Cyclerion Therapeutics, Inc. (CYCN) Earnings Call Transcript & Summary

Good morning. It's great to have you all joining us this morning to hear about our clinical results for 6463 and CIAS. We're very excited to have the discussion we you this morning. This is our safe harbor statement. Just to remind you that we're very, very likely to make forward-looking statements, and this information and the other information that's necessary that's linked to it is on our Investor site of our website, and they'll be available to you at any time. This presentation also will be recorded and available on the website for some time to come. Let me spend a few minutes introducing the speakers and the agenda for this morning. I'm Peter Hecht. I'm the CEO at Cyclerion, and I'm joined by several fabulous leaders in the neuroscience research and drug development space. Dr. Steven Hyman is a core Institute member of the Broad Institute of MIT at Harvard, and he directs the Stanley Center for Psychiatric Research there. He's a former Director of the National Institute of Mental Health, he was provost at Harvard University and he's a renowned leader in neuroscience research as well. Steve also has just joined the Cyclerion Board just this week, and we're very excited to have him on the Board and excited to have him here today to share his independent voice on the data and the opportunity both in the CIAS space and in the need for better cognitive therapies in general. You'll also hear from Dr. Bruce Kinon. Bruce is our Vice President of Clinical Development. He has a long career in psychiatric care and also in drug development in the CNS. And you'll hear from Dr. Jennifer Chickering who is our Vice President of Clinical Strategy and was the clinical study director for this CIAS program. To briefly summarize the agenda for today. I will spend a few minutes providing context and introducing the company and then turn it over to Bruce who will provide a brief overview of the CIAS disease state and unmet need for better therapies and also CY6463, our clinical drug candidate. Jennifer will take you through the study design and the data summary for today's study release. And then we'll look forward to hearing from Dr. Hyman on his perspective on the drug and the data. And we will have a live and open Q&A session. [Operator Instructions] Before we dive into the study data, I just want to make a minute to give a brief overview of the work we're doing here at Cyclerion. We're a clinical-stage company on a mission to develop treatments that restore cognitive function. And our work is really focused very heavily in the NO-sGC-cGMP pathway. This is a fundamental pathway for signaling in the CNS. And there's a wealth of research really on the importance of this pathway and its multidimensional roles in CNS biology, including cerebral blood flow, mitochondrial function, inflammation and neuronal function. These are areas of very intensive research in academia and in biopharma and in areas of very intensive interest for new pharmaceutical drug development. Deficits in various aspects of this pathway signaling have been linked to multiple CNS diseases, including in schizophrenia and its various symptoms. The drug, 6463, is an oral, once-daily, small molecule that was designed by our team at Cyclerion. We have very strong intellectual property into the 2040s, including composition of matter. And it's a positive allosteric modulator of soluble guanylate cyclase, a receptor for nitric oxide. It's the first sGC stimulator in clinical development that crosses the blood-brain barrier, and that's allowed us to access this critical area of pathway regulation and activity in the CNS. And our experience with this drug, now in multiple clinical studies, has established what's really a very strong safety and tolerability profile in more than 150 patients, including patients with schizophrenia, as you'll hear today. The study today really goes nicely with the MELAS data that we released a few weeks ago. And we're really, I would say, very excited to see from both of these studies promising signals of the pharmacology that we had seen preclinically. And to see the preclinical data translate is very unusual and very exciting. And we're seeing in this study, as you'll hear from the presenters, a large positive effect size on cognition after only 14 days. Cognition is really an aspect of schizophrenia that's debilitating to patients, and there's no good therapies today. And it's a critical aspect as well of numerous other CNS and neuropsych populations. The translation, really, of these pro-cognitive effects and also, as you'll hear, anti-inflammatory effects as well and objective biomarkers in inflammation has been, I would say, very, very encouraging and in some ways, to me at least, surprising given the lack of good translation in the CNS space historically. And I think that's a signal of how good the signal strength that we're seeing is, that it cuts through the noise inherent in a lot of CNS development. Just a quick snapshot of the pipeline. We've talked briefly already about MELAS and the cognitive impairment study. Just to let you know, we have also a study enrolling currently in a subtype of Alzheimer's disease with microvascular pathology. And we also have a differentiated second molecule that is a CNS penetrant, sGC stimulator 3018. That's in the late stages of IND preparation, and IND-enabling studies are nearly completed there. So with that, I'd like to turn it over to Dr. Kinon and let him take the stage.

