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

Okay, great. Let's get started. Good morning. Welcome to our CNS-Focused Investor Event. We're pleased to have you join us. Today's webinar is going to be centered on IW-6463, our oral once-daily CNS-penetrant sGC stimulator. We want to tell you why we're so excited about its drug attributes and its therapeutic potential. And we want you to take a dive into the initial indications that we've selected to explore its full potential. And we'd like to describe to you the adaptive and learning approach that we're taking to development of this molecule. Next slide, please. We're going to be making forward-looking statements during the course of this discussion. You can read our full safe harbor statement by accessing this presentation along with recent press releases on our website. I am Peter Hecht, I'm the CEO, and I'll be your host for today. I'm joined by several of my colleagues, including members of the management team and our CNS program team. Given the short time together, we're not going to have introductions and have people describe their bios, but all of the bios are available on our corporate website. We're especially pleased and honored today to have 2 outside clinical specialists join us and share their perspective on the 2 diseases we're tackling, Dr. Marni Falk and Dr. Eric Smith. Dr. Falk and Smith will each spend some time talking about the patients, the unmet clinical needs and the opportunity for new therapeutics in these first CNS indications. We thank them for making the time to join us today to share their perspective. With that, I'd like to turn it over to Cheryl Gault, our Head of Strategy and Corporate Development, to introduce you to the program. Thanks. Cheryl?

Great. Thank you, Peter. Cyclerion is a clinical-stage biotech company, pioneering the advancement of sGC stimulators in 2 important therapeutic areas, sickle cell disease and CNS. In sickle cell disease, we have an ongoing Phase II study, investigating our sGC stimulator, olinciguat. We're very excited to announce that enrollment has closed with 70 patients and dosing has been completed. Our program team was relentless in driving both enrollment and follow-up in this important study despite the challenges presented by COVID-19. We expect to release top line data for this study in late Q3. Sickle cell disease is a debilitating multisystem disease and patients need a comprehensive treatment. We're very pleased to see 2 new treatments enter this market. These are important advances, for sure, and their positive receptivity is really encouraging. We also believe that there continues to be significant unmet need in sickle cell disease and that there's plenty of room in this market for more innovation. This is why we're excited to learn more about the clinical profile of olinciguat from our ongoing study. Given the broad pharmacology of sGC stimulators, we anticipate an efficacious and differentiated profile that will add meaningful new clinical benefit for patients with sickle cell disease, either alone or in combination with existing treatments. We expect to have additional investor events for our sickle cell program once the data from the ongoing Phase II study are available. The purpose of this call is to focus on our CNS program, which is the part of our story which is perhaps less well known, but is certainly no less exciting. As leading experts in the field of sGC, we are advancing the first sGC stimulator to cross the blood-brain barrier. And we believe that this mechanism has the potential to create the next big breakthrough in CNS by stimulating a previously undrugged neurotransmitter system. Other successfully drug neurotransmitter systems, for example, the dopaminergic or the cholinergic systems, opened up entirely new therapeutic categories and created significant market opportunities as a result. This kind of therapeutic potential opens tremendous opportunity to help a wide range of patients suffering from CNS diseases. It also makes our CNS program an exciting part of our strategic focus today and a core part of Cyclerion going forward. Next slide, please. During our time together today, our discussion will center around the following themes: Now is the right time for sGC in the CNS. The increased understanding of patient and pathway biology has increased our confidence; there is a strong scientific and clinical basis for the application of sGC in CNS indications, which we will share; our translational pharmacology study is an important upcoming data set where we expect to demonstrate CNS activity; and lastly, the clinical direction of our program in CNS and how we are thoughtfully picking clinical indications in designing efficient early clinical studies. Next slide, please. For each of these themes, we have a specific objective for the call today and what we hope you get from our time together. By the end of the call, we hope that you have a clear picture of how we intend to create value in the CNS, an exciting yet complex therapeutic area; the broad therapeutic potential of sGC stimulators