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

Good morning. Welcome. We're very pleased that you've joined us this morning. We're looking forward to the next hour in spending some time with you talking about the progress we're making with the development work that we're doing at Cyclerion. We're a CNS focused team, and we all share a very big passion to develop drugs to restore cognitive function. We're going to talk through the scientific foundations of our efforts and why our recent clinical results demonstrating a rapid effect on multiple biomarkers associated with cognition are propelling our portfolio forward in several clinical populations associated with cognitive impairment, including a subpopulation of Alzheimer's called ADv, where we just got our IND cleared by the FDA, so we're pleased to share the details of that -- and design of that study with you today, and we'll be initiating the enrollment soon. And these first studies are just the beginning, the early days of what has the potential we believe of a tremendous opportunity to help millions of people globally suffering from cognitive impairment. Slide 2 is our safe harbor statement. Turning to Slide 3. We're inspired and motivated by the mission to develop treatments to restore cognitive function and by the breadth and the depth of that unmet need. We're shaping and building the right team, a terrific, tenacious team, and what we think is the right time to tackle that big challenge. And we are working with the special group of foundational assets. Cyclic nucleotides have been center stage in biological hypothesis and models of human cognition for a long time. And our data indicate that our approach could finally enable us to be the pioneers who first therapeutically modulate this critical cognition network. Our efforts are grounded in the science of cyclic GMP and sGC. And our strategy to tackle this mission to restore cognitive function includes 3 key elements shown on the slide: First, we're tapping into a fundamental CNS signaling pathway, and our lead program has demonstrated an improvement in biomarkers associated with cognitive impairment in the clinic and preclinically. These results are really exciting, and they reinforce the potential that activating this pathway in the brain could improve cognitive function. Second, we're executing an integrated stepwise development strategy, guided by cognition-associated biomarkers, starting with efficient, signal-seeking studies in well-defined populations with cognitive impairment. This will allow us to evaluate multiple populations in parallel and synthesize the results to refine our subsequent development strategy. Third, fully tackling the enormous burden and breadth of this opportunity will almost certainly warrant evaluation of additional clinical populations and additional molecules over the coming years. We're excited today to introduce you to CIAS and to our differentiated next-generation sGC stimulator, and we'll be guided by the data going forward. The data we're seeing so far clinically and preclinically continue to bolster our conviction and warrant further investment and effort. If we execute well and if we're right in our hypothesis, the data we're generating could generate significant value for patients and for our shareholders. If we can move to Slide 4. I'll go over quickly what we're going to cover in our time together. We'll review the fundamental role of nitric oxide cyclic GMP signaling in this process. We'll have a discussion of our integrated development approach for our lead molecule 6463 and then we'll shift a bit. We'll dig into detail about the newest clinical population we're evaluating, and that's cognitive impairment associated with schizophrenia. And then finally, we'll talk a bit about our next-generation sGC stimulator, which has some unique and interesting properties and where we believe we can unlock additional opportunities in the CNS. We're going to leave some time for Q&A at the back end, so please feel free to submit your questions via the chat function in Zoom anytime during the presentation. We'll do our best to compile and answer as many of those questions as we can in the last few minutes of the hour. If you'll turn to Slide 5, we'll introduce you to today's speakers. I'm Peter Hecht, I'm the CEO. And I'm very pleased to be joined today on the call by several of my colleagues in R&D. We're especially honored to have Dr. Andreas Reif with us this morning. Dr. Reif is a leader in neuropsychology -- neuropsychiatry, sorry, and has a longstanding research focus in the role of this pathway in CNS diseases and particularly in schizophrenia. With that, I'm going to turn it over to Dr. Andy Busch, our Chief Scientific Officer, to talk through the importance of the sGC pathway and the CNS, and specifically as it relates to cognition. Andy?

