The evolution of the treatment failures for Parkinson’s disease has striking similarities with Alzheimer’s.
Just like in Alzheimer’s, traditional TNF inhibitors massively reduce the risk of developing Parkinson's.
XPro is the only drug candidate directly targeting soluble TNF, and perhaps the only one to allow remyelination.
Other efforts to modulate the immune system, or glial activity, have shown moderate success in Parkinson’s and seem to confirm modulating glial activity is a right approach.
Alzheimer’s is the second largest of the neurodegenerative diseases expected to be worth about $8.4 billion by 2026, with an annual CAGR similar to the inflation rate that’s currently dominating the markets.
While the meanwhile infamous clinical hold related to manufacturing questions is still ongoing due to - in my humble opinion - a too slow-moving FDA, I wanted to get my thoughts out on XPro for Parkinson’s disease. We know INmune Bio has been pretty vocal about XPro’s ability to address all neurodegenerative diseases, and their wish to expand their pipeline to all of those.
How realistic is that, really? Let’s take a look at the second largest of those diseases, Parkinson’s disease.
Parkinson’s disease is characterized by misfolded α-synuclein protein, and a loss of dopaminergic neurons in the substantia nigra of the brain. That part of the brain is responsible for the production of dopamine, which controls movements and muscle tone. Drug therapies employ dopamine or dopamine precursor, L-DOPA. They however show no effect on the neurodegenerative process.
Much like in Alzheimer’s disease, efforts so far to reduce alpha-synuclein have not led to much benefit for Parkinson’s patients. There is abundant literature on trial failures, which I won’t cover here, but as an example of recent coverage, one can look here. Current efforts to find cures for the disease are diverse, and apart from misfolded α-synuclein, are also looking at mitochondria, the inflammasome, genes linked to Parkinson’s such as LRRK2, etcetera. Quite some articles have been published on the role of inflammation in Parkinson’s disease. And when one says inflammation, one generally also says microglia. Both are clearly inextricably mixed.
There is a much higher incidence of Parkinson’s in people with inflammatory bowel disease. The incidence of the gut-brain axis has also been highlighted by the team behind INmune Bio at several occasions.
There have been some efforts to try to modulate glial activity by repurposing drugs. Contrary to the many other domains with consistent failures, they have reported positive results, but all in all I find these moderate.
In Parkinson’s, like in Alzheimer’s, large retrospective studies have shown that traditional TNF inhibitors considerably reduce the incidence of Parkinson’s.
XPro stands alone as a drug candidate targeting only soluble TNF, and also as a drug candidate targeting TNF directly. Animal testing has shown that XPro, possibly as the only drug candidate, can promote remyelination and reduces nigral cell loss including loss of dopaminergic neurons, reduces glial activation, and attenuates neurodegeneration and behavioral deficits.
Inflammation and microglial activity in Parkinson’s
On September 20, 2022, an article came out with the name: Alzheimer’s Might Not Be Primarily a Brain Disease: A New Theory Suggests It’s an Autoimmune Condition. The ‘autoimmune’ part is then related to overreactive glial cells, which I’ve covered.
The same has been said regularly on Parkinson’s in recent years. Just some examples:
The next step then is: could we treat Parkinson’s by modulating the immune system, like we seem to be able to in Alzheimer’s? It appears we could. Much like in Alzheimer’s, the neuroinflammatory cascade associated with Parkinson’s disease begins with misfolded α-synuclein. That results in neuronal cell death and chronically activated glial cells, that overproduce tumor necrosis factor alpha and other cytokines. Misfolded α-synucleinelicits microglial immune responses leading to a neurotoxic cascade, (perhaps mostly) within the substantia nigra. Reactive microglia secrete neurotoxic factors that include proinflammatory mediators further accelerating neuronal cell death.
