Good afternoon, everyone. Welcome to day two at the Piper Sandler Healthcare Conference, the 37th Annual Piper Sandler Healthcare Conference. This is David Amsellem from the biopharma research team . So we're delighted to have Cognition Therapeutics with us. We have Lisa Ricciardi, President and CEO. Thanks so much for taking the time to.
A pleasure to be here. Thank you.
Speak with us, and lots going on, so I just want to dive right in, so I wanted to start at a high level on CT1812 and really go through the underlying mechanism of the molecule and how it exerts its neuroprotective effects. I think that'd be a good refresher for folks listening in.
Yep. So the drug was designed to block the effects of toxic oligomers. So the way it works is it binds to two proteins on the surface of neurons. They're referred to as TMEM97 and PGRMC1. And when it binds, what happens is the adjacent oligomer receptor complex has what we call a conformational change. I said during Testing the Waters , this is like I put a garage on my house, my neighbor gets water in his or her basement, right? It's a downstream effect. And that effect is reduced binding affinity. The oligomers do not bind. So the ones that are bound are released. And what we see is a return to health of those synapses. We saw it in our SEQUEL trial. We've proven this over and over in a variety of studies. But that's the simplest way to talk about it.
Unlike antibodies, we are not peeling anything out of vessel walls.
Yep. Understood. Okay. And that has, I would imagine, has safety implications as you think about it. Yeah. So we could talk about it a little bit later. So let's go into the CT1812 clinical program in dementia with Lewy bodies. I know that there's an Alzheimer's program, but lots going on in DLB. So as a starting point, though, talk to the overlapping pathology between DLB and Alzheimer's.
It's a great question, David. And it's getting further elucidated all the time. So what we know is patients that have Alzheimer's disease, of course, they have amyloid plaque. But 50% of them have very large proportions of alpha-synuclein, which is what you see in Parkinson's disease and Lewy body dementia. If you were looking at Lewy body dementia patients, 80% of them would have the findings of elevated or abnormal plaque burden. So the two populations with more research look more and more have overlapping pathology is what I would say. And that was the reason we thought Lewy body dementia made so much sense as a second indication for us after Alzheimer's disease. Because we knew how the drug worked and we thought this population has no drugs and our drug appears to work against both of those sets of toxic proteins.
Before we dive into the clinical program for CT1812 and DLB, I wanted to take a step back and just talk about how these patients are currently managed. There's nothing approved for DLB. It's a whole range of off-label uses of medications with all kinds of limitations. There's different functional domains that are addressed. But can you talk to just the management of these patients currently?
Yeah. It's such a good question. The biggest challenge is diagnosis. So depending on what gets impacted first in a given patient, if it's their movement, if it's GI symptoms, if it's the neuropsych symptoms, they will end up at a different doctor. And what we have observed and been told is it generally takes seven visits, three different specialists, and a year and a half to get these patients diagnosed. The cognition part is rarely the first thing that brings patients in. They're falling because of the Parkinsonian condition that's driven by the alpha-synuclein toxicity. The neuropsych symptoms are probably the most devastating. Aggression, agitation, alarming symptoms that make it hard for them to be cared for at home, hallucinations and delusions. And then the cognitive symptoms eventually show up, but not typically first. So how are they managed? Not well.
GI symptoms, they get all kinds of things for constipation, sexual dysfunction. These patients can't take the atypical antipsychotics because of their dopamine considerations. And so one of the things we're most happy about is we can address those symptoms and not make patients worse. Sometimes patients get rigid, they're hospitalized, they get not paralyzed, but the antipsychotic drugs are very problematic. So it is a cocktail of symptoms and a cocktail of treatments, what you have today, with a long time to figure it out, unfortunately.
Yeah. So you have the SHIMMER study in DLB. Let's go through the outcomes of SHIMMER. I guess what's interesting to me here, just looking through the data, is the benefit across a number of domains, cognitive to functional to behavioral. So I mean, this is a multi-part question. Can you talk through the data here, but also talk to what that implies for how you design a Phase 3?
Oh, it's a great question. So yes, we have results across all the symptom domains, the strongest being in the neuropsych symptoms, then in the cognitive symptoms, movement disorders, and a big impact on fluctuations, which is captured as part of the cognitive symptoms. These patients, if you go on YouTube and you just do a quick search and you listen to patients talk about this, you would be very disturbed. They wake up and they have no idea, is today going to be okay? Am I going to be able to focus? It's physical as well. I listened to one man talk about, "Oh my God, last week I needed a walker. This week I don't." Like they really don't know. So there is a whole set of symptoms.