in the CNS, this is by virtue of the multidimensional pharmacology that can be achieved by stimulating this untapped neurotransmitter system; what we expect from the upcoming results in our translational pharmacology data; and lastly, our development approach and why we are so excited about the opportunities in the first 2 focused patient populations we intend to pursue. Next slide, please. So let's start with now is the time. Rapidly evolving scientific understanding of disease and pathway biology in the CNS makes for a big opportunity for new drugs. We are focusing on understanding the intersection between patient biology and pathway biology to raise the odds of clinical success. We have important clinical data coming in late summer, which will help inform future development. Next slide. So here, just a few comments on how we think about capturing potential in the high-reward therapeutic area, that is the CNS. There's no doubt that CNS is a high-reward space, where the unmet needs are huge given the rapidly growing patient populations and the dearth of approved and effective treatments. Any mechanism that provides real clinical efficacy is going to be very valuable clinically and commercially. And the rapidly evolving science, both genetic insights and technologies, is making new drugs more tangible. This dynamic creates a lot of interest from both investors as well as industry partners, those who are looking to add novel treatments to build their portfolios in CNS, and we are the innovators here. We have the first CNS-penetrant sGC stimulator advancing forward in CNS diseases. We also appreciate history. We're learning from the programs that have come before us in the CNS and are applying those learnings to our program; specifically that it's imperative that we continuously work to increase the understanding of the disease biology in order to effectively identify the right patients to study; that we're getting adequate CNS exposure to have a pharmacologic effect; and that we're investing early in the development of biomarkers that can help to translate our scientific understanding into the clinic and can guide future clinical development. This is a very exciting time to be in CNS drug development. The scientific landscape is rapidly evolving. And if we have a drug that really works for patients, we know we'll be making a difference in the lives of many and building a core CNS franchise in the process. Next slide, please. So I think the question is, how do we raise our odds of success in the CNS? Well, our approach is to focus on the intersection of 3 things: important unmet patient need where a new treatment will be clinically valuable; sound biological rationale for the application of the sGC pathway; and selecting genetic and phenotypically defined patient populations where we can reduce variability. We believe that in focusing on the intersection of these 3 things, we're pointing our mechanism at the indications where it's most likely to have the biggest impact and, therefore, give us the best chance to detect a signal in early clinical studies. Beyond indication and patient selection, the other ways that we believe we can raise the odds of success are pursuing multiple indications in parallel, which is critical to driving both near and mid-term value, leveraging a biomarker-based development strategy, whereby clear results are derisking for future studies and designing small nimble studies that take advantage of the latest brain imaging analytics. Lastly, we're exploring an R&D collaboration in order to support the development of more indications in parallel. A great partner can bring expertise and capabilities and help us increase the total investment that can be deployed against what we see as a really big opportunity in the CNS. Next slide, please. So this page gives you a bit of a road map, if you will, of where we are and where we're going. IW-6463, our CNS-penetrant sGC stimulator, has completed Phase I, and the results there were very encouraging. We then initiated a translational pharmacology study in elderly subjects. And this is a study that will allow us to demonstrate that the biomarkers that moved in our preclinical work can be translated to humans, thereby enhancing our confidence as we move forward in the clinic. We expect these results in late summer. The next step, of course, is moving into patients, and we have plans to move IW-6463 forward in 2 indications to start: MELAS, which is a rare mitochondrial disease; and Alzheimer's disease with vascular pathology, which we call ADv for short, and this is an identifiable subset of mixed dementia patients. Both of these initial indications have a compelling scientific rationale, and for both we have selected a defined and identifiable patient population and a patient population where we can apply a biomarker-based development plan. You'll hear much more detail about these indications in the clinical section to follow. But first, I'd like to turn the call over to Dr. Mark Currie and Dr. Andy Busch to talk about the scientific underpinnings of our CNS program. Mark?