There may be a role for the innate and adaptive immune system here, including the immune system of the gut. I won’t go into this too deep, but I like this article that considers that Parkinson’s is partly an autoimmune disease, and which relates to T-cells recognizing alpha-synuclein in the nervous system of the gut. As it happens, Malú Tansey who has co-designed XPro and is a shareholder and consultant to INmune Bio, also pointed in that direction at several occasions, including recently in a May 2022 interview entitled: ‘The Gut-Brain Connection & Importance of Microbiomes in Parkinson’s Disease’. Some other articles that she co-authored on the matter:
- In Nature – and this is a truly good read, but I’ll just include the photo to keep things simple: The gut-brain axis: is intestinal inflammation a silent driver of Parkinson’s disease pathogenesis?
- In Nature Reviews. Immunology: Inflammation and immune dysfunction in Parkinson disease
- In Neurobiology of disease, an older article: Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention
It has also been shown that patients with inflammatory bowel disease in the U.S. had a 28% higher risk of developing Parkinson’s disease. That study used data from 170 million people in two large administrative claims databases.
Immunomodulation as a target for Parkinson’s disease
In light of the above, are there ways to modulate the immune system / glial cells to effectively treat Parkinson’s? Before I get into TNF inhibitors and XPro, a little word on three other ideas, candesartan cilexetil, sargramostin and a CD22 inhibitor.
- Candesartan ciletexil, a drug to treat hypertension, was found to have neuroprotective effects in rat models models of Parkinson’s disease. It did so by reversing the activation of microglia and reducing their secretion of cytokines. That’s familiar lingo by now, but it isn’t to the larger investment community. Improved outcomes in a mouse model have also been reported, but in humans, insofar as I see, one study from 2022 has reported no benefits on cognition in Parkinson’s patients.
- Sagramostin is an FDA-approved recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) that functions as an immunostimulator. GM-CSF was reported to activate microglia in response to amyloid pathology without also augmenting microglial release of pro-inflammatory cytokines. Preclinical work had shown that the increase of the number of activated regulator T cells in neurotoxin-injected mice produced a greater than 90% level of protection of the dopamine neurons when compared to mice that did not receive the increase of these cells. The regulatory T cells were found to mediate this neuroprotection through suppression of the microglial response to the neurotoxin. Again this sounds familiar. In 2017, Sargramostim had produced good results in a Phase 1 trial in Parkinson’s, but results were modest. Sargramostim has also been tested in a Phase 2 study in Alzheimer’s disease. In 2021 at CTAD, results of that study were published. There was a beneficial effect of sargramostim on MMSE which was retained at the first follow-up visit at 45 days after the end of treatment. In contrast, there was a poorer mean ADAS-Cog-13 score in the sargramostim group compared to the placebo group at the first follow-up visit. That difference disappeared by the second follow-up visit at 90 days after treatment. Other neuropsychological measures showed no statistically significant effects. placebo. Plasma levels of neurofilament light neither changed significantly. All-in-all I call these results moderate.
A two-year Phase 2 trial in Parkinson’s in ten patients was started in 2019 and should be ended by now, but has yet to report data. Results in five patients after one year, without a placebo group however, showed no decline in motor symptoms in these patients and improved UPDRS part III scores from baseline by about 5 points. This is the link to that trial, which is being led by Partner Therapeutics. There are plans to submit an IND and to run a larger trial. Not unimportantly, the title of the May 2021 press release by the University of Nebraska on this trial was: “Immune transformation shows promise for Parkinson’s disease.” Finally, whereas adverse events were considered mild, they did exist. Adverse events reported were injection-site reactions, increased total white cell counts, and bone pain.
- Is blocking CD22 an option? Recent advances in medicine often take a big data approach to see which genes are mostly involved in disease activity. CD22 is a protein that would be able to restore microglial homeostasis. In 2019, researchers reported on a CRISPR-based screening experiment that tried to identify genes involved in phagocytosing activity of microglia. Microglia appear to be the only cells in the brain that produce CD22. As they get older, CD22 becomes more active. Mice injected with brain matter waste (myelin debris) and a CD22 blocking antibody had less debris compared to the control mice. This result suggested that blocking CD22 on microglia increased their ability to phagocytose. And the hope was that this could be done without alerting the immune system.
