Cognition Therapeutics, Inc. (CGTX) Earnings Call Transcript & Summary

Good morning, and welcome to the Cognition Therapeutics Investor Webcast. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Cognition website following the conclusion of the event. I'd now like to turn over the call to Lisa Ricciardi, President and CEO of Cognition Therapeutics. Please go ahead, Lisa.

Thank you. Good morning, and welcome, everyone. My name is Lisa Ricciardi. I'm the President and CEO of Cognition Therapeutics. Today, with my colleague and advisers, we will take you through the results of our proof-of-concept Phase II study referred to as the SHINE trial of CT1812 in patients with mild to moderate Alzheimer's disease. Turning to the next slide. For your reference is our forward-looking statement noting some of the statements that we may make are forward-looking and subject to various risks. We encourage you to read this. Turning to Slide 3. In brief, you are all aware that 35 to 45 -- 40 years of research looking at the amyloid cascade hypothesis has produced much [ great ] science, a lot of papers and 2 approved drugs. Today, we and all those in the field look at treatment approaches for Alzheimer's disease with a broader focus. At Cognition Therapeutics, the opportunity we see before us is focused on the oligomer hypothesis, that is an understanding very well established in the field that the most toxic form of amyloid is in fact in the oligomeric form. These oligomers are believed to be responsible for significant cognitive decline. What is our solution to this? Cognition's lead asset referred to as CT1812 is an oral small molecule that antagonizes amyloid oligomers through a unique mechanism of actions, leading to what we believe is a neuroprotective effect. Today, we hear to review our completed proof-of-concept Phase II study in patients with mild to moderate disease. In this study, we believe we have strong signals of efficacy across multiple endpoints of Cognition, though we did not demonstrate statistical significance for these endpoints. This trial also provided movement in certain biomarkers, which demonstrated a neuroprotective effect. CT1812 is an oral once-per-day drug easily administered to patients, which based on these results may confer efficacy benefits as monotherapy and potentially in combination with other drugs. In addition to our SHINE results, we have multiple other studies running, including another proof-of-concept Phase II study in dementia with Lewy bodies. We refer to this as our SHINE trial. And with our partners, the ACTC collaborative group, we are now running a trial with 540 patients who have early disease. Last, our proof-of-concept MAGNIFY trial is evaluating CT1812 for the treatment of geographic atrophy secondary to dry AMD. Now let me turn to the agenda today. First, we will briefly review the development history of CT1812, we'll review the results of the SHINE study, including cognitive measures, functional measures, safety and tolerability and biomarker findings. And after reviewing the SHINE study, we will invite commentary from a leading neurologist in the Alzheimer's field. We'll conclude with a question-and-answer period. I'd now like to introduce our speakers. Presenting here this morning, I'm joined by my colleague, Dr. Tony Caggiano, CMO and Head of R&D; Dr. Jort Vijverberg, who is a staff neurologist and trial specialist at the Amsterdam Alzheimer's Center, Jort was a PI for this trial in Amsterdam; and Dr. Martin Sadowski, who is Professor of Neurology, psychiatry, biochemistry and molecular pharmacology at NYU, where he also runs or is the Director of the Alzheimer's drug trial program. He is widely known as an industry leader on Alzheimer's disease landscape and trials. I'd now like to turn the program over to my Chief Medical Officer, Dr. Tony Caggiano.