Thank you, Peter, for this opportunity to discuss this important topic. I am a psychiatrist in addition to being a drug hunter. And before my career in the pharmaceutical industry, I was a clinician managing the care and treatment of many patients suffering from schizophrenia. Although my patients and I, in many instances, were successful to stabilize disturbing psychotic symptoms, the attainment of sought-after social and vocational goals remained out of reach. Cognitive impairment, a quiet symptom of schizophrenia, fraughted much of these efforts. A treatment for cognitive impairment remains a priority unmet need in schizophrenia. Schizophrenia is a complex, chronic and disabling disorder. Schizophrenia is one of the top 15 leading causes of disability worldwide. At a prevalence of approximately 1% of the population, 21 million worldwide and 2.7 million affected in the U.S., schizophrenia is associated with significant health, social and economic concerns. Schizophrenia onset occurs early in development, detracts from mainstream social and vocational maturation and has a chronic unrelenting cost leading to many years of cumulative disability. Financial costs associated with schizophrenia in the U.S., approximately $281 billion in 2020, are disproportionately high relative to other chronic mental and physical health conditions, reflecting both direct costs of health care and greater than 3x this amount to the indirect costs of unemployment, lost productivity, criminal justice involvement, social service needs and other factors beyond health care. Core cognitive deficits are the chief determinant of long-term disability in schizophrenia. The vast majority of schizophrenia patients, nearly 98%, suffer with cognitive deficits in memory, attention, acquisition of knowledge, processing speed, reasoning, executive function and social cognition. These deficits overlap with measures of general intelligence or IQ, which may be apparent in school performance years before psychosis onset and may progressively decline in some individuals at a rate of 1 IQ point every 1 to 2 years of illness. As a group, patients with schizophrenia performed significantly worse than controls on almost all neuropsychological tests. A minority of patients who do perform at the median of cognitive norms are considered to have probably missed their potential due to their illness for even a higher level of cognitive performance based on early achievement trajectories and familial factors. Impairments in memory, attention and reasoning and problem solving are generally worse in schizophrenia compared to other serious mental illnesses such as bipolar and major depressive disorders. Cognitive deficiencies are neurocognitive rate-limiting factors to optimal social and vocational functioning. A substantial correlation between functional capacity and cognitive performance is found in schizophrenia. This is illustrated by the graph, by the dynamic positive relationship between performance-based cognition scores, as assessed by the Matrix Consensus Cognitive Battery, and the abilities of individuals to perform everyday tasks considered necessary for independent living, as assessed on the University of California, San Diego performance-based skills assessment, or UPSA. Cognitive impairment and negative or deficit symptoms, but not necessarily positive or psychotic symptoms, are predictive not only cross-sectionally but also longitudinally of adaptive life skills in persons with schizophrenia. Current antipsychotic treatment does little to improve cognitive impairment. New treatments for CIAS may have the potential to improve outcomes throughout the life cycle of patients with schizophrenia. As I mentioned, no pharmacological approaches to improve cognition have yet been successful to yield approved treatments. Therefore, treatment innovation may depend on the search for new disease targets that may mediate CIAS and increase the ability of patients to participate fully in the community and live independently. The CY6463 is a soluble guanylate cyclase, or sGC, stimulator that amplifies endogenous nitric oxide-sGC-cyclic guanosine monophosphate signaling. Nitric oxide-sGC-cyclic GMP is a fundamental central nervous system signaling pathway. This pathway's machinery is broadly expressed throughout the CNS in neurons, glial cells and vasculature, and deficits in this mechanism are linked to multiple CNS diseases. 6463 is a positive allosteric modulator, or PAM, that amplifies endogenous nitric oxide signaling. Robust preclinical data demonstrate the potential for 6463 to consistently address multiple aspects of CNS disease across illness domains associated with mitochondrial function, inflammation, neuronal function and cerebral blood flow. Nitric oxide-sGC-cyclic GMP dysfunction is implicated in CIAS pathophysiology. Network analysis of pathways, protein-protein interactions and genetics link nitric oxide-sGC-cyclic GMP signaling to schizophrenia. Compromised prefrontal and hippocampal nitric oxide signaling are implicated in cognitive deficits in schizophrenia and reduced cerebral spinal fluid cyclic GMP is observed in schizophrenia. In addition, 6463 has been found to improve dendritic spine morphology, increase long-term potentiation, increase gamma EEG power and improve cognitive performance in preclinical models. Therefore, targeting sGC is a promising therapeutic approach in CIAS where new therapies are greatly needed. And in conclusion, nearly all people with schizophrenia, approximately 98%, have cognitive deficits. Core cognitive deficits are the chief determinants of long-term disability in schizophrenia. Nitric oxide-sGC-cyclic GMP is a fundamental CNS signaling pathway with dysfunction implicated in CIAS pathophysiology, and 6463 is a positive allosteric modulator of sGC that amplifies endogenous signaling, offering a promising therapeutic approach to the treatment of CIAS. Now Jennifer will review our clinical data of 6463 in the treatment of CIAS. Jennifer?