Hi. Thanks, Peter, for this introduction and for already pointing out the relevance of the NO-sGC-cyclic-GMP pathway. It indeed is fundamental for brain function, and I'm going to show the principles and the profounding experiments leading to our conclusion. Next slide, please. The NO-sGC-cGMP pathway is depicted on the left-hand side. You can see that NO is synthesized out of arginine through the neuronal NO synthase. Once it is synthesized, it acts to stimulate the soluble guanylate cyclase, which then generates cyclic GMP out of GTP. And cyclic GMP as a second messenger has numerous very important elementary cellular effects. It is, of course, the stimulator of protease kinase G (sic) [ protein kinase G ], it can directly gate ion channels. It is degraded by the PDE. The stimulation of PKG, the stimulation of ion channels, again, has further downstream effects. Some of them depicted here, phosphorylation of CREB, induction of BDNF and these downstream targets then are relevant for very important cellular effects and physiological effects, such as regulation of vascular function, improvement of bioenergetics through gene expression and increased ATP production, reduction of neuroinflammation through NF kappa B inhibition and finally, an increase in synaptic plasticity. And what is important to understand is that under pathophysiological conditions, in aging at different diseases, this pathway at different locations is disrupted. With CY6463, we have the first blood-brain barrier permeable compound, which goes into the brain to stimulate sGC and rescue what is disrupted or not fully functional. From the scheme I showed you here, we can conclude that amongst several aspects, there is an important role of this pathway in learning and memory, and I'm going to show you on the next slide some of the underlying experiments. I'm going to lead you through changes brought about 6463 on the morphology in vitro experiments as well as then in vivo pharmacological experiments. Let's first look on the left-hand side on aspects of morphological plasticity. What you can see is in the upper row, what this spine density along the dendrites in a young controller can easily identify that. In an age control, this spine density significantly decreases with aging. Treating an aged mouse with 6463 can rescue the spine density back to the normal level of a young animal, showing that you actually have a direct effect on the morphology and the resulting plasticity of neurons. In the middle, you can see in recordings in hippocampal slices that indeed in a neurodegenerative model, the so-called R6/2 mouse, the long-term potentiation, the potential measured post-synaptically is significantly decreased compared to control animals. However, already concentrated -- small concentrations of 6463 in the range of 7 to 10 nanomolar can improve this long-term potential. And if we get up to a concentration above 40 nanomolar, we can fully rescue long-term potentiation, bringing it back up to complete control animal. Finally, this obvious observation results in each in vivo learning and memory. On the right-hand side, you can see the Morris water maze experiment in which a rat has to find in a water tank where it is dropped on the left, a submerged platform on the right through only orientation at one individual signal. And what you can see is a young rat really rather quickly can identify and find that platform. An aged rat has a much more difficult time, very often being confused, very often being in the wrong part of the water and taking much longer to find the submerged platform. If this old rat indeed is then treated with 6463, it can learn faster and can reach faster the submerged platform. Rather quickly, it reaches a performance similar to a young rat. Next slide. In summary, that very nicely shows you that NO-sGC-cyclic GMP pathway plays an absolutely critical role in brain function. sGC stimulation with 6463 amplifies the NO-sGC-cyclic-GMP signaling. Morphologically, ex vivo and in vivo data demonstrate the important role of sGC in synaptic plasticity, learning and memory and very clearly demonstrate that 6463's ability to restore deficits in these endpoints. Based on these results, we developed a clinical development strategy, which are now shown to you by Chris Winrow, our Head of Translational Medicine. Chris?

