CervoMed Inc. Common Stock H.C. Wainwright 28th Annual Global Investment Conference

Thank you, Emily. Good afternoon, everyone. It's my pleasure to update you on the progress we have made over the last several months, over the last year on our neflamapimod clinical program, which is focused on dementia with Lewy bodies and is expanding to other neurodegenerative diseases as well. This is my forward-looking statements slide. I would encourage you to read our various securities filings for more details. CervoMed is a clinical stage company based in Boston, developing therapies for age-related major neurologic brain disorders. Our lead drug is neflamapimod, an oral drug with which we target neuroinflammation and the effects of neuroinflammation on the disease process in a range of disorders. We are the leader in developing the first specific therapy for dementia with Lewy bodies and have expanded the program over the past year into additional disease indications as well. This is neflamapimod, oral small molecule drug.

A very specific inhibitor of this kinase, which I will describe in some more detail, p38 alpha, which is a key driver of neuroinflammation and more specifically, the toxic effects of neuroinflammation on the nerve cell. It's been extensively profiled both pre-clinically and clinically, with multiple studies demonstrating target engagement. Well profiled from a safety standpoint. We have a good understanding. In fact, this is a clear strength in terms of our safety margins, both in terms of preclinical studies, toxicology studies, as well as the clinical safety window we have. Profiled in multiple diseases, but again, our focus and our lead indication is in dementia with Lewy bodies, where most of my presentation will be focused. The past year has been a great one for us.

We've made really major progress, reporting out clinical data from our second phase 2 study with dementia with Lewy bodies, which, as I'll describe, largely replicates the data from our first study. It provides additional learnings, which then has set us up to move into and work with regulatory agencies to define a path into and through phase III, towards eventual approval in dementia with Lewy bodies. We've made progress on the CMC side, the manufacturing side, non-clinical side as well. Again, expanded the program into additional disease indications as well. Again, my focus will be on dementia with Lewy bodies. Second most common neurodegenerative dementia after Alzheimer's disease, third most common chronic age-related neurologic disease after Alzheimer's and Parkinson's disease. Very major high unmet medical need.

I think what's ultimately most important is that it actually progresses clinically faster than does Alzheimer's disease when you stage match with the average time from diagnosis of DLB to requiring nursing home care or full-time assistance only being about 2 years. That said, from a clinical development standpoint and a drug development standpoint, what's interesting about DLB is that even though it's a worse disease, more impact on patients, more caregiver burden, and moves faster, underlying it in the early and middle stages, the amount of neuronal loss and frank neurodegeneration is significantly less than is in Alzheimer's disease. The underlying disease, the neurons are sick. They're impacted, in particular in a very specific part of the brain called the basal forebrain, and a very specific type of nerve cell, the acetylcholine, which is one of the five major neurotransmitters. The nerve cells that produce that neurotransmitter.

But that disease process, as opposed to what happens in the hippocampus in Alzheimer's disease, again, there's less fixed, irreversible damage and neuronal loss and death. And it is fundamentally more treatable if you're in the right stage and the right subset of patients with disease. Now, what has come about over the last, especially 5 years, is a really much better understanding of what drives that disease in that part of the brain, the basal forebrain cholinergic system. And it is about neuroinflammation and the interplay between neuroinflammation and the protein alpha-synuclein, which is what makes up Lewy bodies. So Lewy bodies is the pathology that you see with dementia with Lewy bodies. You also see it with Parkinson's disease. It is the equivalent, in a sense, of what amyloid pathology or tau pathology, the equivalent for DLB or Parkinson's disease is Lewy bodies.

The protein that makes that up is this protein alpha-synuclein? Again, think of it as what A-beta is to Alzheimer's disease, alpha-synuclein is to DLB, though I would say that the link to alpha-synuclein and the very specific mechanisms by which alpha-synuclein induces neuroinflammation and induces a disease process, in many ways is now better understood than it is with Alzheimer's disease. But the key target is the neuroinflammation, and at the end of the day, this has been really very strongly demonstrated in the paper that came out just over the summer. But it is the largest single evaluation of neurodegenerative disease pathogenic mechanisms. It's the largest proteomic profile, 5,700 samples in CSF and plasma, profiling Alzheimer's, Parkinson's disease, PD, DLB, and FTD. And what stands out is that for DLB, this is the front page of the article.