Good morning, everyone. And thanks, Cheryl, and thanks for you who are participating on this event. sGC is a validated -- clinically validated target. The pathway had many successful drugs. And most recently with the sGC stimulators, there's clear evidence that the pathway can be used -- approach can be utilized to deliver a meaningful therapeutic option for patients. The pathway in the CNS is evolving, and we're learning a great deal. It's very clear the system is expressed -- highly expressed throughout the CNS. And that has -- when we take a systems approach in map way -- pathway mapping, we see very clear evidence that this pathway is critical to basic neuronal functions and also has a role in neuropathophysiology. IW-6463 represents a clear breakthrough. It's the first sGC stimulator that crosses the blood-brain barrier. We'll show you that it has activity in at least 4 key domains, and we'll go into more detail around these domains. But to set it up at the beginning here, what we see is clear evidence of improvements in cerebral blood flow; cellular bioenergetics; neuro -- we'd say decreases the neuroinflammation and improvement in neuronal function. Next side, please. So when you look at this pathway, I will start with how it -- the regulation of the pathway. Arginine is converted by the enzyme nitric oxide synthase. This enzyme then converts so that you produce nitric oxide endogenously. It then activates -- this nitric oxide, then activates the soluble guanylate cyclase as a stimulator. This causes the conversion of GTP to cyclic GMP. And what we see with this effect of the endogenous nitric oxide, we can potentiate that effect with an sGC stimulator, so that you get this, even more increase of cyclic GMP, but it's in alliance with the system -- the endogenous system that's boosting the endogenous system. The pathway has been a source of multiple breakthrough drugs over the many decades and years for advancing drug. Nitric oxide donors go back over 100 years, nitroglycerin being used for angina treatment and other cardiovascular disorders. More recently, PDE5 inhibitors came forward for erectile dysfunction, BPH and PAH. And then even more recently, the first sGC stimulator, which was advanced by my colleague, Andy Busch, that we see the utility of this pathway, this approach for treatment of PAH and there are further indications in other cardiovascular diseases. The nitric oxide system is critical and it plays essential role in CNS diseases. We've map -- done a great deal of pathway mapping and network analysis for examining the role in CNS diseases, and we'll go into detail. But obviously, we believe that Alzheimer's disease with vascular pathology and MELAS represent two of the exciting potential areas we may be able to help patients with this approach. sGC is optimal for boosting the pathway in the CNS. As we said before, it amplifies the endogenous signaling, increasing the cyclic GMP level for a longer period of time in higher concentration. And what we don't -- and you'll also that no attenuation of the response that you see with NO donors. Next slide, please. Examining this broad rich effect of the sGC stimulators in the CNS and then also this pathway and what it's doing in in the central nervous system goes to a number of fundamental activities. What we see is that we can enhance cerebrovascular smooth muscle function and vascular function. We increased cerebral blood flow in localized areas that matches to the energetic needs of the brain. We also see decreased vascular inflammation and improvement in the blood-brain barrier so that we decrease -- increases in permeability. Also, we see the pathway of anti-inflammatory, so we block the inflammation that is occurring in the vasculature and also in monocytic cell lines. So we see a reduction in pro-inflammatory cytokines in the brain. And then if you look at the effect on metabolism, and these effects are broadly across the systemic effect, what you see is we decreased glucose levels in diabetic animal models that we've examined, but also when we've looked at diabetic patients. And we see also reduction in lipids, in particular, LDL cholesterol. When you also then go and further examine what this pathway activities may be able to generate, we see improvements in cellular bioenergetics, including improvements in mitochondrial function, in cell lines that have -- from patients that have mitochondrial diseases. We can improve the production of ATP and there's evidence that this system stimulates mitochondrial biogenesis. Also excitingly, this system acts directly on neuronal function, it is a nitric oxide, is a neurotransmitter, well defined. And so we're boosting the activities of the -- with an sGC stimulator of the nitric oxide neurotransmitter function, which is often centered around improvements in cognition, memory and executive function and alertness. So all of these broad pharmacologic effects are critical in our sense of thinking through potentially improving the lives of patients that have MELAS and also Alzheimer's disease with vascular pathology, and ultimately we think in a number of other potential CNS diseases. Next slide, please. And with that, I'd like to also just end with a pretty exciting concept that nitric oxide is the next big area for a direct effect on a neurotransmitter system. Drugs that have been highly successful -- drug classes and multiple drugs and are potentially having effect on CNS function. As we well know, as shown in this slide, there are multiple classes. As an example, the SSRIs for treating depression and mood disorders made a major advance. And we think nitric oxide has its role in neurotransmission and ultimately sGC stimulators with IW-6463 being the first-in-class have that potential also to bring forward really important drug class, and that the innovation is the beginning of an innovation with IW-6463, and we expect future drugs in this class also to help patients. So with that, I'll turn the presentation over to Andy Busch. And Andy is our Chief Innovation Officer.