Thank you, Bruce. As Peter mentioned, I was the Study Director for our signal-seeking study in CIAS, and I'm excited to be here today to share the results of the study with you. On the next slide, I'll review the design of the study. This was a randomized, double-blind, placebo-controlled, multiple-ascending dose study. As shown in the schematic, the study was run in clinic. Participants checked in to the clinic on day minus 3. We established our baseline, and then participants dosed once daily with oral tablets for 14 days. They checked out the following day and then came back 2 weeks later for a final safety visit. The participants in the study had to be 18 to 50 years old and diagnosed with schizophrenia. They had to have stable, moderate symptomatology with a PANSS less than or equal to 70, and they had to be on a stable, single antipsychotic regimen. We finished the study with 4 sequential cohorts of 12 participants each, randomized 8 to 4, active to placebo. Escalation to the next dose was based on safety. Our cohort started at 15 milligrams and escalated to 30 and then to 60, which we repeated in the fourth cohort. For analysis, placebo was pooled across the cohorts. The next slide shows an overview of assessments of the study. Our primary endpoint was safety. And in addition to adverse event collection, we had a range of safety assessments typical of a study like this, including vital signs, clinical labs, ECGs, PANSS and extrapyramidal symptom assessments. For PK, we collected samples at multiple time points, including more intensive sampling on a couple of days, in addition to trough time points across the study. To measure cognition, we assessed cognitive performance with a computerized battery, and I'll tell you a little bit more about that in a minute. We collected plasma samples for an inflammatory biomarker panel, and I'll tell you a little bit more about that in a minute as well. We also included a range of EEG endpoints including resting-state qEEG, a number of ERP tasks and sleep EEG. And because we're still working with our EEG experts to fully analyze those data, we won't be presenting EEG results today. We conducted this study at 2 sister sites, Hassman Research Institute with Dr. Elan Cohen and Collaborative Neuroscience with Dr. David Walling. Now I'll move on to the results, starting with the baseline characteristics in the next slide. As Bruce said, nearly all people with schizophrenia have cognitive impairment. In this study, we found that main scores on the cognitive tests were about 0.5 to 2 standard deviations lower than those of age-matched controls, which is consistent with chronic schizophrenia. I mentioned that we required participants to be on a stable, single, antipsychotic background regimen, and we're developing 6463 as an adjunct to standard of care. And the atypical antipsychotics for our study population are listed on the bottom left. You can see that most of the participants were on risperidone or aripiprazole. On the right are the baseline characteristics of the study population. This is for the whole population, but it was generally balanced across the treatment groups. The population was predominantly male, about 80% Black/African-American, about 23% Hispanic/Latino. The mean age was about 37; mean BMI, about 30. 15 was the mean for years since diagnosis, and the main PANSS was about 55. Now I'll move to the next slide, and the results for our primary and secondary endpoints of safety and PK. 6463 was well tolerated across all dose levels evaluated, so 15, 30 and 60 milligrams, all well tolerated with mostly mild adverse events. All AEs were transient and there were no SAEs or severe AEs and no dropouts due to AEs. The most common AE was headache, and all but one of those was mild. In addition, there were no signals on any safety assessments including clinical labs, vital signs and ECGs. Our secondary endpoint was PK. And in the graph on the right, you can see the trough plasma concentrations for the 3 dose levels across the days of the study. The PK for once-daily 6463 was as expected and consistent with our previous clinical studies with approximately dose proportional exposure, low intersubject variability and similar accumulation across the dose levels. And note, based on the graph, that 6463 is at or near steady state by about day 13. On the next slide, I'll tell you a little bit about the assessment of cognition, our exploratory endpoint of interest in this study. We assessed cognition at multiple time points during the study. So here's that schematic again, and you can see the little tablet icons showing that we assess cognition at screening to familiarize folks with the assessment, at check-in when participants had to demonstrate that they could complete the assessment, at day minus 1 to establish a baseline and then on days 2, 7 and 14. And based on the PK that I just showed you, day 14 is the main time point because it's our steady state time point. We measured cognitive performance in this study using the CogState Schizophrenia Battery, an 8-test digital battery that meets the same requirements and follows the same framework as the Matrix Consensus Cognitive Battery but with reduced burden on the participant and the study in general. We're focusing on the composite scores from this battery: the overall composite for general cognition and the composites for the cognitive domains of executive function, memory and attention. Our analysis of cognition is change from baseline in the 6463 group versus change from baseline in the placebo group. And as this was a signal-seeking study, we are focusing on effect size, so the standardized mean difference between those ranges. Here are the effect sizes for the 15-milligram dose on day 14, our steady state time point. Effect sizes are displayed as a heat map for the cognition composites. So green is a positive effect over placebo. For the 15-milligram dose, we saw a strong positive effect of 0.6 on general cognition. And this effect size is quite a bit greater than the minimum bar of 0.3 that we were looking for, and it's generally considered clinically relevant in neuropsychiatry. You can also see green, so positive effect sizes, for the cognitive domains of executive function and memory; and no effect on attention, in gray. The 30 and 60 mg doses, which are not displayed here, showed no effect on general cognition, so also gray. So 30 and 60 were well