What we think is that by addressing the underlying mechanism, if you will, that is getting rid of the toxicity preventing the alpha-synuclein and the A-b eta to bind, we think that by getting rid of that, this is behaving like a disease-modifying drug. I have no idea how important those labels are or will be going forward, but you want to see the benefits in the patient's ability to move, get dressed, bathe, leave the house, find their way back, have fewer hallucinations. The agency is very focused on ADLs. So they will say to us, "Okay, really two fewer hallucinations, what does that do?" Well, it might do a lot for the patient, but as an approvable package, they're interested in looking at how do we make the most robust case for efficacy.
Today, what we talked about, press release this morning, Type C meeting, that will be the subject of our conversation with the agency. We have ideas, we have a plan, we know how we want to proceed. We want to have a conversation with the FDA about how do you take all of these things and create an endpoint or set of endpoints that best reflects efficacy and the patient's health.
Yeah. So you mentioned the agency, the division is interested in activities of daily living. So I look at that as one domain, but then there's behavioral, there's cognitive. And I realize it's a hard question to answer because you haven't had the conversation with the agency, but just what do you think is most likely going to happen here? I mean, is it going to be some sort of composite endpoint that's going to be incorporated into the study?
Since we're the first company moving into Phase 3, there really isn't a precedent to inform us. I think what you just articulated is very possible. It makes sense given the strength of the data across very disparate symptoms. We have investors say to us all the time, "Oh my God, this drug clearly works." It's doing something in Alzheimer's disease and Lewy body dementia, even in ophthalmology. The question is, in this indication, how do we best measure it? I think that'll be a partnership with the FDA to figure out how to do that.
So you press released the Type C meeting this morning. Can you just talk about timing and minutes and then next steps?
Happy to do that. So the Type C meeting we've indicated is in the second half of January, so kind of around the corner. We'll all have our winter holidays, go to J.P. Morgan, and then we'll be at the Type C meeting. Minutes follow that. We found with the FDA for End- of-P hase 2 meeting, the minutes were within 30 days. And despite what we all read about changes at the FDA, they were right on time. So we anticipate that as well. We also indicated that the EMEA, we have a meeting with the European authority for Alzheimer's as well. So for us as a company, AD, Lewy body, U.S., EMEA, we're putting all of this together to identify the best path forward. And we don't think we can do two sets of clinical trials at the same time, but this is a crucial time for us.
We are so excited that the agencies have been very responsive.
Do you think, I mean, given the absence of an approved drug for DLB, do you think in the U.S. at least you can get to a filing on one pivotal trial?
That's a really good question. I think when we talk about it internally, we don't have input from external advisors on this topic. Our general sentiment is, you know, if you get a 0.0000 whatever p-value, some just overwhelming indication of results, possibly. I don't know. There's nothing for these patients. So it's easy for you and I to sit in these chairs and think people in Washington will agree with us.
Yeah, and it's just hard to prognosticate how the agency would think about it.
That's right.
Okay. Fair enough. So we will stay tuned. We'll know soon enough. So wanted to move on to mild to moderate Alzheimer's. So you have the SHINE study. Before I go into that, though, a big part of the study was looking at the subgroup of patients with a lower p-tau217 burden. So at a high level, can you talk to the importance of p-tau217 burden in Alzheimer's?
Right. It's another great question, David. Thank you. So p-tau217 tells you about brain structure and health, right? Which is different from symptoms. In our corporate deck on our website, we illustrated and we said there are patients who are moderate. I mean, they're not doing well and mild. And for every single patient, we identified how much p-tau they had. So you will have patients who are moderate patients, meaning they're going to severe, they're probably not functioning all that well, and they have a low level of p-tau, which is surprising. And you have early-stage patients that have high levels. So the point is the level of burden measured in the brain is not necessarily correlated with symptoms.
What we saw is, when we screened patients for the level of tau burden, game changer in terms of the results, like 95%, 100%, 108% slowing of Alzheimer's disease in that group of patients. That was half the patients. Because we took the median and took the lower half of patients based on their p-tau level.
So this is something that it's interesting because you bring up a point that there's some counterintuitive aspects here where you have a patient that has or highly symptomatic, but their burden is pretty low. So what do you make of that? Because you did take the patients who were below the median and you did see a real impact. So how should we interpret that as it relates to understanding the role of p-tau217 burden?
I think the role of p-tau217 is, as I said earlier, a measure of the structural impact on the brain. And that's all it can tell you. And we have to accept the fact that behavior is sometimes different, or rather the impact of symptoms is different. What we do know is these patients responded so much more positively that the FDA said, "And by the way, this is a commercially available blood test. Like the burden is low to find these patients." And the FDA were very emphatic about if you can find patients with a higher likelihood of responding, that's your target. You want people to have access to a drug that could help them.
By the way, is this a blood-based test?
Yeah.
Okay. That's important.
And it seems like the last couple of years, you and I wouldn't be having this conversation, right? These things are moving along quickly, which is great.
Let's go through the SHINE data here and just in terms of the specific cognitive and functional outcomes you saw in the patients with the lower p-tau217 burden.