Thank you, Lisa. We are very pleased to discuss the results of our COG0201 SHINE study, which is the first proof-of-concept study of our lead drug, CT1812. CT1812 is a small molecule oral experimental therapeutic, which was developed in our Pittsburgh, research labs. All the intellectual property is wholly owned by Cognition Therapeutics. Our data have demonstrated that CT1812 displaces toxic amyloid beta oligomers. And we believe because of this mechanism, the drug has a strong potential to treat Alzheimer's disease. CT1812 safety and tolerability and certain CNS functions have been explored in smaller Phase I and Phase IIa trials. We have completed trials of target engagement, neurophysiology and anatomical effects of CT1812, we have -- where we have shown that the displacement of amyloid oligomers normalizes the EG patterns and shows trends for slowing brain atrophy in people with mild to moderate Alzheimer's disease. Now turning to the SHINE trial. The first patient -- our first participant was randomized in the SHINE study in October of 2018. Following an interruption due to COVID, the final participant completed the trial in May of 2024. I will take us through the clinical outcomes, and then ask Dr. Jort Vijverberg, who is a principal investigator in this study to comment on the data and review the biomarker and safety results. In our presentation, you will see consistent slowing of progression across clinical outcome measures, a favorable safety and tolerability profile and taken in total, this evidence compels us to advance CT1812 to the next stage of development. The Cognition 0201 SHINE study was a Phase II proof-of-concept study in adults with mild to moderate Alzheimer's disease. The study randomized 153 participants across more than 30 sites in the United States, Australia, Netherlands, Spain and the Czech Republic. Following informed consent, participants were randomized evenly to receive 300 milligrams of 1812, 100 milligrams of 1812 or placebo once daily for 6 months. All study participants were adults with the diagnosis of Alzheimer's disease. This was confirmed with amyloid PET imaging or amyloid and tau measured in the cerebrospinal fluid. Participants had to have an MMSE between 18 and 26, and no excluding laboratory or MRI pathologies. Participants were permitted to be on a stable regimen of approved cognitive enhancers, including acetylcholinesterase inhibitors and memantine. The primary objective of the study was safety and tolerability. Exploratory outcomes included the ADAS-Cog 11, ADAS-Cog 13, MMSE, ADCS activities of daily living and ADCS clinician's global impression of change. In this study, while assessing safety and tolerability was the primary endpoint, we prespecified in the statistical plan that the ADAS-Cog 11 -- that ADAS-Cog 11 was the first outcome measure with a combined 100- and 300-milligram dose group compared to placebo. This was analyzed using a mixed model for repeated measure with treatment as the main effect and visit baseline score and ApoE4 status as covariants. From a subset of patients, which was approximately half of the total, we pulled cerebrospinal samples at 2 time points, before treatment and after 6 months. We did this in order to analyze canonical biomarkers as well as to run exploratory proteomic and phosphoproteomic analyses. These results are available on the convention floor as posters. In this study, 372 patients were screened, 153 were randomized and 150 qualified for the modified intent-to-treat analysis population. There are 25 discontinuations with the majority of those discontinuations occurring in the 300-milligram dose group. Here on this slide, Slide 10. We have the baseline characteristics of the patients included in the study. Most of the characteristics were well balanced between the different treatment groups. The mean age was approximately 73 years. 60% of our participants were female. The average MMSE score was 21.37 and 60% of our population were carriers for the ApoE4 G. Now turning to the cognitive endpoints. Cognitive assessments were performed at baseline and at 6-, 14- and 26-weeks following initiation of study drug. And all the figures you'll see today, the placebo group is shown in gray with open white circles, combined treatment group, which is the primary analysis are shown in blue diamonds. The 100- and 300-milligram dose groups are shown in closed blue and open blue triangles, respectively. All data are derived from a modified intent-to-treat population, meaning those people who receive study drug and completed at least 1 post-treatment visit with a cognitive assessment. Across all of the figures' shown worsening is in the downward direction and improvements are shown in the upward direction. As a reminder, the MMSE was used as the main inclusion criteria and the ADAS-Cog 11 was prespecified as the first of the clinical assessments in our analysis plan. The primary analysis is a comparison on the pooled 100- and 300-milligram dose groups with placebo. As you'll see here and as expected, the placebo-treated patients continued to worsen as measured by the ADAS-Cog 11 scale throughout the course of the study. By contrast, those treated with CT1812, there is a slowing of disease progression on this scale and an overall slowing of 39% compared to placebo at the end of the study, which while -- would did not achieve statistical significance. A few observations include to that the ADAS-Cog 11 and indeed, across most scales, patients treated with either 100 milligrams or 300 milligrams showed a clear and early benefit by the midpoint of the study, and participants receiving 100 milligrams performed similarly to those receiving 300 milligrams. Again here and throughout the other clinical assessments. On the right, you see the MMSE data, where we had similar findings. Patients on drug showed early benefit in the pooled group compared to placebo with placebo predictably continuing to worsen over the course of this study. We have additional data for more exploratory cognitive endpoints as well. Here, we have scores from the ADAS-Cog 13 and the cognitive composite. As you would expect, the ADAS-Cog 13 profile looks very similar to the ADAS-Cog 11 with an overall effect of 39% slowing in the pooled CT1812 treatment group relative to placebo. In the cognitive composite assessment, we saw a 50% slowing in the pool CT1812 group relative to placebo. Moving on now to the functional measures. We have reported results from the ADCS Activities of Daily Living and the ADCS Clinicians Global Impression scales. Within the CGIC or CGIC, you do not see a lot of difference between the active and placebo groups over the course of the study. However, by the end of the study, the curves begin to separate. There's a 28% slowing in the pooled group compared to placebo group, a very similar profile as seen in the Activities of Daily Living. The slowing of progression becomes clear towards the end of the study. Typically, functional metrics have been more difficult to measure and will require a larger and longer studies. Looking at the exploratory clinical endpoints in total, in the SHINE study, CT1812 demonstrated a consistent positive improvement compared with placebo across multiple endpoints of cognition over the course of this study. In addition, multiple endpoints have p-values of less than 0.05. These include the 100-milligram dose on the ADAS-Cog 11 and ADAS-Cog 13 at day 98. We also learned that the 100-milligram dose did as well or better than the 300-milligram dose in many of the clinical assessments. This will become important as we explore safety and tolerability and as we plan dosing and trial design in our next phase of study. Another important point from these data is the magnitude of effect. When you look at the rate of decline in CT1812 compared with placebo-treated patients, you observe a relatively large and consistent change across all or most of the clinical measures. Given the rate of progression of the placebo-treated patients, CT1812 rescued approximately 40% of the total decline, depending upon which scale you observe. As shown here in the prespecified first cognitive assessment of ADAS-Cog 11, there was a 39% slowing compared to placebo. This is consistent throughout all of the assessments. The magnitude of effect here compares generally favorably to the percent improvement of cognitive efficacy measures of monoclonal antibodies, which have been more recently approved in the U.S. By way of example, the total effect of lecanemab over 18 months was approximately 30%, and the magnitude of effect was just over 1.5 points on the ADAS-Cogs scale at 18 months. For a proof-of-concept study with 150 participants powered for detecting adverse events, we believe these are very promising data. Now I will turn it over to Dr. Jort Vijverberg to discuss safety and biomarker findings. Jort?

