Good afternoon again, everyone. This is Ami Fadia, Biotech Analyst here at Needham. Welcome to the next session with Cognition Therapeutics. I have with me Lisa Ricciardi, who's the CEO of the company. I also have with me Tony Caggiano, who's the Chief Medical Officer. Thank you both for taking the time to be with us today. What I'll do is turn it over to Lisa for the presentation.
Great.
We'll find some time at the end for some questions.
Perfect. Thank you, Ami. I appreciate being included in today's talk. Thank you, listeners, for listening to our discussion of zervimesine, a once-daily neurodegenerative drug, as we begin our preparations to enter Phase III. We took the company public in the fall of 2021, so you can see all our forward-looking statements. Today, what we'll cover is a very brief overview, a discussion of DLB and Alzheimer's disease trial results. We will not cover our results in geographic atrophy. Let me begin by saying, over the many years Cognition Therapeutics has been around, we've received an inordinate amount of grant income. We punch above our weight in this area, $170 million in grants, which is really the only way a small company can accomplish as much as we have in terms of scientific and clinical work. Now, where we are today is studying DLB psychosis.
That is our next planned study. We think we may be the first to the market with a formal indication for this patient population. One of the factors driving us, of course, is the tremendous results in our prior study of this population, which Tony will cover. The other fact is the realization that this is a huge driver of costs and family trauma, is what I would say.
Patients who become psychotic are typically not able to be cared for at home, so you face that whole disruption of patients being institutionalized. More on that as we go further. Very strong data in Phase II, with an effect on patients of lowering over time disease progression, which we're very excited to further study. We have had over 450 patients treated with our drug so far, so we know we have a very modest safety profile for this particular population.
Once a day drug in our Alzheimer's study, there has been no need for surveillance, no ARIA anticipated with our mechanism, and we're very pleased with our patent situation. This is a limited view, 2040 with patent term extension. Over time, we'll look forward to making other claims about our drug and the ability to commercialize it going forward. In brief, zervimesine is a once daily oral drug. It was designed to penetrate the blood-brain barrier. Binds to the sigma-2 receptor, which is shown on the right here, which is these two proteins, TMEM97, PGRMC1. I think it might be valuable for people to address further questions to Tony at the end of the panel. Potential first for DLB, Fast Track in Alzheimer's disease. Let me tell you about what we have done so far. We have rich clinical information. We are running right now a trial called START.
This is a 545-patient trial. The population are Alzheimer's disease patients who have early and mild forms of dementia. This trial was funded by an $80 million grant. Again, not the kind of study easily accessible to a small company. In addition, right now we're running what we refer to as an expanded access program. To be honest, Ami, this came from the families of patients who are in our trials. They wanted to stay on drug, and we indicated, as a small company, we have to put our money into the next larger trial to move the whole company forward. They provided the funding so that we were able to offer drug to patients who had safely taken the drug, as well as other patients outside of just SHIMMER.
The subject of much of today's discussion will be SHINE results and SHIMMER results led by Tony as he takes you through that. I'm going to turn this to Tony. People have asked us, "Gosh, what are you doing as a company?" We say, "We've had to have important regulatory conversations and then make a decision on what we're doing next." Tony , over to you on this.
Sure. As Lisa mentioned, we've had a couple interactions with FDA recently, both on our DLB program as well as on our Alzheimer's program. For the DLB program, we went to FDA to seek some advice on how we would advance our molecule, zervimesine, through registration trials. We had a good, productive meeting with FDA, and we and FDA both agreed that our strongest signal within the SHIMMER trial was within hallucinations and delusions. They advised, and we think correctly, that we should go and seek advice from the Division of Psychiatry. We'll be doing that and then providing an update in the future after we've had that meeting, where we'll understand how to advance this program. That will be occurring later this year. As we mentioned, we also had an end-of-Phase II meeting for Alzheimer's disease.
Here, as you would expect, we are looking for agreement from FDA on how to design and execute Phase III trials. Briefly, we agreed to run our trials in mild to moderate Alzheimer's disease, enriching this population for individuals who have a p-tau217 blood level at baseline which is below a certain point, and we'll get into some more details around that later. We'll be running trials that are six months in duration, a single dose of drug of 100 milligrams versus placebo, and looking at traditional outcome measures like ADAS-Cog and ADCS-ADL, but also FDA has agreed that we can use composite outcome measures, such as were used within the Eli Lilly and Eisai trials. Most likely this trial will also follow with an open-label extension to allow people to continue dosing. If I can go to the next slide.