Great. Thanks, Andy. So good morning. I'll be providing an update on the 6463 clinical development, and will also provide some insights into the momentum that we're building with our portfolio of CNS penetrant sGC stimulators. In addition to our preclinical findings you just heard about, we have data from our clinical translational pharmacology study where we also saw effects across a number of different objective endpoints. These data were most recently presented at the American Academy of Neurology meeting last week by Chad Glasser. And some of these findings include effects on EEG, with increases in posterior alpha power, improving event-related potentials or ERPs in the form of N200 latency, effects on saccadic eye movement reaction time and also reductions in neuroinflammatory biomarkers within the cerebrospinal fluid. The next slide, we have a range of data sets that have guided us through our development of 6463. And this includes the preclinical work that you heard about from Andy, specifically around synaptic plasticity and cognition. And in addition, we've seen effects on neuronal function, neuroinflammation, mitochondrial activity and bioenergetics as well as effects on cerebral vasculature. Clinically, we've observed consistent effects across a range of objective endpoints that have been linked to cognitive performance. And so taking all of this together, really, this data has led us to identify a key role for sGC stimulation and cognition. And we see a strong opportunity here for investigating the potential of 6463 to improve cognitive function across a range of diseases. It's well-established that cognitive impairment is a debilitating aspect across a range of CNS disorders. And there are millions of patients and their families that struggle with the impact of these diseases and their effects on cognition every day. We're actively pursuing clinical studies to understand the potential for sGC stimulation in neurodegenerative, neuropsychiatric and mitochondrial diseases. And you'll be hearing more about the specifics of our current pipeline activities in ADv, CIAS and MELAS shortly. It's also important to recognize that that 6463 and other CNS penetrant sGC stimulators may offer opportunities across a range of indications. And here, we show some examples, and we're really going to be guided by data to identify and execute upon these further opportunities. We've taken a very direct approach to integrate disease-relevant biomarkers, as you heard from Peter, to guide our studies and to really focus on targeting patient populations with cognitive impairment. These include patients with Alzheimer's disease and vascular pathology, MELAS and cognitive impairment associated with schizophrenia as well as other diseases where an sGC stimulator could have an effect on cognitive impairment. In terms of the endpoints that we're looking at and how we're conducting these studies, we're designing parallel studies and examining a distinct set of patient populations to enable us to look at an in-depth assessment of the pharmacology within the clinical setting. We're conducting efficient signal-seeking studies and using these focused studies to guide larger and longer studies and to help refine our understanding of the endpoints and the patient populations themselves. We're also using disease-relevant biomarkers to accelerate and guide our development program, and you'll be hearing more about this strategy as we continue through the presentation. This slide summarizes our current portfolio. And what you can see here really is the momentum that we're building by advancing these parallel studies and seeking to understand the effects of 6463 in exploratory studies in the prioritized patient populations. As a reminder, we've completed a robust set of Phase I studies that we've talked about on prior occasions. These studies in healthy participants demonstrated excellent tolerability, pharmacokinetics with a daily dosing profile and showed that we hit our CNS exposure target and impacted CNS neurophysiology within these healthy participants. In terms of indications, we've previously talked about mitochondrial disease or MELAS as well as our work in Alzheimer's disease with vascular pathology. And one of the new approaches that we're going to be discussing today is the opportunity that we see in cognitive impairment associated with schizophrenia, or CIAS. You'll be hearing from Dr. Reif shortly about this opportunity and the connection to the sGC pathway. And then Jennifer Chickering is going to be describing in greater depth the studies that we're building out for CIAS. And we're continuing to gain the momentum here across the portfolio as we advance the next-generation of CNS penetrant sGC stimulators. And this is exemplified by CY3018, our newest molecule positioned for clinical development. And Andy will be talking a little bit more about our next-gen efforts. On the next slide, I just want to take a couple of minutes to provide updates on our ADv and MELAS studies. And firstly, the ADv study is expected to initiate mid-2021 as an exploratory study, incorporating objective endpoints, again aligning with what we learned from that clinical translational pharmacology study and building in a range of cognitive endpoints on top of that. This is a 12-week study in about 30 participants, and we're really using a defined enrichment strategy to identify patients that we feel would be most responsive to 6463. In terms of specific updates, we are very happy today to announce that we received the Clear to Proceed notification from the FDA for our IND that we recently filed and are now actively engaged in our start-up activities for this study. The protocol we've designed incorporates input from a range of key opinion leaders, and we expect our first patients to be enrolled in the middle of this year. This, of course, is barring any complications that might arise from COVID-19 related delays. We're continuing to work with external experts across the field. And as an example, in addition to this study, we're engaged in a collaboration with Dr. Budson at Boston University to specifically look at the relationship between EEG endpoints and cognitive measures across a range of different dementias. And this work and other activities are really going to help inform our program as we move forward and also identify other opportunities in other areas where cognition is affected. In the next slide, in terms of MELAS, our study in mitochondrial disease, enrollment in our study and site activations have been impacted by COVID-19, and we are now expecting data to be available by the end of this year in 2021. We're understandably disappointed in this delay, but recognize that this is a high-risk population, and we expect enrollment to increase as more individuals become vaccinated. In general, across clinical research, we have seen more sites opening up over recent weeks, and we're working closely with our sites specifically to increase patient enrollment. As a reminder, this is an exploratory signal-seeking study, incorporating objective pharmacodynamic endpoints. We designed a 29 day open-label study, and this is in about 20 adult participants. We're using a focused enrichment strategy to guide the design and enrollment of these patients, and we're working with the key mitochondrial disease centers of excellence across the United States. Furthermore, we've engaged in collaborations with a number of scientific thought leaders in mitochondrial disease. And this includes a really exciting set of additional preclinical studies with Dr. Falk at the Children's Hospital of Philadelphia to investigate the potential impact of our sGC stimulators on mitochondrial function. The next slide. So at this point, very pleased to introduce Dr. Andreas Reif. Dr. Reif is the chair of the Department of Psychiatry, Psychosomatic and Psychotherapy at University Hospital in Frankfurt, Germany, where he's also a full professor. Dr. Reif has conducted clinical and preclinical research and is the author of over 400 peer-reviewed publications and 60 reviews and book chapters. He's conducted and led clinical studies and is an expert in the neurobiology of nitric oxide. And the importance of the nitric oxide sGC pathway in neuropsychiatric diseases. At this point, I'll turn over the presentation to Dr. Reif, who's going to be talking to us about his interest and the excitement around the potential for sGC stimulation and 6463 for cognitive impairment associated with schizophrenia. Dr. Reif?