Thank you, Tony. So as we just mentioned, the primary objective of this study was to assess safety and tolerability of the CT1812 in people with mild to moderate Alzheimer's disease. CT812 has been studied in honor small trials. As we explore the adverse events, you can see that the treatment emerged at first events were well balanced between the treatment groups and the placebo, with 76.5% in the treatment group and 78% in the placebo group, experiencing at least one adverse event. As expected, there were more drug-related adverse events in the 300-milligram dose group treated with CT1812. Discontinuation for the CD1812 were 22% in a 300-milligram dose group compared with 6% in the placebo group. But importantly, there were no discontinuation due to AEs in the 100-milligram dose group. All the adverse events were mostly mild to moderate and well balanced between the active and placebo treated patients. Also, serious adverse events were well balanced with approximately 4% and 6% in the 100- and 300-milligram dose group with only one event amongst those related to the study drug. The serious adverse events in the placebo group were around 10%. There was one death reported in this trial with the period in the placebo. As described previously, elevation of the liver enzymes, ECT and [ LLT ] having observed with CD1812 treatment. Here, we show that [indiscernible] enzymes innovation occurred only in the 300-milligram dose group with no reported elevation occurred in the 100-milligram dose group. All enzymes' innovations were transit and without serious liver diseases. So looking more in detail at the nature of the adverse events, we are now showing that the most frequent adverse events reported by the system organ class and performed terms, show that the most frequent the adverse events occur at frequency of more than 5%, that's including the urinary tract infections, nasopharyngitis, falls, post lumber function pain, headache and anxiety as well as the previous mentioned enzyme elevation, but were limited to the 300-milligram group. Also as described previously, the number of individuals with [ adverse ] events was to say in the active and placebo-treated participants at 76.5% and 78%, respectively. So you can say that the full safety and tolerability profile CT1812 and in the -- as demonstrated a favorable profile. Also, you can see that the adverse events were mild and moderate in severity. We saw that some minimum percentage of adverse events were treated in placebo growth is the same percentage, around 76.5% to 78%, respectively. There was no discontinuation due to AEs in the 100-milligram dose group. Most of the discontinuation in the 300-milligram group were reported -- were due to the liver enzyme elevation. So as also previously mentioned, we have seen sporadic elevation in the liver enzymes in the drug treatment. To date, all have been reversible upon stopping the drug. There has been no incident of elevation in the bilirubin and no other signs of serious liver enzyme. Overall, a very safe profile for CT1812. Now let's go to the biomarkers in this study. We built CSF samples for biomarker analysis in approximately half of the individuals that were randomized in this trial. Yes, most of all participants have CSF at the beginning of the trial to access amyloid total levels for screening, thereby confirming to diagnose and if they qualify for joining the study. However, the CSF draw at day 182 was optional. You can see more information on the biomarker results on our poster 95767. However, I want to point out that we have a consistent reduction in the neurofilament light chain in the active groups compared to placebo, with a significant reduction in the 300-milligram dose and a strong trend in the 100-milligram dose. As you know, NFL changes may reflect disease progression in Alzheimer's disease. So we're pleased to see these findings with CT1812 treatment. The other biomarkers measuring including Pita, [indiscernible], GFAP, SNAP25, neurogranin, synaptotagmin and [indiscernible] did not have significant changes over the 6 months. Also Cognition is also performing detailed proteomics and phosphoproteomics that access other changes reflected target engagement and disease modification. In this analysis, we identified pharmacogenomics biomarkers, reflecting broad range of changes impacting synaptic biology, including immune response, vesicle trafficking and oxidate stress. Please see also details in our poster. With that, let me turn the presentation back to Tony Caggiano.