Thank you very much, Mark. I think Mark nicely laid out the groundwork and the ideas of the importance of the NO-sGC-cyclic GMP pathway. I think it is very clear from the description you've heard that this pathway is validated pathway in a number of cardiometabolic diseases. Going towards a difficult area, such as the CNS, it was our utmost importance for us to really validate this pathway to the best we can for diseases of the CNS. For that purpose, we did a network analysis, which we utilize to disease linkage, the pathway to our genetics network to the human interactome back to several drug pathways. Doing that and analyzing over 20 databases across the platforms described at the top, we came to the result, first of all, that this is a validated approach because what we found was indeed cardiometabolic diseases which were the ones where sGC -- different types of sGC stimulators were shown in the past to produce beneficial effects, such as diabetic nephropathy, heart failure or pulmonary hypertension, but we also saw with a very high significance popping up several CNS diseases. Some of those listed on the right. This gives us comfort that indeed, we can link the pathway by means of human interactome and genetics to CNS diseases. With that, we employed, of course, a battery of preclinical experiments to see effects of our brain permeable compound, IW-6463, on hallmarks of neurodegeneration. And you see that on the next slide. What you can see here is the summary of experiments we have performed to test for effects of our compound on cerebral blood flow, cellular bioenergetics, neuroinflammation and neuronal function. What we found on cerebral blood flow was indeed in rat brain an increased blood flow, an increased blood flow in the area where we believe it is important for a number of neurodegenerative side effects. So we do find indeed an increased blood flow in the hippocampus, in the thalamus or in the reticular activating system and believe that this increased blood flow is our significant benefit in these areas. Cellular bioenergetics. We do see, indeed, in cells of Leigh syndrome patients, patients with a mitochondrial disease, an increased ATP production, and we also see a restored gene expression in cells from those patients because we find a nicely increased TFAM expression increase, which is important for mitochondrial increase of gene expression. On neuroinflammation, we see both in rat as well as in mouse models an impact on LPS-induced neuroinflammation. We can see that, indeed, we can decrease, with the compound, inflammation markers such as ICAM-1, VCAM-1 and IL-6, both in mouse and rat models in different cell types. And finally, we can also show that we improved neuronal function both in experiments testing the function as well as the tissue composition. We can see an enhanced memory performance, and we can see an increase in spine density in aged animals. And indeed, those aged animals, from the structure of their spines, looked like young animals after treatment with 6463, and we also could show an increase of long-term potentiation in neurodegenerative disease models. Next slide. Overall, we developed a very attractive nonclinical profile, which we concluded needs to and warrants clinical development. We do see, as described, a pharmacological activity across distinct important domains for neurodegeneration. We do believe that the preclinical results were nicely designed to get directly translated in relevant clinical settings. We do find a very significant CNS exposure and target engagement demonstrated in multiple species. We do see no evidence of CYP enzyme inhibition and also the compound is no P-gp substrate. Finally, we have a nonclinical toxicology profile, which is consistent with other sGC stimulators in development or which have been approved. I think all those criteria made it very clear that we have all the reasons to advance this compound to clinical development. About this clinical development, you'll hear now from Chris Winrow, our project leader for the compound IW-6463. Chris?

Great. Thank you, Andy. Certainly, this is an exciting time for IW-6463. And as you can see, we're really at an important aspect of the program development. We are taking a rational approach for indication selection, and we've completed -- conducted 2 Phase I studies that I'll be going into more detail. The data from these Phase I studies really has served to inform and will serve to inform our clinical development. We completed a Phase I study. This is our first-in-human study and had a successful study where we identified well-tolerated doses and achieved our targeted CNS exposure. We have more recently conducted an elderly translational pharmacology study. This study has been focused on CNS target engagement and will read out later this summer. And we're really taking an opportunity here, as you heard from Andy, to look at which aspects of what we've observed in the nonclinical space is exciting effects on key hallmarks of neurodegenerative disease, which of these we'll be able to look at clinically and find true translation. So the next slide. This slide lays out our early development strategy. As you can see, it is a biomarker-focused strategy and really enables us to move and gain a lot of insights from each of our studies to inform upon the next stage. In terms of our first study, the Phase I first-in-human study, really, the key goal there is to confirm safety and exposure of the molecule. We conducted this study and incorporated in addition to plasma pharmacokinetics, a single cerebral spinal fluid set of samplings from the subjects. This enabled us to look at