I'll talk a little bit about our data from the Lewy body dementia trial, which we called SHIMMER. For those of you who may not be quite as familiar with Lewy body dementia or dementia with Lewy bodies as you are with Alzheimer's disease, this condition presents with really diverse symptomatology. Whereas Alzheimer's is generally a memory disorder for most of the disease course, DLB presents much differently. These folks have behavioral issues such as hallucinations and delusions, cognitive function like memory impairment, as we see in Alzheimer's disease. Their symptoms fluctuate remarkably, which is one of the hallmarks of the disease. They have motor dysfunction, much like you see in Parkinson's as well.
Given that this was our first trial in this condition, we looked broadly at these different symptom domains as well as at global function as well, to try to understand how any changes within these different symptoms were impacting individuals. Here are some of the assessments we used to look at these different symptom domains. Some of them you may or may not be familiar with. Many of them have been used many times, like the UPDRS Part III you'll see in Parkinson's disease, the ADCS-ADL of assessment of activities of daily living that we've used quite often within Alzheimer's disease. We'll point out each of these scales as we go through the subsequent slides. SHIMMER or COG1201 was a study of 130 individuals with Lewy body dementia defined by their clinical symptoms. This study was supported by a $30 million grant from the NIA.
Here, individuals were randomized evenly to one of two doses of drug or placebo and treated for six months. Now, as I mentioned, because this was our first study in this indication, and because DLB presents in a very diverse way, we looked broadly again at their behavioral conditions, cognition, fluctuations of symptoms, their motor function, and then again at general function using the ADCS-ADL. What we find most remarkable about the data coming out of SHIMMER was the consistent effect across the different symptom domains that we've defined. What we're presenting here is a percent slowing, meaning that as the placebo individuals continued to worsen, this is the percent of that lost function that we were able to protect within each of these symptom domains.
You can see again that across the board, we had significant reduction of worsening of this condition, which was also reflected in the ADCS-ADLs. Again, what we mentioned before is that some of the most striking effects of this study were within the neuropsychiatric symptoms, particularly hallucinations and delusions. The data we're showing you here are derived from what's known as the NPI or Neuropsychiatric Inventory, which looks at 12 different symptoms, which you'll see on the right side here. There's an overall inventory score on the left. These data on the left are plotted as those treated with placebo shown in gray, and you can see that their score continues to worsen throughout the six months of this study. Whereas those individuals who are treated with either the 100 or 300 milligram dose of CT1812 worsened much more slowly than those on placebo.
In fact, you can see that at the end of the study, they're really very much the same as they were at the beginning of the study. When you look on the right, you can see how each of the individual symptoms contributed to this overall inventory score. Again, much of this was driven by anxiety, delusions, hallucinations, agitation, aggression, which is important because these are symptoms which are known to be very troublesome for individuals with DLB. In the next slide, you'll see that not only could we observe that these symptoms were stabilized for those who were taking CT1812, but their families could recognize that as well. Along with the Neuropsychiatric Index comes an NPI Distress Scale.
Rather than looking at how these symptoms are getting better or worse within individuals with the condition, here we look at how these individual symptoms cause distress for their primary caregiver, usually their husband and their wife. Much like you saw on the previous slide, here on the left total score, you can see those individuals whose loved ones were treated with placebo, their distress is continuing to worsen. Whereas if their loved ones were treated with CT1812 at either dose, you can see their overall distress was really quite similar at the end of the study as it was at the beginning of the study. What makes this more convincing as well is that when you look on the right side, it's the exact same symptoms that were driving the comments from their caregivers as the physicians observed to be stabilized within the participants.
As we mentioned following our discussions with FDA, we intend to pursue the neuropsychiatric symptoms within DLB, particularly hallucinations, delusions, but also anxiety and agitation. Given that these are four common symptoms within DLB, we've shown the score simply looking at those particular four symptoms out of the NPI-12, and here we've called it the NPI-4. What you can see is when you look at these symptoms together, there's really a very strong treatment effect, in this case, a p-value of 0.001 when you look at how those on placebo are progressing compared to those on drug. Again, this is where we intend to pursue hallucinations and delusions within DLB. As Lisa mentioned before, we have an expanded access program going on right now.