Thank you, Jort. We appreciate you taking time to review the key data from the SHINE study. We'd like to reiterate here that we met our key objectives of studying safety and tolerability, having identified a dose, which is a positive efficacy signal as well as a favorable safety and tolerability profile. Specifically, the 100-milligram dose showed an efficacy trend nearly identical with the 300-milligram dose group and had no participants with elevated enzymes, and no discontinuations due to AEs in this 100-milligram dose. In this study, there were no new safety signals. We had a strong and consistent trend demonstrating potential efficacy of slowing cognitive decline in people with mild to moderate disease. We believe the magnitude of effect is consistent with other drugs recently developed and approved. We believe the biomarker data supports the true effect of slowing neurodegeneration. We are excited to see this novel drug with a new mechanism of action, further explored in additional studies to demonstrate both the magnitude and durability of these effects. Lisa?

Tony and Jort, thank you for a fantastic conversation. For Cognition Therapeutics, this trial represents an enormous milestone, the result of years of scientific research and clinical development. We believe we have a path forward with a novel drug that could be used as monotherapy or in combination with other AD drugs to mitigate the devastating impact of Alzheimer's disease. We've gained clarity on dosing and safety and look forward to designing our next study. Before studies -- before we turn to Q&A, let us acknowledge the people who have made this study possible. Our thanks go to our SHINE participants and their study partners, our clinical investigators around the world, the U.S. and international clinical research partners, our own clinical operations staff. And finally, we thank our many funding partners, including our investors, the NIA and the ADDF. Now I misspoke a moment ago, we're not going to turn to Q&A just yet. We are going to turn this conversation over to Martin Sadowski for his comments. Martin?

Good morning. Thank you for having me here today. I think I would like to share the excitement. I think that for a number of years, probably for the past 20 years, the whole Alzheimer's field has been following paradigm of an effect of a better oligomers on synapsis, oligomer-mediated synaptic neurodegeneration number of therapeutic targets have been identified, but it has been always put in the question, whether this is a valid therapeutic mechanism, which can be harnessed to develop drugs. I think the Cognition Therapeutics has developed something unique and has proven its efficacy all the way along. There are extensive pivotal studies that demonstrate example target engagement done by multiple different investigators from different institutions, truly showing that CT812 engages target, which is the sigma-2 receptor and displaced oligomers. Now we do have another big milestone in that research, which is demonstrated by Cognition Therapeutics that truly clinical application of CT1812 improves cognition and slows down functional decline. The therapeutic index of this new agent is very favorable, 100 milligrams dose seems to be extremely effective with minimal side effects, 300 produces some side effects, so that delineates therapeutic index to which further studies can happen. And then I'm very excited to look forward where Cognition Therapeutics will take this drug in further development, which segment of the disease, they will target and how they will pair this drug with other therapeutics to which that to each CT1812 is inherently complemented. Thank you.

Terrific. Thank you, Martin. We will now turn this over to Q&A. Mike, will you lead us through the questions?

[Operator Instructions] So our first question comes from Mayank Mamtani from B. Riley.

Congrats on the encouraging results reported today. Maybe just to kick off with the team, maybe to ask, Tony, how would you categorize the 3- to 6-month low for ACOG and MMSE given, obviously, you have a statistical signal at 3 months. Just want to hear your views on disease modifying nature of CT1812 and what you may expect once longer treatment duration is incorporated?