Yes. Good morning from Germany. Thanks a lot, Chris, for this very kind introduction. The pleasure is all mine to present a little bit of data and my views on cognitive impairment associated with schizophrenia, and the specific role of the nitric oxide synthase and sGC pathway therein. Can we have the first slide, please. Next slide, please. Thank you. So most of you may know the predominant symptoms of schizophrenia that are termed the so-called positive symptoms of schizophrenia. They're not called positive because they are any good but because the patient is kind of generating things which are not there, and that means hallucinations, delusions and related symptoms. These are the first symptoms that come to people's mind when they talk about schizophrenia. Lesser known are the so-called negative symptoms. And these are symptoms such as avolition, decreased thrive, anhedonia, et cetera. Even lesser known is that nearly all patients with schizophrenia suffer from cognitive deficits. And these cognitive deficits are now regarded as the most prominent and the most disenabling symptom cluster in schizophrenia. These symptoms might well underlie even the positive and negative symptoms. As you know, schizophrenia is a very prevalent disorder. Schizophrenia affects around 1% of the adult population. That sums up to around 2.7 million in the United States or 21 million worldwide. So a large number of patients suffer from cognitive impairment associated with schizophrenia in the United States and also all over the world. What do these cognitive impairments comprise? This relates to memory deficits and impaired learning, probably also as a consequence of impaired working memory and, therefore, diminished reasoning. More executive functioning impairments such as attention deficit and reduced processing speed. And from the patient perspective, especially diminished social cognition can have a major impact on people's life and kind of move away people out of their peer group. Next slide, please. So what does this bring about? What is the consequence of cognitive impairment in schizophrenia? Schizophrenia is having its age of onset in life relatively early. The usual age of onset is between the 20th and 25th year. And as you can imagine, this is a very important time of life. Usually, you get your professional training there, you go to university or you learn your profession, you build the foundations for your family and so on and so forth. And if you suffer from prominent cognitive impairment during that time of your life, this can have long-lasting effects on your overall career, your professional and family life from there on. And that means that cognition is tightly linked to your everyday functioning. And if you improve cognition, that will also positively affect functional recovery. And also, thereby, the ability to participate fully in the community and to live independently. As a consequence of cognitive impairment, most of the cost of disease that is attributed to schizophrenia actually relates to cognitive impairment. Only about 1/4 of all costs associated with schizophrenia are due to direct medical costs, but the largest share of the cost due to schizophrenia can be attributed to indirect costs, such as unemployment, productivity loss or other forms of indirect medical costs that then can be traced back to cognitive impairment. So to wrap it up at that stage, cognitive impairment is a huge problem, and it's a very important unmet clinical need as we do not have any medication, any drug that really targets and improves the cognitive impairment in schizophrenia. If at all, the medications that we use currently, which are mainly dopamine blockers, decrease cognitive or impair -- cognitive impairment even further, and there's not a single substance on the market that targets cognitive impairment. Next slide, please. My interest in the NO pathway and schizophrenia goes back for more than 20 years now. And initially, I started the effect of genetic variation in nitric oxide synthase and to link that first on an association level, but then also with an endophenotype approach to schizophrenia I think would demonstrate the genetic variance and nitric oxide synthase are indeed associated with schizophrenia and with cognition in schizophrenia. More recently, we became interested in the interaction of NOS1 with an adaptor protein called NOS1AP and how this mechanistically links the NO pathway to cognitive deficits in schizophrenia, and I will come to that in a few seconds. Next slide, please. How does nitric oxide and sGC relate to schizophrenia pathogenesis. Since decades now there is a hypothesis called the hypoglutamatergic hypothesis in schizophrenia. This means that you have a hypoglutamatergic state at the NMDA synapse. And this is depicted here in that cartoon. These neurons are most predominantly found in the prefrontal cortex and in the hippocampal cortex. In a hypoglutamatergic state, less glutamate is released from the presynapse, which is shown here on the left side of the schematic. Glutamate activates the NMDA receptor and thereby allows calcium influx in the postsynaptic neuron. Calcium, in turn, activates NOS1, which then releases the gaseous neurotransmitter, nitric oxide. And now, as I've said, the gaseous neurotransmitter then therefore diffuses freely over the cell membrane where it can activate SG cyclase in adjacent neurons, in glial cells and also the presynaptic neuron. However, here, we want to zoom in to the postsynaptic neuron. Nitric oxide activates soluble guanylate cyclase, sGC, which forms cyclic GMP out of GTP. And cyclic GMP, in turn, then activates downstream pathways, including CREB activation, BDNF release that then in turn causes an underlying synaptic plasticity. So hypoglutamatergic functioning causes fewer cyclic GMP and thereby empowers synaptic plasticity and that underlies especially memory and learning deficits as well as other cognitive impairments in schizophrenia. Next slide, please. In our approach, which we have preclinically targeted, we tried to manipulate exactly that pathway by overexpressing NOS1 adaptor protein. This adaptor protein interferes with the coupling of NOS1 to the NMDA receptor. Usually, NOS1 is coupled to the glutamate receptor by PSD-95 and upon binding of NOS1, adaptor protein NOS1 is sequestered from the NMDA receptor and thereby NO release is shut down. And we were interested in the functional consequences, this diminished NO formation and thereby also diminished cyclic GMP formation has. And we could show that this first has morphological consequences. You can see that on the right side of this cartoon. Again, you might -- may have remember the images that Andy has shown you in the beginning with aged rodents. And just like in aged rodents, we have morphological abnormalities here that reduced spine density and that also caused morphological abnormalities in spine formation and spine morphology here. If you compare that to the left side, which would be the normal state. So here, inhibition of NO and cyclic GMP causes morphological abnormalities. And these are very reminiscent of the abnormalities you find in postmortem tissue of schizophrenia patients. Furthermore, we could show in rodents also that this goes along with cognitive impairment, especially in spatial memory. Such reduced synaptic plasticity that you can see on the right side causes a disturbance of prefrontal cortex and hippocampal function and in humans, this can be measured by EEG and functional MRI, although EEG is preferable here due to cost and speed of -- the space and the time resolution. And we propose that this mechanism of a diminished NO-sGC-cyclic-GMP pathway, therefore, underlies cognitive impairment schizophrenia. Next slide, please. So to sum it up, multiple lines of evidence, and I just showed a few today implicate reduced NO-sGC-cyclic-GMP signaling in schizophrenia generally and specifically in cognitive deficits in schizophrenia. This is a downstream mechanism of the hypoglutamatergic state, which is well-established to the pathophysiology of schizophrenia and such compromise prefrontal and hippocampal NO signaling underlies cognitive deficits in schizophrenia. And therefore, we believe and I believe and, therefore, I am very excited to participate here today that targeting the NO-cyclic GMP pathway is a very promising therapeutic and novel approach in the treatment of cognitive deficits in schizophrenia. With that, I thank you for your attention and hand over to Jennifer for the next part of the presentation.