What we saw in July of 2024, we went to the AAIC in Philadelphia and we showed the intent-to-treat population. There what we saw was about a 38% slowing of disease progression. By the way, the antibodies had come out just ahead of us and they were 25%-30%, somewhere in the exact same range. They were studying a less severe population. They were studying mild patients. We were studying moderate to severe. The first results people looked at and said, "Well, great, it's oral, but why is that so different or important?" Right? We're judging this by the market reaction. We then got the second tranche of our data from our CRO and saw in this population, half of our patients with lower levels of p-tau, almost no progression of disease over six months, like 95% reduction in disease progression.
So we looked at the ADAS-Cog-11, the MMSE, the ADAS-Cog-13, ADAS-Cog-13. Across everything we measured, these patients performed far better with CT1812 treatment. That is to say, protecting the real estate that they had. And the same thing was true with ADL, 60%, 70% slowing of that inherent deterioration. So those were terrific findings. A good indication where to go.
And that was at how many months post or how many weeks? That was at six months.
Yeah.
So I'll come back to that, but you had your End-of-Phase 2 meeting and then so just walk us through the outcome of that End-of-Phase 2 with the agency.
Great discussion with the agency, and honestly, we always say to investors, we couldn't have asked for anything more, so the agency agreed. First of all, if you're thinking down the road to a label, you're talking about mild to moderate Alzheimer's patients, and they weren't immediately jumping to, "Oh, it's only those with low p-tau." None of that. We studied mild to moderate patients. That was number one. Number two, they said, "Enrich the population for those with lower p-tau. Do the best job you can for these patients." Three, use one dose. We had two different doses. The 100 and 300 were overlapping in both SHINE and SHIMMER, and the agency said, "You have fewer side effects at 100. Use the 100." We were prepared for the agency to say, "Oh no, study 50.
You don't know how they're going to react." So that was the third thing that we agreed on. Endpoints, they said, "You can look at a composite. You can look at co-primaries." We were surprised by that. We thought they would be much more stringent. So in the poster that was at CTAD on Monday, we talked about, "Okay, if we're measuring with ADAS-Cog-11, if we're measuring with the iADRS, this is how it would look." So we're evaluating all of these things. One of the benefits of the iADRS is that it may mean a slightly smaller trial. So it's less cost, it moves more quickly. And the last thing, the duration of the trial. So we were very surprised when they said, "You can run a six-month trial because you showed separation.
The moderate patients declined enough to show separation." So for us, what we're evaluating is, do we want one six-month trial, one longer trial? What's the right thing to do here? Because what you would really hate is to find out, "Oh, we needed seven months and the whole thing was a bust," right? We're trying to carefully evaluate how do we best structure the study to ensure the inherent efficacy of the drug is captured and shown.
So to be clear, you haven't decided on primary outcome measures just yet.
That's right.
In terms of p-tau217 burden, numerically, I mean, what is that threshold below which you're including patients?
Turns out to be really easy. One picogram per milliliter. We literally took everyone in the study, 155 patients. We looked at their p-tau217 level, ranked them high to low, drew a line in the middle. It was pretty simple. Now, we work with a group in Amsterdam. It's called the VU. And it has a huge brain research institute, a huge number of patient samples, long-time partner to the company. And when we looked at their data, they used a slightly different assay. It's just about the same in terms of the cut below which we will capture patients. So it varies based on the assay you're using, but we think that's probably in the right ballpark.
Now, do you include mild patients? Like you look at MMSE scores that are just mild and you include those with your lower p-tau burden, or do you have to include moderate patients as well, or that?
No, it's mild and moderate in the range.
It would be moderate.
Yes, 18 to 26. That was what was on the poster. MMSE of 18 to 26. And as we have shown in our current corporate deck, the patients who have the 26, right? Out of 30 questions, they get 26, right? They're in pretty good shape. Some of them have very low levels of p-tau. And the more severe ones who are getting everything wrong, they're the 18 of 30, right? Some of them have low or high levels of p-tau. So as I said, symptoms and measurement of brain tau are not necessarily correlated, which is why we want to do the blood test. And we're not screening for mild over moderate or vice versa. We're not looking to parse that.
Yeah. It sounds like if I'm conceptualizing p-tau217 burden correctly, that's almost a marker of, I want to say, rapidity of progression. Is that one way to think about it? Or is it, I mean, because you're getting moderate patients who have low burden, right? And so again, there's sort of a counterintuitive aspect here. But how do I conceptualize that low burden? I mean, you might have moderate disease, but a low burden. Does that mean that you potentially, if you're taking drug, you have the ability to slow that burden because you slow that disease progression because your p-tau217 is low?