Yes. Thanks for the question. As we had anticipated and believe probably the beginning of development, we believe that we would have a relatively rapid onset of effect based on the mechanism of displacing oligomers and the potential effect there and quite immediately helping the activity of synapsis. I think the potential for demonstrating long-term slowing of neurodegeneration will require longer studies. We're optimistic that when we do those studies that are longer in time, you'll see that effect maintained or perhaps even extended.

Got it. And then just for Dr. Vijverberg, and even Dr. Sadowski on the biomarker end points. Could you maybe just point to -- I know that a lot of the data is just coming out on the relevant CSF biomarkers that's supportive of target engagement, particularly for [indiscernible] displacement? And also, if you could put in context the NFL data set reported here, perhaps relative to what has previously been seen by the amyloid antibody trials. And then I have got last follow-up.

Do you want to take on the [indiscernible].

I was pointing to you, but I can liberate first. So -- maybe first on, so the takeaway from the NFL data is that, of course, NFL is a broad biomarker. So if we put it in perspective, it's a neurodegeneration marker used in other indications like MS, AS. And in AD, it's a marker of progression. So if you look at the graphs shown before, you see that the placebo group increases over time on that marker. So there is neurodegeneration going on. And in the CT1812 group, you see a down regulation of that marker. So it's suggesting that the CT1812 is, yes, conducting [indiscernible]. However, it's a biomarker that is moving in different directions, in different studies. So fully say that CT1812 is doing that. It's -- we need to dig in that more. In perspective to other findings on CT1812, we saw in another study with vMRI that is also showing that on treatment on CT1812, the volume stays better in the treatment group compared to the placebo group. So in that case, it's for neuroprotective mechanism of action of CT1812. And maybe my colleague can elaborate maybe in a different study.

Yes, I think that I would agree with everything that simply shows us that CT1812 is a very dynamic drug that exerts its therapeutic neuroprotective benefit early on during the treatment. You can see a change in NFL relatively early. And the treatment and the effect is consistent. Furthermore, please be mindful that the change in NFL and it is very much dose dependent, okay? As Tony has shown that in patients who were put on placebo NFL went up essentially 0 in patients with 100-milligram dose and when we [indiscernible] on 300-milligram dose. So this is a very strong effect, pretty much seen on the groups like 20 patients -- about 20 patients per group. So the effect is really strong, despite very statistical power of the group test, okay? So it tells us that you really have sitting on some type of biological effect, okay? And if you can put this in the context, you imagine that CT1812 target synopsis, protect synopsis, but the synopsis are connected to neurons by dendrites and axons, okay? And that NFL is the marker of health on dendrites and axons health. So you essentially protecting the end -- the neuronal connections, but -- and by protecting neuronal connections, you essentially protecting that entire then [dendrite ] of the neuron, this is my interpretation -- very encouraging results. Now in terms of the other biomarkers [indiscernible] that have been studies -- there was a plethora of biomarker studied by proteomics in the spinal fluid looking into the immune system affecting synapsis in Alzheimer's disease, [indiscernible] pathways and other pathways involved in synaptic biology, which goes into the 100 to 100 proteins. And there are meaningful changes in those biomarkers. So again, this will tell you this is the track, which does the job as it -- you can [indiscernible] dose the finding in the way that this is a drug which does the job it was designed to do. Target synapsis protects the synapsis from the toxicity of oligomers and appears to have an extensive effect on the biology of not only the synopsis, but only in the entire neuro, of course, treating patients with advanced disease in whom a lot of neurodegeneration has already happened, patients who already lost a lot of neurons, a lot of synapsis, okay? So you're not getting probably huge clinical change, but the clinical change that you see is approved that the drug you apply is effectively working on the target that it was developed.

That's helpful. Very comprehensive. And then regarding the 300 mg dose LFT elevation learnings, would your expectation to have a similar observation with the ongoing SHIMMER study? Maybe this is for Tony. And also was curious to see the CNS disorder, headache get better as a side effect as a safety marker on drug [indiscernible], are you able to comment on what ARIA rate you've observed in the study?

Yes. Thanks, Mayank. It's a several questions. So your right, the 300-milligram dose is one of the doses in the SHIMMER study. which is the study in individuals with dementia with Lewy bodies. That study also has the 100-milligram dose. And -- I mean, yes. we would expect to see similar effects across these populations, right, the DLB study is recruiting very similar age population, I would expect to see very similar effects at the dose groups. Your next question was related to -- remind me your next question here, Mayank.

Headache and ARIA rate.