Thank you, Dr. Reif. We certainly share your enthusiasm about the potential to modulate the NO-sGC-cGMP pathway for the treatment of CIAS. And I am very happy to be here today to introduce our new 6463 program in CIAS and share the outlines of our first study. If you move to the next slide. As Dr. Reif laid out, it's well-known that deficiencies in NO-sGC-cGMP signaling are associated with cognitive impairment in schizophrenia. And so it follows that targeting this pathway is a promising treatment approach. We believe sGC stimulation by 6463 is the best approach for enhancing this signaling. And we base this on 4 main things: one, 6463 specifically targets sGC, the central node in this key cognitive pathway and the source of cGMP, as depicted in the figure on the right; two, sGC is a proven druggable target, that's been demonstrated in the periphery. And now with 6463, we have the first opportunity to apply this mechanism in the brain; three, 6463 targets the critical brain regions and cells supporting cognition; and four, as a positive allosteric modulator, 6463 amplifies endogenous signaling, that means 6463 can boost the NO-cGMP signal while maintaining the spatial and temporal nature of that signal. That's clearly important in preserving the fidelity of neurotransmission and the synchronization of neural oscillatory activity. So for all of these reasons, we've had CIAS on our radar for a while. The icing on the cake for us was our recent clinical data, where, as Chris reviewed earlier, we saw clear signals in biomarkers associated with cognition. Those data spurred us to move quickly into CIAS, an indication with tremendous unmet need, as Dr. Reif just reviewed. If we move to the next slide. CIAS is our third indication for 6463 and our first neuropsychiatric population. Our overall aim is to run an efficient first study and generate data to inform dose, patient and biomarker selection for next steps. To that end, we have 3 main study objectives: first and primarily, to confirm the safety, tolerability and pharmacokinetics of 6463 in this patient population; second, to confirm target engagement in the CNS and explore signals relevant to cognition; and third, to evaluate these things, safety, PK, target engagement and exploratory signals across a range of dose levels. Those are our objectives. And now if we can move to the next slide, I'll outline how we're planning to meet those objectives in our first study. Consistent with our first studies in ADv and MELAS, our emerging design in CIAS is centered on early signal seeking. Therefore, we want to control as much as we can to maximize our opportunity to see a 6463 signal. We plan to do that by running this study in clinic. It will be randomized, placebo-controlled and double-blind. We'll enroll adults with symptomatically stable schizophrenia, who are on a stable antipsychotic regimen. We'll evaluate once-daily dosing for 14 days and around 50 participants across sequential cohorts. As our primary objective is confirmation of safety in this population, we'll be looking comprehensively at that via typical assessments. And on the exploratory signal seeking front, we'll be including pharmacodynamic and efficacy relevant assessments. We're planning a broad battery of EEG-based tests. That battery will capture both resting state and task-related spectral effects. And of course, we'll also capture an array of ERPs, event-related potentials, that measure the functional activity of brain circuits. We're working on exactly what that battery will look like, but we expect to include a number of tasks, including auditory oddball tasks, so we can look at a wide range of ERP components like mismatch negativity and P300. The ERPs reflect the information processing that underlies cognition, and many ERPs are diminished in schizophrenia, reflecting the pathobiology of CIAS. We also plan to assess cognitive performance using a computerized cognitive test battery. Specifically, the CogState Schizophrenia Battery, which covers all the domains of the FDA-backed MATRICS consensus cognitive battery, the MCCB. And we'll be assessing both EEG and cognitive performance at multiple time points across each 2-week cohort. The final point on this slide, we plan to select the dose levels for our cohorts based on data from preceding cohorts with the aim of maximizing our learning in this study. Our approach to development of 6463 in CIAS, which is outlined on the next slide is consistent with our approaches in ADv and MELAS. We're leveraging mechanism and efficacy related biomarkers, beginning with our first study. As Dr. Reif shared, CIAS is an area of great need. It's also a challenging indication for development. And so we're applying learnings from other programs in this therapeutic area. For example, in our first study, we're evaluating 6463 over a range of dose levels, that's to evaluate safety, while we push pharmacology, and this will give us an early look at our therapeutic index in this population. Results from this first study will guide our next steps. In terms of those next steps, we recognize the challenges and are in active learning mode. We're working with therapeutic area leaders with experience and expertise as well as assessing innovative analytical approaches. We are in the early stages of building our development plans. But clearly, we'll want to evaluate the efficacy of 6463 for the treatment of CIAS over longer periods in an outpatient setting, where we'll need to address issues like compliance and placebo effects. In addition, we expect to explore patient selection strategies to identify people who may be most likely to benefit from sGC stimulation with 6463. These are the learnings that we would then take into a pivotal program. Cognitive impairment is a debilitating and untreated facet of schizophrenia. The cost of cognitive impairment is high to people with schizophrenia, to their families and to society. We envision once-daily 6463 as standard of care therapy on top of antipsychotics, and we're hopeful about its potential to improve both cognition and function in people with schizophrenia. And now I'll turn it back over to Andy to introduce our next-gen sGC stimulator. Andy?

