The $10 billion unicorn in INmune Bio: The road from amyloid inhibition to GLP-1 agonists, part II

Summary

The previous blog post discussed the history of drugs targeting amyloid and how commercialization in the Alzheimer’s space is currently looking.

The current blog will discuss the potential of GLP-1 agonists for the treatment of Alzheimer’s disease.

The treatment landscape for Alzheimer’s disease

The treatment landscape for Alzheimer’s disease looked like this in 2024. The updated landscape for 2025 has not yet been published insofar as I’m aware.

About two-thirds of that landscape regards disease-modifying drugs, either biologics or small molecule drugs. The red therapy candidates are related to amyloid. That’s about 22 on a total of about 127.

Semaglutide shown in yellow is categorized as a drug targeting ‘inflammation/immunity’ and. XPro (pegipanermin) is listed in yellow as well.

Metformin is another insulin sensitizer traditionally used as diabetes medication.

Solanezumab and Gantenerumab, two anti-amyloid antibodies, were reported to fail in 2023. Remternetug is another anti-amyloid antibody in trials for Eli Lilly.

A word on Alzheon’s failed drug valiltramiprosate

Valiltramiprosate is (was) Alzheon’s amyloid-targeting drug candidate in pill-form, which failed recently in Alzheimer’s patients who are ApoE4 homozygous, despite showing significant cognitive benefits in MCI patients. In the full analysis set, comprising both MCI and mild AD, valiltramiprosate demonstrated an 11% slowing on ADAS-Cog13 (P = .607), 23% slowing on CDR-SB (P = .309), 29% slowing on DAD (P = .279), and a 17% slowing on Mini-Mental State Exam (MMSE; P = .454). In the MCI, a nominally significant 52% benefit on ADAS-Cog13 and a 102% improvement on Clinical Dementia Rating-sum of boxes (CDR-SB) was seen. In the mild AD population, valiltramiprosate treatment favored placebo on all outcomes, showing an –18% slowing vs placebo on ADAS-Cog13, –7% slowing on CDR-SB, –5% slowing on DAD, –7% slowing on MMSE, and –20% slowing on A-IADL. ARIA was identical in patients on treatment versus placebo.

As an INmune Bio investor, valiltramiprosate was a serious competitor, as it was the only amyloid-targeting antibody with promising efficacy that does not come with safety concerns, and I believe safety is quite underestimated for purposes of commercialization. Alzheon made the mistake of using the bluntest of rating scales, ADAS-Cog13, to target a patient population that is very early in the course of disease. We have learned that that may be enough to make the trial fail. Also, though APoE4 homozygotes are supposed to have high levels of amyloid buildup, the trial did not screen for the presence of amyloid, which – as I have mentioned – is an essential part of the recipe for success in recent trials for Leqembi and Kisunla, implemented by INmune Bio as well.

I will now discuss the potential of GLP-1 agonists for the treatment of Alzheimer’s disease below.

The potential of GLP-1 agonists in neurodegenerative diseases

GLP-1 agonism may come with reduced dementia risk

In a small meta-analysis, the aggregate relative risk of AD for people with diabetes was identified as 1.5, so people with diabetes have a 50% higher risk of developing dementia compared to those who do not have diabetes. Post-hoc analyses of the outcome of trials of semaglutide and liraglutide have shown that, in people with Type 2 diabetes who took either a GLP-1 agonist compared to placebo, there was a 53 percent reduction in the risk of developing dementia.

That somehow brings this slide to mind, showing that rheumatoid arthritis comes with an 800% increased risk of AD, and that TNF inhibitors reduce that risk in these patients by 60%.

This slide has been compelling to some INmune Bio investors.

Apart from the fact that the numbers for TNF inhibitors are more compelling, and that this effect from current TNF inhibitors is remarkable because they are immunosuppressive (and XPro is not), I want to point out one more difference. Whereas inflammation is a hallmark of neurodegenerative diseases on the basis of which INmune believes it can target 75% of the entire AD population, diabetes is not. Type 2 diabetes is a risk factor for Alzheimer’s. But that’s far from the same.

Mechanism of action of GLP-1 agonists

GLP-1 agonists work by agonizing the GLP-1 (glucagon-like peptide-1) receptor, thereby mimicking the action of the natural hormone GLP-1, which plays a key role in glucose metabolism and appetite regulation, and suppress glucagon release from alpha cells in the pancreas. They thereby enhance insulin secretion only when blood glucose is elevated, and lower hepatic glucose production, especially in the post-meal state. They delay gastric emptying, leading to slower glucose absorption and a reduced postprandial glucose spike.

GLP-1 receptors are present in the brain as well where they can have an effect on insuling signalling.