So you're right. There is [indiscernible] decrease with treatment. But really, these are just reported outcomes with adverse events. What we can take from the adverse event profile from the specific adverse events that we see and from the serious adverse events, right? It's that overall, it's very safe, right? The number of adverse events or the number of individuals with adverse events on drug was about the same in frequency as off drug, right, at 76.5% on drug, 78% on placebo. If you look at the serious adverse events, again, those are very well balanced. And as we reiterated, the only death in this trial was in a placebo individual who had other complications. So overall the profile is very nice. Whether or not there's a true reduction in those adverse events on treatment, we don't know. That is not the point of the study. The point of the study is to show that the drug is safe and well tolerated at these dose groups. Yes. So I hope that answers your question.

Are you able to comment on ARIA rate...

Yes, we had -- we did not observe any symptomatic ARIA. We follow MRIs and this is -- it's not a part of this study. So we are very pleased to see that. And indeed, based on our mechanism of action, we never expected to see symptomatic ARIA either.

Understood. Congrats again.

The next question will come from Jay Olson from Oppenheimer.

Congrats on the results, and thank you for providing this update. I have a few questions. It seems like CT1812 has a large dose response on MMSE. Is there any particular reason why that MMSE endpoint seems more sensitive to dose? And then I have a couple of other questions.

Jort, do you want to take that.

Yes, we see that in the data. But the [indiscernible] is really steady too. So it was used for inclusion and also as a safety measure. And it's -- I think it's promising that we've seen it in the data, but I think really, we need to look at the ADAS-Cog 11 and 13 for cognition efficacy end points rather than the [indiscernible] acceleration. So yes, it's promising data, but it's more for inclusion, for screening and for safety measure. So ADAS-Cog 11 is much more robust to ADAS-Cog 13.

Okay. Understood. And then what doses do you plan to study next in larger and longer Alzheimer's studies, especially since the 100-milligram dose was similar to placebo in terms of safety and tolerability? Would you consider a 200-milligram dose? And then I have one last question.

Yes. Sure, Jay. So we -- as you may or may not know. We are exploring the 200-milligram dose in our START trial, which is a trial of individuals with early Alzheimer's disease, the 540 participant study we're doing in collaboration with Alzheimer's Clinical Trial Consortium. So in that trial, we had the 100- and the 200-milligram dose. In our MAGNIFY trial, where we're looking at the ability of CT1812 to slow progression of geographic atrophy and dry AMD. We're using the 200-milligram dose. Overall, we are very pleased to see that the 100-milligram dose had very comparable efficacy and a very clean safety profile. Again, we saw no discontinuations in the 100-milligram dose due to adverse events. And none of the liver enzyme elevations occurred in those individuals in the 100-milligram dose. So as we move forward, I would anticipate that we'll be exploring that range.

Okay. Sounds great. And I appreciate Dr. Sadowski's comments on NFL. It's great to see you again, Dr. Sadowski. Since CT1812 has a beneficial impact on NFL and it looks like there's a clear dose response, would you consider pursuing NFL as a biomarker to support an accelerated approval pathway.

In this situation? Yes.

Okay. NFL has been behaving always well in Alzheimer's clinical trials as opposed to MS and the ALS. So for some clinical trials, it is exploratory, but I think that in that particular scenario, this particular mechanism of action, NFL can contribute significantly to prove out. One thing, Jay, if I can reiterate on the previous question of yours about the dosing. I think that the Cognition Therapeutics has an idea of what's going to work in general population, what is not going -- what might be slightly toxic in general population. But if let's say one day that moves to the clinic, okay? One day or another, then as clinical neurologists, if you are facing patients who are asking for more [indiscernible], you are always cautious of giving them more than 10 milligrams because the side effects that you're going to get passing the dose of 10 milligrams -- passing the in general target dose for acetylcholinesterase inhibitors can be very bad for those patients, okay? Here, you have a flexibility of dose, you can increase the dose in clinical scenario by 100 -- by another 100 and see how does the liver response. So each liver is different, and you could go slightly beyond the label to kind of provide patients a bit more of the drug. But this is the way how we practice, okay? That's not for now, okay. But that's a little bit -- there is a little bit, I would say, a different -- significant difference between how the toxicity of -- liver toxicity of CT1812 could work versus toxicity of some other drugs, no good ones, which will be dose limiting drugs.

Super helpful. Congrats again on the results.

So our next question comes from Charles Duncan from Cantor Fitzgerald.