Well, thanks, Jennifer. Next slide, please. I think you've heard from Chris a lot about the potential of 6463 in a number of CNS diseases. And you just heard from Jennifer about our new study in CIAS. When we look at 6463, we can see that this compound is passively distributed into the brain. It crosses the blood-brain barrier, as we said before, to reach pharmacological active concentrations in the brain. And what you can see on the left is 6463 being indicated of having a CSF to plasma ratio of about 0.5 to 1. What that means is that we also see peripheral effects of 6463, and these are actually wanted in some of the indications, which Chris has described, for example, in ADv. Well, of course, we are very happy about peripheral effects on the vasculature caused by 6463. However, having said that, we have a scientific rationale for a number of CNS diseases for which we want to reach a maximal exposure with a more reduced peripheral efficacy. Therefore, we optimized a compound, which is depicted here called CY3018 and this compound is actively transported into the brain with a consequence of it producing a CSF plasma ratio of far above 2, which shows that there is a clear CNS specificity and an increased exposure of the CNS through this compound. This does translate indeed also in a relative change pharmacology, where when we look at CNS effects versus peripheral effects, namely gamma power increase versus blood pressure decrease, we can see that 3018 has a very different ratio compared to 6463. So this altogether, together with a number of other experiments, also proving a very positive pharmacokinetic profile and a first preliminary safety profile makes us pretty excited in taking this compound as fast as possible through our IND-enabling development out of the portfolio of indications with a strong rationale for sGC in CNS diseases, which Chris showed you in his presentation. We have selected a few with the strongest scientific rationale and are engaged in ongoing pharmacology experiments, in vivo experiments to identify the first indication we want to go for in human beings. With that, I would like to hand back over to Peter, who will conclude this webinar. Peter?