It's a great question, and I think in a larger trial, we'll be able to look at it. We'll have enough moderate patients and mild patients to take a more fulsome look at that. Right now, what we know is if you take low and high, the low patients have a much, much greater benefit in all aspects of the trial that we're studying.
I'm assuming in the pivotal, you're going to stratify the mild and the moderates to.
You know, we're working on that. We're working on that. It's interesting that you asked that question, David, because I'm not sure how important it is to clinicians.
Fair enough.
Right? I don't know. In our START trial, patients have the ability to come in. These are early-stage patients and they can be on lecanemab or donanemab. And so what we've been thinking about is what is it physicians want to understand so they can treat these patients? And so far, no one has said, "Well, if it's MMSE of this, not that." They're looking at patients who clearly have Alzheimer's disease and they're moving fast and they want to do something for them.
One thing I did not ask is your thoughts on the rapidity of benefits, six months. I mean, that's shorter than what you see with the Aβ-directed therapy. And you have an oral agent here. So what do you make of the speed of benefit here? I mean, six months is a fairly short time period. I mean, mechanistically, and again, I mean, it's a biomarker-enriched population. So how do we interpret that? What do you think explains that?
I'll take you back to a clinical study we did with maybe it was 30 patients two years ago. This was called SEQUEL. So we gave patients drug and it was a crossover. So they were either on drug or they washed out, went to placebo, vice versa. It was one dose of drug, as I recall. The point is using EEG measurements. They were all captured using EEG measurements. In four weeks, you could see that patients' EEG scans were returning towards normal. Like the impact, to your point about rapidity, if you're getting rid of the toxic oligomers sitting on neurons, you actually see a functional benefit quickly. Now, is that going to be our goal in our Phase 3 trial, David? I'm not sure. I don't know if speed matters. What matters is a safe and sustained reduction of progression. Will it happen quickly?
The data we have so far tells us it does. We have another study. It's called SNAP. We put patients in the hospital, put a catheter in their back. They had a five-hour run in and then every hour on the hour, a CSF draw was taken. And what you see, it's just a beautiful chart. The oligomers, you look at it, it's perfect. It's like some kid drew it. Being kicked off the synapses. And that's another, that was more of a mechanistic result. The behavioral result was in SEQUEL. So we see that the drug has an impact quickly. How that will factor into our Phase 3 design, I don't know. But long-term condition, right? So it's not like your kid needs to get back to playing tennis or lacrosse. So getting them back fast matters. It's a different paradigm here.
Yeah. I didn't ask about safety and tolerability, but can you talk about that real quick?
Yeah. We see all the same things that you see with elderly patients that have multiple comorbid conditions. So there's nothing that stands out. The one thing we do follow are changes in liver function tests, AST, ALT. And what we have seen is these are reversible. There is no Hy's Law. There is no change in bilirubin. In fact, we've amended our protocol so that if a patient goes above a three times upper limit of normal, we follow them because they come back down. We previously took patients out of the study. So that is the one thing that we follow. Other than that, in fact, in our dosed population, the serious adverse events were less than what they were in the placebo population. I think the same was true. We had one death and none in the active. So generally speaking, it's a well-tolerated drug.
It's an oral, easy to take. You're not driving anywhere for surveillance on how is your brain doing.
Right. So let's talk about the START study. I know we have about a minute left. So this is early AD, mild cognitive impairment. So just one thing that's unique here is that some of the subjects are on background Aβ-directed antibodies. So I'm just trying to get a better sense of what you're looking to tease out in this study.
The study was designed to be kind of a real-world study, right? That was the goal with our partner ATRI. We knew because over the course of this study being designed and us getting the $80 million of funding, Biogen came out and then came Aduhelm and then came Leqembi and donanemab. The decision was made. Doctors are going to use multiple therapies. We should see how it works in our trial. To date, we have somewhere between 10% to 20% of patients who are on a background stable regimen of one of the antibodies. What we'll see, I think what we're going to find out is safety, what's it like when the drugs are administered concomitantly. We're not looking to dose, stratify the groups and have treatment arms that have equal numbers of antibody and CT1812. It's really more observational data.
But it should be informative for physicians treating these patients.
I know we're out of time, but I wanted to sneak in one last question. Are there other potential neurodegenerative conditions for which you could explore CT1812?
Yeah, absolutely. Parkinson's disease dementia. We've had a lot of inbound requests around that. Multisystem atrophy, a far smaller condition. We're pretty excited, and we had a drug trial called MAGNIFY where we treated patients with an oral drug that got to the retina, the back of the eye, and had the same level of efficacy as the two approved injectables. And so we also think about, wow, when can we get back to studying that? No more shots in your eye. It'll be very exciting. The most close adjacent space, I would say, is Parkinson's. But if our eyes are bigger than our wallets, there's a whole bunch of things we want to do.
All right. More to come. Well, thanks so much, Lisa. Thank you, everyone.
Thank you.