Thanks, Lisa and Tony for sharing these very provocative results, interesting so far. But I wanted to ask the KOLs, if they had a perspective on the apparent efficacy that is seen at week 14, but seems to decline to week 26. Is there a mechanistic rationale that you can point to or some other correlate of activity that would suggest that this is actually what should occur with 1812?

So I don't think we can fully explain this phenomenon. I think that -- I think that one of the hypotheses behind this interpretation of it would be that. The drug provides immediate gratification, okay, so to speak when you give it to patients, -- they -- you're getting improvement after 3 months. The decline on cognitive metrics after 6 months, yes, somewhat declines, the benefit declines. But then as we discussed during the previous meeting on prior to releasing Phase II data. CT1812 just simply displaces oligomers from the synopsis. But those oligomers are still there, right? So something has to say, so what you might be seeing there is certain dynamics between the factor that is damaging the nerves that you're protecting the nerves, protecting the synopsis, you're releasing the oligomers, but you still go into get some oligomers that must be probably what might be happening in those oligomers, which are displaced from the synopsis from the sigma-2 receptors, have to equilibrate, okay? Something must happen to those. They probably in the absence of co-treatment with a better amyloid targeting antibody, they probably being processed by microglia cells. They probably be deposited in better amyloid plaques, okay, for that, okay. So I think that this is a dynamic stage of protection and still having that damaging agents still in the point area of view and some sort of equilibration of that toxic agent that has -- something happens. I mean it would be great to see whether what's going to happen if you got treat patients with -- who are on lecanemab with CT1812. Okay?

Jort, do you want to comment?

Yes. So more from a clinical point of view. If you look at the clinical data of the [indiscernible] the CT1812, you can say maybe in the beginning, more like a symptomatic treatment explained by Martin how it works. But today also in the biomarker data where we see mostly effect on the NFL, you see that it's disease-modifying treatment may be later on in the process. So after 6 months, you see the NFL difference, but also clinically, the function scales are starting to move from each other in favor of the treatment group. So I'll take the first spike in the clinic, maybe some time -- something like symptomatic treatment. But later on, we see signals of more disease-modifying effect. That's going to add to what Martin already said. Yes.

Please notice that after 3 months of treatment, actually, patients are getting better. right? They're not declining at a lower pace, they are essentially getting better and only patients who are treated, you don't get placebo effect.

Both helpful explanations. It suggest -- they both make sense. It suggests another question, which is, would you anticipate the effect size to be larger or less, smaller in an earlier-stage patient population, MCI. And perhaps it's too early to tell with these analyses, but -- do you anticipate there to be a correlate with, call it, disease burden, level of severity, time since diagnosis in terms of the effect size.

So I think I would expect perhaps the effect to be greater in patients with MCI. But the question is which scale would you use for MCI. Would you go with ADAS 11 and MS, or you would go to CDR. And also would you go to [indiscernible], Okay? I'll be interested -- what -- so you would essentially is different scales for early. I mean that's where the -- most of the synaptic activity -- synaptic damage stay. What was the other part of your question?

Well, I think you addressed it. My last question is on safety, perhaps for Tony. Can you give us a sense of the observations made, were they early in the treatment paradigm or later? Or did they occur throughout the course of the 6 months.

So the -- again, the adverse events were really nearly identical between the treated and untreated participants. So these are just events that are occurring throughout the course of the study, as you would expect in an older population with the disease burden. I haven't -- we haven't looked specifically at the rate within each week or so forth. If you're asking particularly about the liver function test elevations, there is a trend that things are occurring sooner upon starting drug rather than evenly throughout the course. But again, cautioning that in 6 months, this is what we see, what we see in the larger and longer trials, we're only now beginning to learn as we have the START trial, which is an 18-month study, which is going -- currently running and our MAGNIFY trial, which is a 2-year study. And there, we're really getting a much better view of when adverse events are occurring, what the nature is. And indeed, as Jort mentioned, right, the true nature of what types of events we'll see, we'll only begin to really understand as we enroll hundreds and thousands of individuals and as this is used more broadly.

And again, by stopping the drug, the liver invitation over transit.

Yes. And in each case, again, the ones that we listed here, right, we had a criteria where we showed that every individual who had elevations more than 3x [indiscernible]. They're all reversible, relatively benign, no concomitant indications of liver injury. And as soon as drug was removed, returned to normal. So Overall, we are very pleased with the profile. Again, the fact that the 100-milligram dose was so clean, makes us very happy, and we believe we see a path forward here.