In short, apart from their direct benefits, they also promote metabolic health because they reduce obesity, which comes with a number of benefits for the metabolism. They are indicated for type 2 diabetes, obesity and cardiovascular risk reduction, and may be successful in NASH and other indications, but not primarily inflammatory ones.

The articles here, here, here and here give good insight into why GLP-1 agonists may work for the treatment of neurodegenerative diseases.

Is Novo’s semaglutide an anti-inflammatory treatment?

GLP-1 agonists, for me, are primarily drugs that target metabolic dysfunction and insulin resistance. They do not target inflammation primarily. However, in her interview, Prof. Lambertsen considered: “So we have a strong hypothesis that probably these GLP one receptors will affect the inflammatory processes in the brain.” and although here data are not yet mature enough, she focuses on whether GLP-41 agonists could drive remyelination and lead to improved learning and memory.

And more recent research shows that GLP-1 agonists do have an anti-inflammatory effect. For example, in animal studies, GLP-1 and its analogs reduced macrophage infiltration in blood vessels, and production of pro-inflammatory cytokines such as IL-6, IL-1β, TNF-α, and CRP. In trial settings, reductions of CRP by 35% and in a meta analysis, reductions of TNF and IL-6 of 25% to 50% were reported. I assume, in that regard, that most of these studies related to patients with metabolic disorders, which come with increased inflammation: obesity and type 2 diabetes. Reduce those, and you reduce inflammation. However, in patients without metabolic dysregulation whose primary drivers of Alzheimer’s are different, e.g. viruses, I am less sure that GLP-1 agonists could drive such reductions in inflammatory values.

Anyway, the above is a good basis to try them in neurodegenerative diseases, though I remark that there is no evidence that they work in a selective way, i.e. promoting good pathways and vice versa. As their effects will be partially related to the resolution of metabolic disease, I’m fairly optimistic that GLP-1 agonists will have some of such efficacy at least in obese patients and patients with type 2 diabetes in these patients. I’m less optimistic with regards to the entire population of Alzheimer’s patients.

Preclinical findings

I am selecting here some of the preclinical research that has been made with GLP-1 agonists. GLP-1 agonists have been associated with neuroprotective properties, such as alleviation or reversal of synaptic loss, cognitive symptoms, inflammation shown by activated microglia, central inflammation and oxidative stress, Aβ synthesis, insulin receptor and synaptic pathology, astrocytic mitochondrial function and neuronal loss.

Clinical evidence

A good overview of clinical evidence to date for GLP-1 agonists can be found on the relevant webpage of the Alzheimer’s Drug Discovery Foundation.

In a randomized controlled trial assessing the effects of dulaglutide in 9901 patients with type 2 diabetes and additional cardiovascular risk factors and a BMI of at least 23 kg/m2, the time time until first instance of a test score that was 1.5 or more standard deviations below the baseline mean score in that participant’s country, representing progression, occurred in 4.05 per 100-patient years in the dulaglutide group, and 4.35 per 100 patient-years in the placebo group (hazard ratio (HR)=0.93; 95% CI 0.85 to1.02; p=0.11). A post-hoc adjustment for baseline cognitive performance showed that patients receiving dulaglutide had a 14% lower risk of substantive cognitive impairment as compared to those in the placebo group (HR=0.86; 95% CI 0.79 to 0.95; p=0.0018).

A small-scale, 26-week double-blind study in 38 AD patients comparing liraglutide to placebo, prevented decline in cerebral glucose metabolism. There were also no blood, CSF, or MRI biomarker changes besides for a decrease of Aβ42 levels.

In a 12-week study in patients with subjective cognitive impairment, no cognitive improvement was identified, but liraglutide treatment prevented functional decline within the default mode network structures in contrast to placebo.

In a 12-month study in patients with AD, randomizing 204 patients with mild AD to either placebo or liraglutide treatment, no significant difference was observed in glucose uptake into the brain, but some positive signals were seen in three of five secondary outcomes. Compared to the placebo group, the liraglutide group slowed cognitive decline by 18% as measured by ADAS-Exec, a cognitive outcome that was a combination of the ADAS-Cog and the executive domain portions of the Neuropsychological Test Battery. On CDR-SB, no differences between both groups were identified.

Clinical trial results in PD

I have been following the GLP-1 agonist space for a while now, and have not been overly impressed by results so far.

In PD, Neuraly’s GLP-1 agonist NLY01 was reported to be safe, but failed to report statistical significance in Parkinson’s disease in March 2023.