tolerated but showed no effect on general cognition at day 14. Seeing no effect here at these higher exposures is not surprising. Inverted U dose responses are common in CNS therapeutics, common in this therapeutic area in particular, and it's also something we've seen with this mechanism preclinically. The positive result on overall cognition for the 15 mg 6463 dose is supported by a series of sensitivity analyses in which we looked at the data a number of different ways including combining day minus 3 assessments into the baseline, accounting for baseline PANSS score, a last observation carryforward analysis and more. And we consistently see a positive effect for the 15-milligram dose. And this positive effect at 15 milligrams is also consistent with the positive effects demonstrated by this dose in our recently completed study in the rare mitochondrial disease, MELAS. Another thing that reinforces the positive results with the 15 mg 6463 dose are the effects we see over the 14-day study duration, and that's displayed in the next slide. So day 14 is just scooted over to the right and I've added days 2 and 7 before it. We see increasing signal over time, so more green over time, which is consistent with the PK as we head towards steady state. We expect the benefit of once-daily 6463 to be durable and to increase with longer treatment. And this is based on a couple of things. First, we know, based on the experience with approved, peripherally active sGC stimulators, riociguat and vericiguat, that effects of this mechanism do not attenuate over time. That is chronic treatment is durable. Additionally, we expect the effect of 6463 to increase with longer treatment, and this is based on the multidimensional sGC stimulator pharmacology that Bruce told you about earlier. This study was only 2 weeks of dosing, so just getting to a steady state. We know based on our preclinical pharmacology that, at that point, we've only accessed a portion of the positive pharmacology we can expect. This increasing benefit with time on treatment has also been seen with those approved sGC simulators. So we're seeing nice effects at just 2 weeks and have reason to believe, based on the mechanism of SGC stimulation, that we will see more over time. I think it's also helpful to put this effect size in a little context, which is displayed in the table on the next slide. This table shows Phase II studies that have had positive results on measures of overall cognition in this population. And I will acknowledge that this is not an apples-to-apples comparison, but I think it's still useful context to understand the magnitude of effect sizes that have been considered relevant in earlier CIAS studies, including the GlyT1 inhibitor that's now in Phase III. The 0.60 effect size in our small study after just 2 weeks of dosing looks quite healthy in this context and we believe clearly indicates that additional evaluation of this mechanism in CIAS is warranted. We can move to the next slide in inflammatory biomarkers. We collected plasma samples for biomarkers at baseline, day 1 pre-dose, and on day 15, about 24 hours after the last dose of study drug, so at steady state. And for this assessment, we use the InflammationMAP panel, a broad inflammatory biomarker panel. We selected this broad panel for a couple of reasons: one, anti-inflammatory activity is a well-known aspect of 6463 pharmacology that we've demonstrated not only preclinically but also clinically in that recently completed study in MELAS; and two, inflammation is well accepted as a disease process involved in schizophrenia as well as other neuropsychiatric diseases. But that's about as far as consensus goes. There are really no well-established biomarkers in schizophrenia, especially in plasma. So based on those 2 things, a broad panel made sense for this exploratory assessment. As with cognition, our analysis is comparison of changes from baseline, and we're focusing on effect size in this signal-seeking study. We were able to measure changes in 47 biomarkers from the InflammationMAP panel. And at the highest level, we're seeing anti-inflammatory effects that are consistent with our known pharmacology. We can move to the next slide, and we'll look in a little more detail. I selected a few biomarkers to highlight here. The biomarkers in the table met 3 criteria. They showed a change from baseline in the 6463 group. That change had an effect size of at least 0.5. And three, the effect size had a nominal p-value less than 0.2. Based on our review of the literature, all of these plasma biomarkers are moving in a favorable direction, that is, they are directionally improving. For example, IL-6 has been implicated in cognitive function with higher levels associated with worse functioning across multiple cognitive domains. And this has been demonstrated in multiple patient populations, including in chronic schizophrenia on atypical antipsychotics. And we are seeing a reduction in IL-6 after 14 days of once-daily 15-milligram 6463. Our interpretation is ongoing, but the takeaway is clear. We're seeing anti-inflammatory activity that is consistent with what we know about 6463 pharmacology based on both our preclinical and clinical studies, and anti-inflammatory effects are relevant in cognition and in schizophrenia in particular. The next slide sums up our results. In this signal-seeking multiple-ascending dose study in participants with CIAS, 6463 was well tolerated at all dose levels with no safety signals, and that was on top of a standard of care antipsychotic regimen. And across those dose levels, once-daily 6463 exhibited dose-proportional exposure. On exploratory assessments, after 14 days dosing with 15-milligram 6463, we saw a robust signal on general cognition as measured by the comprehensive CogState Schizophrenia Battery, which is an instrument we believe is suitable for use on a registration endpoint. And additionally, 6463 demonstrated disease-relevant, anti-inflammatory pharmacology. Before I turn it back over to Peter, I'd like to take a moment to thank a few folks. Our PIs, Dr. Elan Cohen and Dr. David Welling, and the incredible site study teams, thank you very much for your hard work on this study. A big thank you also to my Cyclerion colleagues, especially our CIAS study team. And most importantly, a very special thank you to the participants in this trial. And with that, I'll turn it back over to Peter.