exposure of IW-6463 in the CNS for the first time. Again, this is a really exciting program. This is the first CNS-penetrant sGC stimulator to enter development, and we want to learn as much about the molecule as we can. This enabled us to look at a range of doses, which we then were able to select from and progress into our next study. That second study is a translational pharmacology study. This is conducted in elderly individuals. Just to note that in addition to it being important to determine safety and pharmacokinetics in this elderly group, we also have an opportunity here to take multiple cerebrospinal fluid samples and this would now, for the first time, enable us to look at target engagement within the CNS. So in that space, and I'll go into this in a little more detail, we're able now to look specifically at cyclic GMP levels. And you'll recall, from earlier in the presentation, this is directly produced from activating soluble guanylate cyclase. So an important aspect now to demonstrate CNS activity. Furthermore, this elderly study offered us a unique opportunity. During the normal aging process, nitric oxide bioavailability and nitric oxide signaling is impacted. And this translates into effects on endothelial cell function and has multiple effects on different physiologies, including things like blood flow. So we have an opportunity to build in some additional measures to look at what aspects of our nonclinical hallmarks may translate into the clinic. And I'll be going into that in a little more detail. We're expecting top line data from this study later this summer. And so we're in a really exciting time now and eager to understand more about these studies. We'll then be progressing further into our parallel Phase II studies, and you'll be hearing more about those exciting studies in patients in the subsequent section. On the next slide. So our Phase I studies were conducted at The Centre for Human Drug Research in the Netherlands. This is a premier clinical research site, focused primarily on neuroscience investigations. And really, we were able to conduct some innovative studies even in the Phase I space. Our first-in-human study combined 3 stages, a single ascending dose, a multiple ascending dose and a food interaction study. This enabled us to move quickly through development and at the same time, obtain a wealth of data from these studies. We examined 110 healthy volunteers, the age range was between 18 and 63. We did standard comprehensive safety assessments at the site. And in addition to looking at blood sampling, as I mentioned earlier, we conducted CSF sampling, which enabled us to look not only at exposure in the plasma but exposure of IW-6463 within the central nervous system. And we use amid a wide set of dose ranges. This trial was successful. We identified safe and well-tolerated dose levels with steady state CNS exposure. And these were within the target range that we had identified based on the pharmacology that you heard about earlier across multiple preclinical models. We observed linear and predictable pharmacokinetics, and this is consistent with once daily dosing, a very important aspect of this molecule. We've found clear CNS exposure, good levels of exposure within the CNS. We also observed evidence of target engagement in the form of mild decreases in blood pressure. This is something that is aligned with the sGC mechanism and is observed with other sGC stimulators. Importantly, IW-6463 was well tolerated at all dose levels. We saw no safety signals, no serious adverse events. Any adverse events that were observed were mild, and this enabled us to progress further into development. Also importantly, we observed that IW-6463 could be taken without respect to food. So this, of course, is important in the patient populations that we're interested in helping both in terms of compliance and convenience for dosing. The next slide. We've also conducted a transitional pharmacology study in elderly volunteers. This was also conducted at The Center for Human Drug Research in the Netherlands. We have conducted this study with 24 elderly subjects enrolled. 24 subjects completed the first parallel phase of the study, and 12 subjects completed the full crossover study, and this was due to regulations that were imposed as a result of COVID in the Netherlands. But importantly, the design of our study and our analysis of the design give us confidence that our data analysis will not be impacted. The key attributes here. Again, this is the first time we're looking at an sGC stimulator that's CNS penetrant, are assessing safety, and it's key that we assess the safety in the elderly and also the pharmacokinetics, both in the plasma and the CSF. As I mentioned earlier, we incorporated a number of cerebrospinal fluid sampling events within this study. And this really now, for the first time, enables us to look directly at cyclic GMP levels within the central nervous system to confirm target engagement. The top line data is expected, as mentioned, later in the summer. And I also want to highlight that this is really a unique opportunity. As we age, we do see changes in nitric oxide signaling, as I mentioned earlier, and this can manifest across a range of physiologies. For our purpose, we want to understand how well the exciting observations we saw in the nonclinical space are translatable into people. And to do that, we've incorporated a number of different measures that we'll be examining in the study. To look at improvements in cerebral blood flow, we've incorporated arterial spin labeling examined by MRI. We'll also be looking at bioenergetics. And in that