Exenatide, another GLP-1 receptor agonist, had in 2017 shown that it may slow the progression of Parkinson’s. The results of a phase 3 study were expected to follow mid-2024, and failed (entire study results here). I have expressed my thoughts on this trial in the discord: I saw no trial-enrichment based on the drug's MoA, in fact Parkinson’s disease was targeted but those with type 2 diabetes were excluded from the trial. Insofar as I understand, neuroinflammation is higher in patients with insulin resistance.

Lixisenatide did show better results in a smaller placebo-controlled study: although placebo only saw moderate decline, patients on lixisenatide did not show motor progression over the course of 12 months.

Novo’s Phase 3 trial: a beacon of hope?

The biggest possibility to see an effect in Alzheimer’s comes from two large trial Novo Nordisk has started in 2021, comparing semaglutide versus placebo in patients with MCI or mild AD, confirmed by amyloid PET or CSF Aβ42, for a period of 156 weeks, with CDR-SB as sole primary endpoint and several other secondary cognitive endpoints. Novo’s trial design is explained in detail here. The trial is 95% powered to detect a 20% difference to placebo, and I think that says something about Novo’s realistic ambitions here.

Planned analyses of blood-based biomarkers include NfL, p-tau181, GFAP and hs-CRP, and several other exploratory ones.

That trial should end in 2025, so I expect results from it later this year. 

I add a word on Novo’s trial design as well. CDR-SB is being used as primary endpoint. That’s in line with successes reported by Biogen and Eli Lilly with this rating scale in patients with MCI and mild AD. However, the trial is not enrolling patients whose biology matches semaglutide’s mechanism of action. In my opinion, the trial should have enrolled patients with AD who are obese and/or have type 2 diabetes and Alzheimer’s. Enrolling the entirety of the AD patient population, knowing that semaglutide is only targeting one or more potential drivers of the disease, is risky.

Finally, of all GLP-1 agonists, dulaglutide may have the best properties for AD.

What all this means for XPro

I find these outcomes, so far, all-in-all not very impressive. Most of the trials for GLP-1 agonists ultimately fail. I believe that’s because GLP-1 agonists address some elements of metabolic dysregulation, which may be present in their original patient population on the basis of which meta-analysis have come forth, but which can’t be transposed to Alzheimer’s disease or Parkinson’s disease.

That is different in the case of XPro, as neurodegenerative diseases are characterized by increasing levels of inflammation, which ties in directly to the detrimental activity of glial cells in an inflamed environment.

Novo Nordisk’s trial also does not enrich for people who will respond to therapy because they have insulin resistance or are obese.

Whereas I am hopeful that semaglutide will show some signal of efficacy, which may even boost investor interest, I do not think efficacy will be better than what is currently seen with anti-amyloid antibodies. In that regard, I do quote Christian Hölscher, co-founder and chief scientific officer at neurodegeneration-focused Kariya Pharmaceuticals, which is also developing GLP-1 treatments: “I think there’s some evidence . . . that there’s really a profound metabolic change in the person during Alzheimer’s disease. […] If GLP-1s could reverse this, that would be really exceptional, but I don’t think there’s any evidence for that. […] If those trials show even a small effect, the amyloid strategy will be dead in the water.”

There are no anecdotes of people with Alzheimer’s having been cured taking GLP-1 agonists, and these drugs are now so abundant that I believe that, if that were possible, we may have heard about it by now.

I am not convinced GLP-1 agonists’ anti-inflammatory activity is selective, let alone as selective as Xpro is. I believe that’s what Novo Nordisk has engaged the lab of Prof. Lambertsen for, among other things.

Finally, I believe these drugs primarily address metabolic issues that may also be drivers of neurodegenerative diseases, and in that sense, could be useful as part of combination therapy one day.

Conclusion

I have been writing on this website since 2021, and meanwhile we’re 41 blogs later. Apparently the subject still has secrets for some, although logically I hope to have compiled a set of informative blogs people can refer to once in a while.

In two days, May 2025 will be over, and June will start. June should be the month in which INmune Bio should report data from its Phase 2 trial. I haven't even covered CORDstrom...

That means my time to write what I consider to be most essential to investors is coming to an end.

It should. I have a number of subjects that remain unaddressed. Lack of time is to blame. And I would like to draft at least one more blog post in beauty, with a positive note on Boca ‘Rat’on.

For now, I conclude that the science on amyloid still does not make total sense in my eyes, that Alzheon's valiltramiprosate failed, and that GLP-1 agonists should not be not a threat to XPro’s potential efficacy, in my eyes. In case Novo Nordisk’s trial is successful, efficacy may be all-in-all limited, and perhaps GLP-1 agonists could be added to a combinatory treatment regimen one day.

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INmune Bio investors discord: https://discord.gg/JEA8r7wCGY