What stands out for DLB is the cytokines interleukin-1 beta and interleukin-6. The key neuroinflammatory proteins that in the brain, IL-1 beta in particular, is a key regulator of neuroinflammation, and that becomes a key therapeutic target for DLB. Which for our mechanism then, this is what p38 alpha does. It transduces the signals when interleukin-1 beta binds immune cells or nerve cells into the effects inside the cell that ultimately leads to the damage to the nerve cell. This is the raison d'etre for p38 alpha. In terms of the neuroinflammation cycle is the signaling of interleukin-1 beta. This is from the literature on the left-hand side. It's longstanding literature. But with our drug, it is a potent inhibitor of interleukin-1 beta signaling, and in particular, interleukin-1-induced IL-6 production. Again, the two cytokines that are at the heart of what drives DLB as a disease.

Our potency here is about 3 nanogram per mil or 7 nanomolar. That's very low concentrations, it's very much in the range of what we achieve in patients, and that's directly demonstrated in the right-hand part of this slide where at concentrations that you measure in blood, in that range of 4 nanograms or higher per mil, you see a robust reduction of spinal fluid interleukin-6 levels. In patients with Alzheimer's disease, demonstrating the clear translation of mechanism into in vitro effects into effects on patients on this very specific pathway, that is a driver of what the disease is in dementia with Lewy bodies. This has been worked out in much more detail.

Again, it is the link on the left-hand side between alpha-synuclein and neuroinflammation to the very specific pathogenic steps that leads to disease, synaptic dysfunction, and if unchecked, eventually neuronal death or neurodegeneration, is the protein that our drug targets. The protein p38 alpha and our drug neflamapimod blocks the activation of that and breaks that correlation between the two. This is actually a more broader model of what p38 alpha can do. You can slot out alpha-synuclein and put in A-beta. It's the same effect of blocking the effects of amyloid beta on these pathogenic mechanisms. You can slot in TDP-43, which is a driver of ALS, up above, and the interplay of TDP-43 and neuroinflammation, how it leads to actual axonal transport defects and ultimately synaptic dysfunction, neurodegeneration. The link is p38 alpha. It's the reason why it has potential in a range of neurologic disorders.

We've shown this then very directly and validated that whole model in two different animal models, but in particular, a Down syndrome animal model. Down syndrome, there is neuroinflammation. It's actually linked to a gene on chromosome 21, which is the three versions of which is what causes Down syndrome, the trisomy in the chromosome 21. There's an inflammatory gene marker there. Gene S100B, which increases interleukin-1 beta levels. In this model, the consequence of that is again, disease in the basal forebrain cholinergic system. You see loss of cholinergic neurons in the middle panel. With 1 month of treatment, you see an increase back to the healthy mice levels. We saw behavioral effects as well, and then fully validated the whole mechanistic model because we showed the downstream markers of IL-1, interleukin-1 beta signaling, which are upregulated in these mice.

There's a blockage, and that's what ultimately leads to the reversal of the disease process. We've actually now, in very recent data out of our Phase 2b study in DLB, we've shown that effect directly in humans, that reversal of the disease process, where in that you can do MRIs, you can see the effect of disease as a shrinkage. With treatment with neflamapimod in patients with dementia, with Lewy bodies, there is an increase in volume of 3.5%, while in the placebo group over 16 weeks, there's a decrease, which is what natural history otherwise shows. There's a progressive atrophy or shrinkage of the brain. It's small numbers, but it's significant. Then you can see the effect very directly on the right-hand side. Those placebo patients who were decreasing, in particular, the 4 here and the 3 down in here, decrease.

When they went on to neflamapimod during the extension phase, there is actually either a stabilization or actually an increase. You can see that direct effect linking all of the translational work and mechanistic work we have done. Before going to the clinical data, that part of the brain, again, as I said that it is reversible. The neurons are sick. They are not dead. But as the disease progresses, you get neuronal death and loss in other parts of the brain, in particular in the hippocampus. If you do progress with that, you see evidence of it is always in association with Alzheimer's disease co-pathology, amyloid or tau. With that, your ability to have a reversal or that better treatment effect, patients effectively become less treatable. That is why we focused on the patients who have pure DLB. From a clinical standpoint, you measure this effect now.

In DLB, the best clinical endpoint is the Clinical Dementia Rating Sum of Boxes, or CDR Sum of Boxes, which is a measure globally of dementia, both cognition and the effects of cognitive deficits on function down below. It works. This is the singular endpoint that works the best to follow disease progression in DLB. It is historically well accepted in Alzheimer's disease as a primary endpoint, but having gone to the regulatory agencies over the past year now, we have agreed and we have aligned with regulatory authorities, and they have signed off. FDA, the Europeans, the U.K., Japan, all signed off this as the primary endpoint that could lead to approval in DLB. This is the Phase IIa result, which we published in 2022 and 2023. There is a significant reduction in the rate of worsening in the CDR Sum of Boxes.