically, with all that we know from the abundant animal studies and all of the succesful and impressive biomarker results from the Phase 1 trial in AD, using XPro as a selective TNF inhibitor instead of a traditional TNF inhibitor in TRD sets up the TRD trial for huge success. Put otherwise, if even a traditional TNF inhibitor can do the trick, there’s no reason to doubt XPro can.
One last quote from the KOL webinar by Dr. Charles Raison:
“So improved more specific TNF antagonists may represent novel precision medicine-based treatments for the subgroup of depressed patients with elevated inflammation. This look for precision-medicine in psychiatry has been the holy grail, and again, it really looks like these immune molecules may be our first targets for that kind of approach.”
Andy Miller will also be the person of interest for the upcoming Phase 2 study.
May we see a TRD time trial?
The TRD study will be a six-week, blinded, placebo-controlled study of XPro in 90 patients with TRD.
One of the questions that came up during INmune Bio’s KOL webinar was whether patients would be willing to enroll in such a study. As a reminder, XPro is administered subcutaneously like a diabetes shot, so I preliminarily don’t see any issue there.
But the following question and answers are remarkable:
RJ Tesi:“Compliance is a big factor. Do you believe that patients with treatment-resistant depression will accept an injectable drug? And I'll remind you this is a once a week sub-cu injection like an interference shot, or like an insulin shot.
Dr. Charles Raison: "I'll toss in the simple observation that they were willing to accept brain surgery, right. So I mean, the list was long of people that are willing to have their cranium taken off and electrodes put in their head. They'll accept boxes in their chest to stimulate their vagus nerve. They'll accept, you know, multiple seizures while they're knocked out. They'll accept transcranial magnetic stimulation which takes days and days and days of sitting there. Depression is arguably the most unpleasant state a person can be in, and you know, when you really got depression, it's hell, and so sure, if something works, they'll definitely accept it.
Dr. John Schneider:"I would just add to that you do see some adherence issues coming in major depressive disorder but in the TRD group, I think at least the evidence I've seen is of the change in treatment regimens. These people are very much trying to find something that works, and that's evidenced. […] You know there's other interesting general purpose antidepressants that are novel. I'm involved in some of that, and for instance, we're running an 80-person study in mostly treatment-resistant depression. For that 80-person study we have 15 000 people that have filled out the questionnaire to be in the study. There is a huge huge need.”
I believe having picked up that Andy Miller has been asking INmune Bio to start this trial for years already.
The above may bode well for particularly enrollment, and could contrast with the delays of the high-risk MDS/AML trials.
Isn’t depression a mood disorder?
The question arises: isn't depression a mood disorder instead of a neurodegenerative disease? The more specific answer is that neuroinflammation can trigger depression.
Neuroinflammation, mood disorders and cognition in CNS diseases even coincide to a large extent. There’s ample proof, whether it’s more science-based or from one’s personal experience.
“Neuroinflammation involves a combination of psychological, neuroendocrine, and nervous systems resulting in changes of neurotransmitter metabolism, dysregulation of the hypothalamuspituitary-adrenal axis, pathologic microglial cell activation, impaired neuroplasticity, and structural and functional brain changes affecting cognition and emotional behavior. Inflammatory cytokines have been postulated to be the possible link and culprit in the disruption of these systems. The outcome of any type of dysregulation of the immune system in the brain might lead to occurrence of depression, anxiety.” Abstract from the article: The role of neuroinflammation on pathogenesis of affective disorders.
Other recent and interesting articles in this regard, stressing the presence of chronic, low-grade inflammation in several neuropsychiatric disorders, are:
- Role of neuroinflammation in the emotional and cognitive alterations displayed by animal models of obesity – mostly the subchapter ‘Brain Inflammation: A Key Player in the Control of Cognitive Functions and Mood’
And there are many more.
Some more links between immune dysfunction and mood (taken from ‘Neuroinflammation in Mood Disorders: Role of Regulatory Immune Cells):
Patients with systemic autoimmune diseases display a higher risk for mood disorders. And patients with mood disorders have a higher frequency of inflammation-related conditions, including metabolic syndrome, diabetes mellitus, and gout.
That an acute peak in inflammation can affect our mood can be drawn from personal experience. When our body gets sick, or after an accident, inflammation goes up whether peripherally or locally. We feel tired, lack energy, and our mood is disregulated. The temporary peak in inflammation that is our body’s response to such circumstances come with mood-related effects. Once the sickness goes away, or the injury is repaired, we refind our energy and our mood becomes normal again.
Going back to depression, and this is again taken from INmune Bio’s September 30, 2020, KOL webinar:
“So, it's a very sweet story, interferon alpha is a driver of inflammation. It activates some early mechanisms that turn on TNF. The more TNF you get in response to interferon alpha, the more miserable and depressed you are, really suggesting that blocking TNF might have powerful antidepressant effects. So what we've said so far is that, you know, if you inflame people, on average, especially when the inflammation is chronic, they get depressed, and it's got something to do with activating TNF because the more that inflammation activates TNF, the more depressed people get. Do depressed people as a group have elevated TNF? The answer is definitely yes. This is a meta-analysis, when you put studies together, it's very clear that that groups of depressed people have increased inflammation. TNF is the third most often replicated immune biomarker that's elevated, the two that are most reliably elevated are CRP, C-reactive protein, and a cytokine called interleukin-6.”
I would highly advise looking at specifically Dr. Charles Raison’s presentation on INmune Bio’s KOL webinar of September 30, 2020, on TRD (as of min. 16.00). The above excerpt doesn’t do it justice.
Un peu d’XPro pour les ours, s’il vous plait
A bearish temper and mood swings that feel like some of the conditions I have been describing above are the market’s daily cup of tea these days.
With the Phase 2 trial of XPro in TRD starting in the second half of the year, INmune Bio will have three Phase 2 trials running at the same time. Two of these trials are very short, and for the reasons set out above, I believe there’s good chances enrollment of the TRD trial will move ahead much faster than the market is used to these days.
The addressable market in TRD is yet again a multi-billion market, and XPro is this very unique drug with a very clearly designated patient population.
Some days ago, I calculated when I believed INmune Bio could bring results, and how much the share price would need to rise, per day the market is open, to end up where I believe its price will/can/should be when it announces success in MCI and TRD. I think, in fact, that we won’t even have to wait for AD. I came to an additional market cap of about 28 million per day of market open. That’s about a 20% steady price increase on the basis of the present market cap, daily. It won’t go steady like that, sure.
But as shown in the previous blogs and above, I believe chances are huge, and at least much greater than in many other trials I look at, that INmune will indeed announce success in MCI, AD as well as in TRD. And I’m still ignoring INKmune and all of the other neurodegenerative diseases at this point.
In other words, the market can keep on busying itself with only macro-economic problems, but meanwhile, the clock ticks and every day is a day closer to one of those readouts.
So I end by considering, this time in plain English: a little XPro for the bears, please, pardon my French, I’m from the heart of Europe.
INmune Bio is really not the place to showcase a depressive mood right now. There’s too much going on short-term, and way too much at stake. Place your bets, because soon enough rien ne va plus.