case, using the noninvasive magnetic resonance spectroscopy to look at metabolites within the brain. We'd also be examining neuroinflammatory markers. We have CSF samples, as I mentioned, and we'll be able to look at different cytokines and other molecules that are associated with neuroinflammation. And finally, we're looking at neuronal function. We've incorporated quantitative electroencephalography. This is a means to measure cortical brain activity, and we'll be able to compare that to our nonclinical observations as well. And CHDR has developed a battery of cognition and behavioral assessments that we've incorporated into the study in the form of the NeuroCart. So we're really excited about this study. We have a lot of data that has the potential to read out later this summer, and we'll be excited to keep you updated as we analyze those. Next slide. So finally, I just wanted to use this slide to highlight the approach that we've been taking. With the first CNS-penetrant sGC stimulator in development, we understand that we want to take as many opportunities to understand as much as we can about the molecule. From the nonclinical side, we've seen really exciting opportunities impacting the hallmarks of neurodegenerative diseases. And across these 4 hallmarks, we've really worked to validate and incorporate measures within our translational studies to see what these effects might be within the clinical population. We're expecting data later this summer. And we really will be taking the opportunity, not only to look at this biomarker data, but all the data to refine our clinical strategy. And that comes in the form of opportunities for different indications, patient selection, looking enrichment for different biomarkers, endpoint selection, how we can design a trial differently and also helps us in having productive discussions with regulators. We have taken the opportunity to begin development of smaller, shorter studies in focused patient populations, and that's the subject of the upcoming section that you'll be hearing about. So at this point, I would like to thank you for your attention and turn it over to our Chief Medical Officer, Chris Wright.

Great. Well, thank you, Chris. So on this next section, we're going to outline our development approach to our 2 initial clinical indications selected for 6463. These are mitochondrial disease, MELAS, and Alzheimer's disease with vascular features or vascular pathology. We've identified some strong scientific rationale for these indications, there's high unmet needs, and we've also developed some really efficient trial designs as our initial investigations into these areas. This provides us with the opportunity to understand our mechanism and whether it's having an important impact on these key features of the underlying disease pathophysiology. We believe this will mitigate the risk around development in these areas. And it provides us with direction for our later-stage studies using biomarkers and clinical endpoint approaches. So the first disease area we'd like to cover is MELAS, and we're really excited to have Marni -- Dr. Marni Falk here with us today to cover the clinical aspects of MELAS and the unmet need and patient selection there. Dr. Falk is a Professor of Human Genetics of The Children's Hospital in Philadelphia and Director of the Mitochondrial Medicine Frontier Program. I think we're switching over. And if you could try to go -- to unmute yourself, Dr. Falk, that would be great.

Yes. Can you hear me?

That's perfect. Thank you.

Okay, terrific. Well, I'm really excited to be here with everybody this morning. I'm sorry that I'm on audio-only, but hopefully you can hear me okay. As Mr. Wright mentioned, I'm the Director of the Mitochondrial Medicine Program at Children's Hospital of Philadelphia and University of Pennsylvania. And we take care of people with inherited disorders of mitochondrial function. And one of the most severe is mitochondrial encephalopathy with lactic acidosis and stroke-like episodes. It was one of the first mitochondrial diseases ever discovered more than 3 decades ago, and it goes by the acronym of MELAS. Genetically defined, it's mainly caused by mutations in the DNA within the mitochondria that impair the ability of the mitochondria to make energy. And unfortunately, it causes very serious brain problem, central nervous system, but also multisystemic diseases. There are no approved therapies, although we're starting to gain insight into the pathophysiology, which again is why we'll share with you we're really excited to see what IW-6463 really can do. As you can see in the schematic of a person, there's really no organ that couldn't be affected. And while lots of people, it turns out carries this mutation, not everybody gets all of these symptoms. So it's very heterogeneous. And there's both different genetic mutations that cause it and symptoms that can occur. But the most devastating that causes death and severe dysfunction are the neurologic features. And it involves the central nervous system, the autonomic nervous system and the peripheral nervous system. One of the biggest problems and probably why it got diagnosed is -- as one of the first syndromes ever is that it causes stroke. And as you can see on the upper left image, it causes stroke in high energy demand areas, these aren't blood clot strokes that follow a vascular distribution or embolic stroke, these are metabolic strokes. These are high energy demand areas that are really quite thick. We know that it has to do a little bit with the vascular endothelial reactivity and also just a mismatch of blood flow to demand. Often, these