So, how far are we here? Nowhere, it seems. Epratuzumab is the only CD22 antibody that has been developed so far, by Immunomedics for cancer, but it has also been tested in lupus. Those trials failed to produce a meaningful result. In the end of 2021, Immunomedics has been taken over by Roche in a $21 billion deal, mostly related to cancer drug Trodelvy. No further progress has been made in neurodegenerative diseases, insofar as I know.
Traditional TNF inhibitors massively reduce the risk of Parkinson’s
That brings us to the question: can XPro as a selective TNF inhibitor be of help here?
I mentioned patients with inflammatory bowel disease who were reported to have increased risk of Parkinson’s disease above. Their risk of developing Parkinson’s went down significantly if they were exposed to anti-TNF therapy. It became even lower than that in the general population. The incidence of Parkinson’s disease was not less than 78% lower in patients with inflammatory bowel disease who received anti-TNF therapy, compared to those who did not. I would call that a significant effect.
Anti-TNF therapy has become one of the most common treatments for inflammatory bowel disease. But anti-TNF inhibitors are not approved for diseases of the central nervous system, so one cannot administer them to Parkinson’s patients. And in healthy individuals who do not suffer from a leaky blood-brain-barrier, they may not be able to cross that barrier.
The above report actually comes pretty close to large studies that exist in Alzheimer’s disease that show significant reduction of Alzheimer’s disease in patients treated with TNF inhibitors. A retrospective study on 8.5 million adults showed a significant increase in the incidence of Alzheimer’s in patients with rheumatoid arthritis compared to those without rheumatoid arthritis. But the patients on anti-TNF therapy (but not other immunosuppressive drugs) had a significantly lowered risk of Alzheimer’s. Looking closer, most of the decrease was associated with treatment with Etanercept. Whereas infliximab, adalimumab and certolizumab are antibodies, infliximab is a fusion protein that is half antibody/half receptor, and functions as a ‘decoy receptor’ that binds to TNF floating around in the body. At this point, the level of details is above my pay-grade, but I did want to mention it.
XPro for Parkinson’s
XPro is the only TNF inhibitor fit for the brain. Unlike etanercept and other nonselective TNF inhibitors, XPro does not block signaling by membrane-bound TNF, but selectively inhibits neuroinflammation mediated by type 1 receptors, does not suppress innate immunity or myelination mediated by type 2 receptors.
Contrary to etanercept, it does not suppress neurogenesis, learning, and memory in adult mice. We also know since 2022 that it leads to remyelination in an MS model. I believe both these findings are very important.
INmune Bio’s CJ Barnum’s focus as a doctoral researcher was Parkinson’s, I believe. This is, among others, where this has led to with regards to XPro and Parkinson’s models:
- Peripheral administration of the selective inhibitor of soluble tumor necrosis factor (TNF) XPro®1595 attenuates nigral cell loss and glial activation in 6-OHDA hemiparkinsonian rats. (CJ Barnum, Malú Tansey et al.)
Skipping to the results here:
“Irrespective of start date, XPro®1595 significantly reduced microglia and astrocyte number in SNpc whereas loss of nigral DA neurons was attenuated when drug was started 3, but not 14 days after the 6-OHDA lesion.
Conclusions: Our data suggest that systemically administered XPro®1595 may have disease-modifying potential in PD patients where inflammation is part of their pathology.”
- Delayed dominant-negative TNF gene therapy halts progressive loss of nigral dopaminergic neurons in a rat model of Parkinson's disease (CJ Barnum, Malú Tansey et al.)
“Remarkably, when examined 5 weeks after the initial 6-OHDA lesion, no further loss of nigral DA neurons was observed. Lenti-DN-TNF also attenuated microglial activation. Together, these data suggest that TNF is likely a critical mediator of nigral DA neuron death during the delayed and progressive phase of neurodegeneration, and that microglia may be the principal cell type involved.”
- Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats (this one is with Malú Tansey only)
- Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease (this one is with Malú Tansey only, but Simon Stott, the director of Research at Cure Parkinson’s who runs this marvelous blog which has been the basis for part of the content here remarked that four of the seven scientists having published this article work for AbbVie).