This is a program where we're allowing individuals that have DLB or had been in the SHIMMER trial to receive CT1812 or zervimesine. They're receiving one dose, 100 milligrams daily. Initially, this was designed as a 12-month program, but we announced not too long ago that we expect to be able to extend that treatment period for many of these individuals. I think, in addition to allowing folks to have exposure to the drug through the expanded access program, it's great for us to hear comments coming out of caregivers, physicians, and participants within the study feeling that they are receiving a benefit from this drug. Obviously, this helps motivate us to go on, really, to seek registration so that all people have a chance to receive this drug.
We're always asked, Tony and I, by investors about anecdotal feedback, and what we can say is this is exemplar of that. There's a lot of it. We do get good feedback, and it is exactly that. It's anecdotal feedback that patients, in fact, are doing better, which is how the whole program got started in the first place. That's pleasing. It's not scientific, but it is, as Tony said, compelling for us.
Yeah. As we mentioned, there's a few more steps that we need to take here. We completed a meeting with the Division of Neurology, and we'll now be moving on to the Division of Psychiatry, and the purpose of that is just simply that this division has seen many drugs in development and then for approval based on things like hallucinations and delusions, anxiety and agitation. It's really the most appropriate division for us to work with to plan those registrational trials. Obviously, we also have an Alzheimer's program going on right now. The reason we're in both Alzheimer's disease as well as in Lewy body dementia is because of the ability of CT1812 or zervimesine to prevent the binding of both Aβ as well as alpha-synuclein oligomers to their targets and cause toxicity.
Now, what's particularly interesting, and we think really useful given our drug, is the fact that many of these people, whether they have Alzheimer's disease or Parkinson's disease or dementia with Lewy bodies, have both amyloid and alpha-synuclein pathology. Because of this, we think that our drug may be particularly suited for these conditions. The SHINE study was a study we conducted and reported data out a little over a year ago on mild to moderate Alzheimer's disease. This study recruited 150 individuals with mild to moderate Alzheimer's disease and confirmed amyloid pathology, which was assessed either by PET imaging or CSF sampling. Here, these 150 individuals were randomized evenly to two doses of drug or a placebo, treated for six months, and we followed their safety as well as their cognitive function throughout the course of the six months.
This study was conducted in the United States, Australia, Netherlands, Spain, and the Czech Republic. Much like we saw in our SHIMMER data, what we think is most impressive here is really the consistent effect across all the outcomes that we followed in this study. What we're looking at here is the % slowing of progression, much like we had reported in the SHIMMER study before, in individuals that came into the study with lower p-tau217, and we'll explain why we did that in a little bit. What you'll see here is if we look at cognitive function through measures like ADAS-Cog, or we look at functional and global measures like the ADCS, Activities of Daily Living, or Global Impression of Change. These are two different pairs that FDA likes to see when you're looking at cognition and function.
We'll go through some of that data here. Now, the reason that we looked at those individuals with the lower p-tau217 were because of the data that were coming out of the Eli Lilly and Eisai trials of donanemab and lecanemab. In those trials, Eli Lilly and Eisai reported that individuals who came into the study with the lower p-tau217 responded more favorably to the drug. Now, obviously, those are different drugs than CT1812, but as those drugs remove amyloid and our drug blocks the ability of amyloid to hit its target, we thought it would be wise to conduct a similar analysis in a pre-specified manner, where we took the individuals who had lower p-tau217 coming into the trial and defined those as an individual group and looked at their outcomes. A comparison of that full intent to treat in those lower p-tau217 individuals is shown here.
On the left side, we have the ADAS-Cog 11 scale, which is a typical scale of cognition, looking at all participants within the study. What you'll see is that those individuals treated with placebo, as shown in gray, are continuing to get worse throughout the six months of the study. Whereas those treated with CT1812, as shown in orange, are worsening 38% slower. Now, obviously, this is a smaller trial than Eli Lilly and Eisai ran with their antibodies, but to give you some context, in those studies, we saw a 25% or 30% slowing of progression. Indeed, this is very much in the same magnitude of change. Whereas when you look on the right side of the slide here, these are the data derived from individuals who came into the study with the lower half of plasma p-tau217.
Plasma p-tau217 is overall a good assessment of both brain amyloid and tau. Here what you'll see is that, again, those people treated with placebo continued to get worse. Those are shown in gray, whereas those people treated with CT1812, as shown in orange, worsened really much slower than those on placebo. In fact, you can see here at the end of the study that their scores are very much the same as they were at the beginning of the study, nearly a complete slowing of the advancement according to this scale. The first thing that many people ask us is, well, if your effect is largely within individuals with the lower half of plasma p-tau217, does that mean you're only treating individuals who have more mild clinical symptomatology? That's not the case.