Great. Thanks, Andy. And thanks to Dr. Reif and to the rest of the team for the great discussion we've had so far. As you've now heard, we have some very encouraging data that our foundational assets are engaging a fundamental and long-targeted signaling pathway in the CNS and that, that's providing an opportunity for us to pioneer on that pathway and potentially treat cognitive impairment across a broad range of patient populations. We're first investigating the opportunity in 3 well-defined patient populations in ADv, in MELAS and in CIAS. These first studies will teach us a lot about the mechanism and its impact in patients with cognitive impairment. And these learnings will inform each other, each study and next steps and enable us to optimize how we design subsequent studies as well. As always, we'll follow the data. And we expect that we'll continue to explore additional patient populations over time, given what we know about the mechanism and the unmet need and the multidimensional nature of the pharmacology that we trigger when we activate soluble guanylate cyclase. I should mention in closing that we honed our operating model very substantially over the past months so that we can direct our investments and our efforts very fully to these priority opportunities. Our monthly operating run rate is now less than half of what it was in 2020. And we're a fully virtual in our operations. We've exited our facilities, and we're a tight, very externalized network team, which allows us to direct the maximum dollars toward the clinical evaluation of these programs. And we look forward to getting the data out of these programs and moving them forward. I would say with multiple patient populations, multiple compounds being investigated and a little good luck never hurts in the drug making business. We think we have exciting optionality as the data reads out and a very compelling investment thesis. And I should also mention that we've just emerged from the 2-year constraints from the tax-free spin that was part of our origins and that also opens up for us some optionality. So between the tight operating plan and the assets we have in hand and optionality on partnering and resources, we'll work very hard to create value for you. We want to thank you for the time so far, and we'll look forward to answering questions. As I mentioned in the opening, there's a chat function. I see a bunch of questions that have come in. I'm going to turn it over to Cheryl Gault, who can help facilitate the Q&A session and aggregate questions. Cheryl?

Great. Thank you very much, Peter, and I'm happy to join this morning to help facilitate the Q&A. Thanks to all the participants who have submitted questions during the session. [Operator Instructions] Please be patient with us for just a minute as we work to sort of compile the questions. What we're trying to do is bucket the questions into a few key themes, and then we can select sort of a representative question from each theme. That will allow us to get through as many topics as possible in our remaining time together. So let's maybe start with a question about the sGC mechanism and its impact in CIAS. So the first question, given that very few mechanisms have worked in cognitive impairment in schizophrenia, what makes you optimistic that this approach will work in such a tough population? And then maybe a sort of related question, what does a win look like coming out of this first study in CIAS? So maybe I'll invite Dr. Reif to take the first part of that question and then, Jennifer, maybe you could jump in for the second part. Dr. Reif?

Yes. Happy to answer the first part of that question. It's a very optimistic statement actually saying that very few compounds have addressed positively cognitive impairment in schizophrenia. I would say, rather none. How does that come about? Most of the compounds that have been tested so far are very unspecific. Most compounds targeted the primary monoaminergic neurotransmitters that are distributed widely over the brain. And this is not specific at all. There were some approaches in targeting the glutamatergic pathway already, mainly by positive allosteric modulators of the NMDA receptors. But then again, that is a very unspecific mechanism. It targets NMDA, but not specifically downstream mechanisms. But here, we interfere with a very, very selective, both in terms of molecular mechanism of action as well as cellular mechanism of action. We target a very specific pathway using our PM. And I think due to this specificity, we not only lose side effects, but we also are more specific in the mechanism of action. And therefore, I would be very optimistic given our preclinical data and also mechanistic human data that we are on target here with CY6463.

So I think I have the second question, which was what does a win look like for this first study? So it's a good question. All right. I'll start by just saying that our first study is designed to be an exploratory signal-seeking study. So just to be clear, it's not powered for any endpoints. Okay. So I think about our expectations for this study on 3 levels. First, and this is consistent with our primary objective. We'll confirm we have a dose range that's well tolerated that we can take into next studies. And that's really the basis of any win. Second, then we're going to be looking to the EEG endpoints. So based on our translational pharmacology study, where we saw positive impacts in 2 weeks, after 2 weeks of dosing. We expect to see positive changes in EEG endpoints in this study as well. And that's in both qEEG and ERPs. And those endpoints, ERPs, in particular, have clear links to cognition. So that's a win for us. So that's 1 and two. Three, we're also including a cognitive performance battery and, of course, would love to see directional improvement in one or more domains. But this is an exploratory short treatment duration study. So we don't know if we'll be able to see changes that separate from placebo in such a short time and effects on cognition may very well lag effects on neurophysiology. So we really have no expectations there. But of course, we want to look and want to gain experience with the CogState battery in this population. Overall, this first study is designed to be an efficient study that looks for signals across several dose levels. So we're leveraging biomarkers, as we are across all our programs, to learn about 6463 and then to inform what we do next in this program.

Great. Thank you, Dr. Reif, and thank you, Jennifer. So next, let's take a question about the mechanism more broadly. So the question is, why will an sGC stimulator be successful in cognition when other drugs in this pathway have not? And specifically, why do you think sGC stimulators will work better than PDE? So Andy, maybe I can invite you to jump in on that question.