These are results in animal models. At this point I believe we can state that they have marvelously translated to humans. In short, XPro appears to be much more fit for purpose than Etanercept.
XPro has no competition targeting soluble TNF
Insofar as I am aware, there are no other drug candidates targeting soluble TNF for the treatment of neurodegenerative diseases.
The closest I find is BioVie, targeting soluble and transmembrane TNF through the inhibition of ERK and Nf-KB. Seeing that only selective TNF-inhibition leads to remyelination, has been shown to be neuroprotective, to lead to neuroplasticity, and is not immunosuppressive, I am going to assume the others may have longer-term issues with that.
Less clarity for NfL?
I have now published two blog articles on the importance of Neurofilament Light Chain, both from an Alzheimer’s and from an FDA point of view which focuses on ALS but addresses neurodegenerative diseases as a whole.
Neurofilament light chain in serum samples is increased in Parkinson's disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson's disease severity.
But I should add, my research was less conclusive here than it was with regards to Alzheimer’s.
The global incidence of Parkinson’s disease is about 10 million people, one million of which live in the US, 1.4 million in Europe and 3 million in Asia. The global market was estimated to be worth $4,5 billion in 2018, and was expected to reach $8.4 billion by 2026, thereby exhibiting a CAGR of 8.1%. Another report mentions a CAGR of 6.5%, and yet another report expects the market to grow to $11.5 billion by 2029.
As a comparison, the Alzheimer’s therapeutics market is growing at a CAGR of 9.3% - some even estimate 16.2%. That puts in perspective current inflation worries. And contrary to inflation, which I assume will eventually go down with the question just being when exactly that will be and how fast that would be, the incidence of Alzheimer’s or the other neurodegenerative diseases in our society does not seem to be dropping any time soon.
All of that doesn’t take into account the longer-term (long-)Covid-fallout as it relates to Alzheimer’s mostly, but Parkinson’s as well. In patients with an already high allostatic/inflammatory burden, the high inflammatory burden may just be the trigger to disease onset. You’ll read my thoughts on that one day, but what I’m reading does not bode well for humanity if we do not find a cure that deals with persistent chronic inflammation due to lingering Covid soon enough. As for Parkinson’s, just some articles:
Long Covid is a separate indication that I may cover later. It’s highly inflammatory, and presents both in the body and in the brain. That looks like an ideal target for XPro to me. Someone once told me that chronic inflammation may be a disease as such, which exerts its effects on the weakest body parts. The future will tell.
Parkinson’s disease is the second largest neurodegenerative disease. Like Alzheimer’s, it also grows at a disproportionately elevated tempo. And this does not yet take into account the longer-term effect of (long-)Covid on the incidence of Parkinson’s disease.
Inflammation appears to be a major factor here too, as is shown through abundant articles, the remarkably higher incidence of Parkinson’s in patients with inflammatory bowel disease, and the risk reduction in patients who are on traditional TNF inhibitors.
Efforts to modulate glial activity with already approved drugs have led to positive results, but these seem to be rather moderate. CD22, a protein that modulates phagocytosing in microglial cells, could be a good target but drug development is nowhere.
From my perspective, XPro’s selective inhibiting of soluble TNF is the most promising development to target Parkinson’s by modulating glial activity. Insofar as I can see, there actually isn’t another development that has attracted my immediate attention as a potential treatment for Parkinson’s.
Contrary to other possible drugs or drug candidates that do not selectively inhibit TNF, XPro leads to neuroprotection, remyelination and neuroplasticity, and is not immunosuppressive. I am going to assume that explains the upward trend of XPro’s Phase 1 results in Alzheimer’s patients up to and possibly beyond the 12-month timepoint. And the preclinical work in Parkinson’s animal models confirms XPro’s efficacy in those models.
On that basis, I am giving INmune Bio’s goals to extend its pipeline one day high chances of success. Others will see that too. And I believe that pipeline may one day feature long-Covid as well, and big pharma will see that too. I’ll write on that another time.