Thank you, Jennifer. I'm not sure whether you guys can see me or not, but let me add my thanks and gratitude to the study participants and the site investigators and to the team for all their hard work. And especially to you for your work in leading a very exciting study and a very challenging one to get up and going. Very, very well done. Thank you very much. I'd like to bring Dr. Hyman into the conversation now. And Steve, if you'd be willing to share your views on both the clinical results in the study and your broader perspective on the unmet need and the previous attempts in this space, that would be very helpful. Thanks.

Thank you, Peter, and hello, everybody. I have been, in some ways, working on this major source of disability in schizophrenia for more than 20 years. When I was NIMH Director in the late 1990s, I worked to bring FDA into this area. And ultimately, although after I left NIMH, they approved a pathway for getting drugs to treat the cognitive deficits, or CS, in schizophrenia approved, which is the matrix battery, something that actually deserves a bit of improvement itself along the way. But at any rate, the therapeutics that we have for schizophrenia, as Bruce Kinon really beautifully reviewed, are all antipsychotic drugs. None of them have a significant beneficial effect on cognitive disability in schizophrenia or cognitive impairment. And indeed, because they all block dopamine, they may, in the long run, actually have at least modest effects in the other direction. Many attempts have been made to improve cognitive impairment in schizophrenia but these have, to date, not been successful. I have to say one of the reasons that I'm pleased to join the Cyclerion Board is just the promise of this mechanism, cyclic G, the cyclases, and the effect size that was apparent in the early trial that was just reviewed for you. Cognition in schizophrenia is getting new attention, but it's not a new idea. In fact, in the earliest modern definition of schizophrenia, and even in the 19th century, the German psychiatrist who defined it called schizophrenia dementia praecox or early dementia. And as Bruce Kinon really nicely pointed out, this is really the source of much of a disability in schizophrenia. Even early in the course of schizophrenia when antipsychotic drugs are working optimally, we do not see typically an ability to go back to school for young people or to go back to work precisely because these cognitive deficits actually begin in the background insidiously even well before the first psychotic episode. So treatment of these cognitive impairments would have an enormous impact on lives and on productivity. And again, I think this mechanism is very promising even though the studies are still very, very early. The effect size is not one that I've seen personally in any early study, and that can give us a certain amount of hope. Although again, with all of the caveats, this is a small number of people and a single initial study, similarly with the inflammatory biomarkers. And I think these were presented with all due caution. None of these have been validated. And indeed, my group at the Broad is working on cerebrospinal fluid inflammatory biomarkers driven by our understanding of the genetics which identified C4 part of the complement pathway, part of the innate immune system, as a key mediator of synapse loss and, therefore, potentially cognitive impairment in schizophrenia. All that is to say that the measurement of serum biomarkers that show this mechanism to be anti-inflammatory is certainly consistent with the idea that this drug, or something else with a similar mechanism, may prove to be helpful. The other thing to be said is that this early study, obviously, was just the addition of the cyclic G compound alone on top of a stable, antipsychotic regimen. One could imagine, should this drug prove efficacious, that it would be administered with cognitive remediation psychotherapies. These are in development and look promising but, by themselves, have a relatively low therapeutic ceiling. And one can speculate, and it is just speculation, that the combination of a drug in this class with cognitive remediation psychotherapies would be even more effective. So that's my overview. I'm really quite excited by at least the potential of this class of compounds. And I see there are some questions, but I assume, Peter, you want to direct the questions.