Sure, Cheryl. I think that's an excellent question. Really good question. And to answer that question, I think we have to understand first, how; and second, where is cyclic GMP elevated, produced or not degraded. And there, you see already a very significant difference between soluble guanylate cyclase activation and stimulation versus PDE inhibition. First of all, across the brain sGC is expressed across all brain regions in a very clear and good distributed way, whereas the PDEs have a very differentiated expression across the brain. The same is true within individual cells. sGC is expressed in neurons, in glial cells, pericytes and in the neurons, and the different PDEs are much more specifically in individual cells expressed. Now when you look at where is cyclic GMP produced and where is it increased, it's important that not an intracellular expression somewhere -- production somewhere has to take place. It has to be at the right spot. PDE is the enzyme, which degrades cyclic GMP close to the plasma membrane, but very often, cyclic GMP, which is not degraded there, does not reach the nucleus, which is important for a number of the effects which we described today. sGC stimulation is in a different place in the cell. The effects of cyclic GMP increase after sGC stimulation do reach the nucleus and clearly will produce a different type of pharmacological response. This was all theoretical, but the proof is in the pudding. And if you look at a number of experiments, you can see pharmacologically in vivo and in vitro indeed a differentiation between PDE inhibition and sGC stimulation. For example, when we do an experiment measuring EEG gamma power in rat brain, we can very easily see a significant and nice prompt increase after sGC stimulation, whereas we don't see any type of effect with PDE9 inhibition. Neither does a PDE9 inhibition increase or affect the effect of sGC stimulation. So I think, theoretically as well as from the results we have produced in pharmacological experiments, we can conclude there is a very significant difference in the question where within the NO-sGC-cyclic-GMP pathway you do interfere and you do act. Back to you, Cheryl.

Great. Thank you very much, Andy. Maybe next, another sort of related scientific question. The question is, is the effect of 6463 more likely to be on neurons or microglia, astrocytes or pericytes? And is the effect of 6463 likely to be due to increased blood flow to the blood-brain barrier? So maybe for that one I can turn it over to you, Chris.

Sure. I'm happy to take that one, Cheryl. So yes, it's a really interesting point. I think as you just heard from Andy, one of the exciting aspects of this pathway is the broad distribution throughout different cell types within the CNS and proximal to the CNS. And I think what we also need to recognize is that there's exquisite control locally, and that's generated by, for example, release of NO in areas in response to that neurotransmitter. So the work that we've done and others have done, I guess, particularly questions around the pericytes and vasculature, certainly, there's a wealth of literature that shows effects for this pathway there. Within neurons, we've seen studies, and you saw some of the LTP data where we see effects that we believe are directly through acting on neurons. And we've also done studies where we've used 3D microcultures, which are -- they don't have a vasculature, and we've been able to see effects on things like inflammation. So that says that it's -- these effects are not only due to the vasculature. We've also conducted studies -- and fMRI BOLD studies where we've used a peripheral sGC stimulator and compared that to 6463 or CNS penetrant stimulator. And we see very different effects directly in fMRI BOLD signal. So we see that the brain activation pattern is much different when we're able to get it into the brain. So it says, in total, there can be effects across a range of these cell types and regions. But we believe that by getting into the CNS, we have a real opportunity here to have effects on things like neuroinflammation, neuronal function, synaptic plasticity and a host of other effects. So I think that's also what's exciting as we think about our indications. These opportunities in different diseases will have different components. So it's really going to be the data that we'll use to guide us there and help understand where the biggest impact might be.

Great. Thank you, Chris. We also have some questions about the timing of study starts, both for the ADV study as well as the CIAS study. So maybe, Chris, I could invite you to make just a couple of comments on sort of the timing for the upcoming study starts.

Sure. So again, just to remind you, our MELAS study is active and underway. So that's 1 of our clinical activities. The ADv study, we just received the Clear to Proceed notification from FDA. So we are actively engaged in start-up activities there with the expectation to start enrolling patients in the middle of this year. And then in terms of the CIAS study, you heard about from Jennifer, those activities are looking to start in the second half of this year.

Great. Thank you. So I think we are just about at time. So I think we'll wrap up the Q&A there. Certainly, if you have any additional questions or would like to follow-up on any of the topics covered in our session here this morning, please reach out to us directly. We're very happy to set up one-on-ones and continue the conversation that way. And I'll just say thank you again for taking the time to join us this morning and making the time to learn a little bit more about our programs. As I think you've heard from us, we're pretty excited about the opportunity ahead for the application of sGC stimulators in patients with cognitive impairment, and we certainly look forward to providing updates as the programs progress. So thanks again for joining, and I hope everyone has a great day. Take care.