Last question for Lisa, assuming resources, financial resources are available. What would you like to do next with this data, which you would like to design and conduct another study in mild to moderate patients? Or would you prefer to wait for the START study to read out?

Thank you for the question, Chaz. I believe, based on the data that we have in concert with Tony, we'll be designing what the next study looks like. This data showed mild to moderate population is a place where we've demonstrated, as Martin alluded to, symptomatic disease-modifying effects, I believe that will be our focus and not waiting on the START trial. The terrific thing about the START trials, it will give us real world examples of our drug used alone and in combination, in this case with [ Leukine ]. So we are so pleased about that trial, but I don't believe there's any expectation we're going to wait for those results. We'll be preparing for an end of Phase II meeting. And as you alluded to, we're raising money to support those studies, a lot of work ahead of us.

Excellent. Congratulations on the data.

Thanks, Chaz.

Our next question comes from Elemer Piros from Rodman & Renshaw. Elemer, you might be on mute.

Yes. Sorry about that. So I think Dr. Sadowski alluded to CDR, which is actually the primary endpoint of the START study, has that been measured here in this trial?

No, it's not been measured in this trial.

Elemer, are you able to hear, the answer is no. That was not one of our endpoints.

Okay. And also, have you looked at the milder subset of patients, subset analysis of the MLC scores between 22 and 26, and is there an indication that the drug might be working better in milder population?

Yes. Thanks for the question. We did divide the population in the earlier and the higher and lower MMSE. And as we would expect and as the world would expect, those -- the more mild end advanced much less. In fact, the placebo individuals at the higher end of the MMSE only progressed less than 1 point of the course of the study. Numerically, we did have an advantage in that group. But again, given that there was a little progression. So again, we do anticipate we will see effects there. But as we had anticipated, and the reason we're running the START trial at 18 months is because it will just take longer for the placebo individuals to advance to a point where we can reliably see a slowing of progression.

I understand. Also, I think someone made a point that there is -- there appears to be a dose response in terms of the NFL biomarker. Frankly, I didn't see much of a difference between 100 and 300-milligram. Is that more the case?

Yes. So if you look at the plot, they're both relatively unchanged. Yes.

So I think it's safe to say that you would continue on with the 100-milligram dose in a upcoming potentially pivotal trial.

You're way ahead of us. I would love your ambition for us. I don't think we've designed the protocol or selected the doses yet, [indiscernible].

So our final questions come from Daniil Gataulin from Chardan.

First, about the background therapy. So I noticed more than 50% of patients in the study were on background therapy. I wanted to ask how those patients performed versus those who were on CT1812 alone?

Yes, absolutely. You're right. So a little over half of individuals are on acetylcholinesterase inhibitors or memantine. So we had required that individuals who are on such drugs being a stable regimen that hasn't changed for a certain period of time before the study. When we split the data speaking now about the ADAS-Cog 11 specifically, when we split the data between those who were and were not on the drug. Those who are not on the drug did a little bit better. But both groups were responding positively. And indeed, if you look at our poster, we have the responses of those on and not on the poster. So that's out there, and you can pull that from our website. But both groups are responding, those not on drug a little bit better, although again, we caution now that we're subgrouping study. So whether that's a real effect or not, it will take longer study -- larger studies to really determine.

Got it. And my other question is, based on the results that you presented today, specifically with the biomarkers. How does that make you think about your START trial and the potential for -- to see a synergistic effect when combining CT1812 with other approved Alzheimer's disease drugs?

Yes. I mean we're excited to see this and think about the data coming out of start. Again, the START trial is 540 individuals with early AD, MCI in that study, we have the 100- and 200-milligram dose group. Based on our mechanism of action, we truly believe this has potential both as a monotherapy and in combination with the monoclonal antibodies and other drugs. We allow folks in that study to be on approved monoclonal antibodies. So we're going to get some very good data as we come out, whether there is potential for additive effects in that population. So we're excited and that study is rolling along right now.

Thank you for the questions. And I will now turn the call back over to Lisa.

Great. Well, thank you, everyone, for your participation this morning. Thank you to Jort and Martin for joining us. We are very enthusiastic about what we've seen in here, a signal of efficacy across multiple endpoints and excellent safety profile, clarification around those exciting insights around mechanism of action. As Martin articulated for us, early effects, later effects. We believe there is a great deal here for us to explore in our next phase of study. And we are very appreciative as we said earlier, about all our investors who allow us to conduct this work in concert with patients and families. So with that, we'll close. Thank you, everyone.