Yes. I'm sure a number of them are directed to you. But before we get to the Q&A, thank you very much for the overview. Let me spend just a couple of minutes summarizing and give a couple of more minutes to questions coming in. I hope you're hearing from us a key theme, which is that the preclinical data that we've generated extensively in our labs and with collaborators and also what you can find in really a wealth of published academic and industry research is translating very nicely into clinical observations, now in 2 different patient populations. And given the general lack of translation in CNS neurobiology and in this space in general, we're finding that very exciting and, frankly, kind of remarkable. As I said in the introduction, I think that, that speaks a little bit to the strength of the signal and the importance of the mechanism. What it's allowing our scientists to do is to peel back the cover on what I think is a really fundamental pathway and regulatory system in the brain. And the more we get confidence in that translation from preclinical to clinical, the more, I think, the previously published and available science will be able to help guide our explorations of the best uses of this drug, and the second molecule as well, in what could be a very broad opportunity in helping patients with a range of neuropsychiatric and neurodegenerative diseases. So I hope you're getting a sense from us of both the potential and the excitement we have here. As I think you've heard from all of us, we recognize it's early days. All of this needs replication and further exploration. But I think the strength of the signal and the objective biomarkers is giving us quite a lot of excitement and enthusiasm. Just in summary, just a few key takeaways and then let's get to the Q&A. The NO-cyclic G pathway is really a very fundamental CNS signaling pathway. You've heard a bunch about it today. It's involved in multiple functions in the brain and in the CNS broadly, and each of these areas of a very intensive focus and effort by many companies and many academic labs across each of these key modes that we've discussed this morning. Our molecule has great pharmaceutical properties. It's shown a very good safety and tolerability profile in now over 150 subjects. It's a once-a-day drug. It's convenient and easy to manufacture. We have very good intellectual property protection on it as well. And it has very good exposure in the CNS. And we're seeing, as you're hearing from us, promising signals and I think mutually reinforcing across the 2 studies that we've really stated on now over the last month with 6463. In CIAS, as you're hearing this morning, particularly a strong positive effect on cognition at only 14 days and where we think that there's room to pick up more effect based on the mechanism of the drug and an improvement in a broad panel of inflammatory biomarkers. And in MELAS, which we discussed a few weeks ago, and the webinar is still up on the Investor site of Cyclerion, we saw improvement in a broad range of objective markers of cerebral blood flow and inflammation, mitochondrial function and broadly in CNS and neuronal circuit connectivity. So with that, I'm going to turn it over to Cheryl Gault, she's been compiling the questions. And I see we have quite a lot of questions, which is terrific. Let's make sure we synthesize them and direct them to the right places. Cheryl?