Regardless of whether people have more mild disease, as shown on the left-hand side of the slide here, or more moderate disease, as shown on the right, if they have the lower plasma p-tau217 at baseline, they tend to do much better. You can see again, just like we saw in the full population, those treated with placebo, as shown in gray, are getting worse. Those treated with CT1812, as shown in orange, are again, very much similar at the end of the study as they were at the beginning of the study, indicating again that p-tau217 or brain load of amyloid and tau is a good indicator of who will respond, regardless of their clinical severity. Overall, we've had a very similar safety profile across all of our different studies. The drug is very well-tolerated.
We only follow one particular adverse events, and those are mild and reversible elevations in AST and ALT, which have never been associated with any changes in bilirubin or any other indication of liver injury. Overall, the drug has been very safe and tolerable and obviously continue to follow safety and tolerability as we enter into registrational trials. The other study we have going on right now is our study of CT1812 in individuals with mild cognitive impairment and early Alzheimer's disease. We call this study the START trial. Here we've fully enrolled 545 individuals who have clinically diagnosed Alzheimer's disease, as well as confirmed amyloid pathology through PET imaging. Here individuals have been randomized evenly to one of two doses of drug or placebo.
As this is the earlier stage of the disease and it takes longer to progress and therefore longer to see a differential between placebo and active, rather than treating people here for six months, we're treating individuals for 18 months, and then following their cognitive performance throughout the course of study. Here, the primary outcome is the CDR Sum of Boxes, which was the primary outcome used in Eisai trial of lecanemab. This study, as Lisa mentioned before, was supported by an $81 million grant from the NIA and is being conducted in conjunction with Alzheimer's Clinical Trials Consortium.
One other point to add is that in this trial, Tony and the other members of the leadership team made the decision to let patients on background lecanemab or donanemab enroll in the study, which will give us pretty good insight, with 15%-20% of that population being on concomitant therapy, both safety and an efficacy signal when used in combination. That could be very valuable as we advance our program. In sum, SHIMMER, SHINE, Geographic atrophy, we feel like we've had the opportunity to study our drug, see strong signals, as well as a very consistent safety profile across multiple neurodegenerative conditions. That's what fuels us to want to go across the line to get starting with DLB psychosis, a Phase III program. Last, on cash, we just filed our K. We indicated $37 million current cash.
That takes us to June of 2027, through the end of the second quarter. Of those grant dollars I alluded to at the beginning of the study, we have $36 million left. That funding is dedicated to the START trial, a 545-patient trial. Money's not fungible, but it will take us through the end of the study and allow us to complete it. With that, Ami, that's the end of our formal comments. Again, thank you for including us, and we'd be happy to take any questions.
Great. Thanks, Lisa and Tony, for the presentation. Maybe just a high-level question around kind of the latest feedback from the meeting with the FDA. What sort of was the key driving factor around the pivot towards focusing on just the psychosis element in DLB? Can you also sort of talk about how you see the longer-term potential of studying this in the broader symptomatology where we saw some evidence of effect?
Tony, do you want to talk about the meeting?
Yeah, sure. This meeting was intended to work with FDA on how we could seek approval in DLB. The shift towards or emphasis on psychosis was really just based on the strength of the data, right? So we can run a trial with looking at, say, hallucinations and delusions that is much smaller, much faster, and therefore cheaper and faster to market. We can get drug to patients, and it's better for the company. That does not mean that the effects in the other areas isn't interesting, and perhaps we could pursue them at another time. It's a challenge for us, it's a challenge for FDA, it's a challenge for every clinician in that we know how to look at hallucinations, we know how to look at motor function, we know how to look at cognitive function.
We don't know how to combine that into one measure that clearly makes sense. While we and FDA and clinicians and academicians are open to that idea, right now, there isn't a good way to just look globally at function for people that have dementia with Lewy bodies. The best path is to pick one of those indications. In this case, for us, it'll be psychosis because the data was so strong. Again, that doesn't mean we won't be treating those other symptom buckets, or symptomatology. That'll still be occurring.
Ami, for investors, we like to remind them that this psych Division, Tony alluded to this, approved the other drugs that are out there, whether it's NUPLAZID, REXULTI, COBENFY, AFICAMTEN. There's other pipeline candidates. We feel like it's important investors understand there are standardized measures that one uses to get an NDA approved in certain conditions such as these, whether it's agitation or psychosis or whatever. We feel like that takes away a lot of noise. How we combine, as Tony said, all those broad symptoms for patients, that's very challenging. Picking one, that's very straightforward and precedented by drugs that are very large category leaders in the market. We feel like that should give investors some positive feedback. As we always say, Tony's right about this. A patient takes a pill, doesn't mean only their psychosis is treated.