Great. Thank you very much, Peter. So we do have quite a few questions that have come in. Thank you, everyone, for entering those. So I'll do my best to combine some of the more common ones so we can get through as many as possible in the remaining time. So the first question is for you, Dr. Hyman. The question is, please provide a comparison and contrast on the sGC positive allosteric modulator mechanism versus the M4 PAM? What would you anticipate to be the advantages of sGC?

Well, the M4 PAM is being developed as an antipsychotic drug, that is, the preclinical assays that were used were the amphetamine test, which is antagonized by directly, or in this case, indirectly, dopamine-blocking drugs. So we don't know whether it would realistically and currently have an effect on cognition. However, I think one of the themes that comes up in the prior failures to improve cognition is that this is a complex, highly finely tuned mechanism. And any intervention with acetylcholine, especially with the muscarinic receptors, raises the possibility of adverse effects on cognition. So these are very different mechanisms tested against different preclinical models with a different symptom profile as the primary target.

Great. The second question is coming to you as well. And the question is, would you anticipate that effective CIAS treatment may mitigate future positive symptom presentation and enhance compliance in chronic schizophrenia?

So this is a really interesting question. We know that the cognitive decline occurs before the onset of the first positive symptoms. We also know that other diseases with cognitive decline, including Alzheimer's disease, is often accompanied by later psychotic symptoms in Alzheimer's disease. Patients can have hallucinations and delusions. So we have to be careful. We only have evidence here for symptomatic improvement in cognition. Whether this or another drug that somehow protected fundamental cognitive mechanisms would mitigate later psychosis is an interesting speculation to be tested much later, but it is an interesting idea. I think what is important, however, is that you would want to administer a drug like this, should it prove efficacious, early in the course. Because if you can protect cognition and allow a young person to complete high school or college, get married, start a job, even if you didn't control the entire disease mechanism, we know that they would have much better societal and productive outcomes.

Great. Thank you very much. The next question is, observing that higher doses did not improve cognition compared to 15 milligrams, would the effect size of 0.6 be near max attainable effect? And could you elaborate on the lack of effectiveness at the higher doses? So maybe, Bruce, I'll invite you to share some thoughts here and maybe also include whether this inverted U has been seen preclinically.

Great. Okay. Yes. No, this is an interesting question. I think that, certainly, this is an area for us to further explore. But it's important to understand that going into the study, we were confident that the 15 milligrams was an active dose. This is based on our translational pharmacology study in healthy elderly and also based on our preclinical studies. In fact, the 15-milligram was purposely selected for our MELAS study as well as the ADV, or Alzheimer's disease with vascular pathology, studies as well. We also wanted to take advantage of the fact that we wanted to study the higher doses because this was an in-clinic study that allowed us to do that, to evaluate the safety and the PK of these higher doses as well as explore the pharmacology in this patient population. And as Jennifer mentioned earlier, it's not uncommon with CNS drugs, for the highest dose not to be necessarily most efficacious. In fact, that's been true also in other work in CIAS in particular. For example, the atai's RL-007 as well as the Boehringer Ingelheim GlyT1 inhibitor that's now in Phase III, also inverted U-shaped dose response curves in their early studies. So we've also seen this with our sGC stimulators in preclinical rodent models of memory. So I think that we want to understand the dose response relationship, and that's what these early studies really give us this opportunity to begin to get some data on this. Maybe, Steve, you would have some additional thoughts on this notion of the dose response relationship or inverted U?