They get the benefits in movement fluctuations and all those other things we showed at the start of the presentation. The indication will be written as a function of what the trial showed, but we know the patients will benefit across the board.
Yeah, I'm just curious. Of course, you would be pursuing the indication in psychosis, but do you plan to leverage that study to study additional endpoints, perhaps as secondary endpoints that might give you some stronger clinical evidence that you can utilize in the future? I don't know if it's a bit premature to discuss that, but just curious about your current thoughts.
We'll know a lot more after the interaction with the FDA and after we get our meeting minutes. Tony , you feel free to share.
Yeah
Thoughts that are, at this point, just thoughts on substudy.
Yeah. The simple answer to your question is yes, we will definitely study other things like motor function and cognition, and we'll have some order and ranking so that those are protected statistically. If successful, we could get them into the label somewhere. Now, as Lisa mentioned, until we meet with FDA, we won't talk about the specifics of that. Absolutely, we'll be looking at things beyond just psychosis.
Maybe just a last question on this program. Between the 100 and the 300 milligram dose, based on the prior data, latest thoughts on what dose you would take forward into the pivotal?
Yeah. We'll be taking forward the 100 mg dose. We had talked about this publicly after the Alzheimer's meeting. We and FDA both agreed that the clinical effect at 100 and 300 mg is quite indistinguishable. Yet, as with all drugs, less is safer. Fewer adverse events, which just made the decision very obvious to us, and FDA agreed, to proceed with a single dose at 100 mg.
Okay. With regards to your ongoing study, Phase III, what is the process for enrolling the patients, and what is the cutoff for p-tau217 to enroll patients in the study?
Let me just clarify, and I'll let Tony fully address the question. Our START trial did not enroll based on low levels of p-tau217. Going forward, that would be a very appropriate way to run a Phase III trial. That trial, START, with 500 patients, was started, I don't know, two years ago, Tony, before we had the insights from our SHINE trial. We'll see a broad group of patients. I think, as Tony has said previously and on our other calls, because those are early-stage patients, we believe likely many of them, most of them, have lower levels of p-tau217 anyway. They weren't stratified for that because that study started before we knew what we now know.
Got it. Okay. Maybe last question. If the START study has strong data, how would you go about balancing the priorities between DLB and Alzheimer's disease? Would you consider partnering one of the programs?
Well, challenging as it is to partner, the real challenge here is that you have a single molecule, so it's very hard to split indications. As we've thought about this, we recognize our START trial will read out next year. At the end of the second quarter next year, that last patient finishes the study, which means in the second half of the third quarter of 2027, we have results. 540 patients, early study, early patients, once a day oral drug. We're extremely excited to see those results. Meanwhile, this trial that Tony was just describing his discussions with the FDA, that trial will be running. All things being equal, first quarter of 2027, we begin enrollment in the DLB study. Investors will have the benefit of unmasking AD results while they're waiting for the DLB trial to finish. That's how we see that going.
People have asked us, why didn't you do another Alzheimer's trial? We said most investors would say, am I going to put more money into Alzheimer's when I'm still waiting for that huge trial to read out? We thought it just made sense. Complete that study. START DLB. It's very possible in a short period of time, we have two excellent results. Talk about a really important neurodegenerative addition to what doctors have for their patients. That's where we hope to land.
Got it. Maybe just in the last minute or two, just going back to your DLB potential trial design. What effect size do you believe you need to show or need to power for that study? Just current thoughts, obviously, ahead of a discussion with the FDA.
Yeah. Well, we have not yet announced exactly what that would be and what the numbers would look like. What I can tell you is that we modeled it very much off of the data we already have, because that's the data we have, and then put in some extra factors for what if it's not quite as good, and what if a few more people drop out. That's how we've proposed the hiring. Once we have that meeting with FDA, we can talk about effect size or % change, total N, and what we think the study will look like.
Okay. Fair enough.
We're very excited, Ami, about being able to talk to investors about that. How big, how much, how long, which patients?
Yeah.
Sure. Yes, indeed. Sounds like we will have some of those answers by the middle of the year.
Yeah, exactly. Thank you again for including us. We really appreciate it. Thank you.
Thank you.
Thank you both for joining. Appreciate it.
Bye-bye. Yep.