Yes. I think you put it beautifully. There's not much to add. I think this is a pretty sophisticated group and don't need to be reminded of the inverted U. But just think of waking up in the morning and improving your cognition with 2 hits of espresso. But by the time you get to 5 or 6, you're now jittery and not paying attention very well. I mean this is a really classical phenomenon. And again, it goes back to this idea that cognition, in its different components -- cognition, of course, is not a unitary function but many different components -- is very, very finely tuned. And too little isn't good, of course, for whoever the mediator is, and too much are often isn't good. Now in terms of therapeutic ceiling, I would just come back to perhaps because of the inverted U, this may be a ceiling dose, at least for many people. However, as I said before, it could very well be combined with cognitive remediation therapies which clearly act by very, very different mechanisms, and they could mutually boost each other's effect. Now obviously, that is a speculation. But certainly, it is something that is very likely to be implemented in clinical trials.

Thank you.

Great. Thanks to both of you. The next question will be for you, Jennifer. And the question is, you described one non-mild headache, can you talk a bit about whether there was any clinical impact or how the patient was treated?

Sure. So that's right, one moderate headache, and there was no clinical impact. The participant received Tylenol and the headache resolved.

Great. Thank you. While I have you, one more for you. The question is, regarding the patient sample, do you believe it's consistent with or representative of a sample that we would target in a later study?

Good question. So I think any next study would be a larger multicenter study. And so we're likely to enroll a more diverse population, it'll likely to be an outpatient study. So it will recruit a little bit different population. But I think in terms of our eligibility criteria, we would expect them to be largely the same, so stable symptomatology, on stable antipsychotic regimen when they come in. The one thing that could change is this study was intended to be hypothesis generating. We have lots of data from this study. And as I mentioned, we're still working through those data to understand them. And so we may learn about ways to enrich our population for our mechanism. But I would expect, in general, for the eligibility criteria to be largely the same. I mean we're very happy with the results we're seeing here, and so we wouldn't want to tinker too much.

Great. Thank you, Jennifer. Another question for you, Dr. Hyman. This time, for this mechanism, positive allosteric modulator of sGC in psychiatric disorders, when do you believe is the best time to intervene with this as a potential therapeutic agent? Is it like early in the patient journey, around first psychotic break or later?

Yes. No, I do believe early, as I mentioned. What happens when people are cognitively impaired is that they fail to meet, in this case, late teen and young adulthood milestones, and they are at a social disadvantage. If you can mitigate impairment and improve cognitive function, it's a benefit in itself, but also it critically allows young people to negotiate these important life steps. And there's a lot of evidence without pharmacology that people who are able to negotiate those early steps like finishing school, getting a job, forming a family, have much better outcomes. So we would really want to start early. I would add that there's so much interest in that. The NIMH now has a large public-private partnership, it's called the AMP, Advancing Medicines Partnership (sic) [ Accelerating Medicines Partnership ], that comes out of the NIH Director's office, in schizophrenia, looking at the onset of schizophrenia prior to the first psychosis and trying to find biomarkers that can guide treatment.

Okay. Thank you. So I think we probably have time for one more question, so I'll give this one to you, Dr. Hyman, as well. The question is, in a world where everything fails, are you optimistic about this? And if yes, do you believe that a 0.6 effect size, if it were to replicate in future studies, would be clinically meaningful?

So one has to be appropriately skeptical because everything has failed. On the other hand, I have not seen, it doesn't mean it doesn't exist, but I have not seen this kind of effect size yet. And I think you saw some comparisons on an earlier slide, perhaps from Jennifer, with other mechanisms. The effect size is large enough to give me hope, and it's certainly not the end of history. I mean, perhaps, combining this with cognitive remediation would give this more. And clearly, we have a long way to go before we have mechanism-based disease course-altering therapeutics. But I think I've demonstrated, at least to myself, my optimism about this mechanism by joining the Cyclerion Board.

Great. Thank you for those comments, and thank you very much for making the time to join us for the call this morning. Thanks to all of our other speakers as well. And I think with that, we will wrap up the Q&A this morning. Appreciate everyone making the time to join the discussion, and hope everybody has a great day.