happen under stress. And what you can see in the right is what was mentioned before, an example really of metabolism in the -- within brain. It's called magnetic resonance spectrography. And if you put your voxel/PROBE over the area of the brain of interest, you can start to see the chemicals in that region. And where it says lactate, there shouldn't be anything there, nothing really detectable. And so there's too much lactic acid because the cell can't make or the brain can't make energy or ATP properly through the mitochondria, so it has to do it anaerobically, and that leads to lactic acid buildup. So these are really very troubling disorders. There are no approved therapies. We've started to learn over the last decade around the world that we can give some medications that improve nitric oxide flux, simple things like arginine with citrulline, and these can help both to prevent the stroke and also stop the strokes when they're happening. So it's super-promising, but we don't know that we have the most potent therapies yet to target this pathophysiology. Next slide. So now you understand that mitochondrial diseases are pretty heterogeneous. They're a rare disease that collectively there's a most common inborn error of metabolism affecting at least 1 in every 4,300 people, which in the U.S. translates to a rough estimate of about 65,000 people. There's lots of different presentations. We discussed MELAS. There's just some other very common presentations: Kearns-Sayre syndrome; Leigh syndrome, which is primarily pediatric; depletion syndromes where you don't have enough mitochondria; and really just a severe range of multisystem disease. But us and others have looked into what percentage of the time you get neurologic manifestations. And unfortunately, it's really high. So once you manifest with these syndromes, one of the most devastating problems is neurologic disease. And so we estimate while MELAS is a very confined set of very cleanly delineated genetic causes that present with the strokes as well as dementia and seizures and blindness and hearing loss and other problems, all told, all mitochondrial disease patients are at very high risk for neurologic problems. Really, under stress is when they come out the most and they're most at risk for stroke. And so one of the things that we do know is that a lot of the time, not always, but in many, especially with the neurologic problems, there's a nice biomarker of mitochondrial disease that we can follow and that is lactic acid. So while it's not perfect for any -- every type of mitochondrial disease, it is quite good in people with the neurologic manifestations. So we're really excited about this study that's going to really target what patients prioritize as their most important problem that they'd like to have treated, which are the neurologic problems and for which we really don't have great therapy. And we're also excited about the design of this trial because it's going to focus, and what the FDA advises, should be a really targeted genetically similar subset of patients with clinical symptomatology. And if you can show there in a small disease population a therapeutic benefit, later you could extend that to the more heterogeneous causes that might be overly complex to solve in 1 full basket study. So we believe that this is really an exciting opportunity to bring a therapy that's targeting known pathophysiology in a more potent way in patients who can really benefit directly potentially from the approach. The next slide. So IW-6463 will potentially impact the pathophysiology of MELAS at multiple points. And what -- as I mentioned before, the mutations in mitochondrial DNA, often in tRNA, genes involved in mitochondrial translation have a common effect. They don't make energy properly or ATP as the end result. And we know now that there's reductions in critical amino acids involved in nitric oxide production, and that's why some of the therapies that we use because we have nothing else available are tried. And so we do use arginine off-label to treat the strokes. And you can see that, that would work by repeating citrulline and arginine that becomes efficient. But IW-6463 can also directly impact the pathophysiology at several points, so we hope that it will be even more potent and safe. And so I'm excited to pass along Chris to you who will explain the specific clinical trial plans that we hope will get underway very soon to test the efficacy of this drug in this disease.

Thank you very much, Marni. Could you go back to the prior slide, please? Great. So I just wanted to take you through in a little bit more detail about what we think the therapeutic potential of 6463 is on the impacts of mitochondrial disease on mitochondrial energy production. So as Marni mentioned, in the context of the energy defect, you have decreasing levels of citrulline and arginine and those can be supplemented. But in addition, MELAS leads to a number of other pathophysiologic elements. So there's a further decrease in NO synthesis and worsening NO deficiency because of vascular dysfunction. There is also a compensatory mitochondrial proliferation, which also impacts the vasculature. And both these factors, which impact the vasculature, can cause decreased blood flow and additional oxidative stress. And as we -- as you may know, oxidative stress leads to decreased production of NO, which leads to further NO depletion. And so while citrulline and arginine can help ameliorate part of the disease defect, as you can see here, based on what we've learned about 6463, we really feel that it could have a broad impact across multiple aspects of the pathophysiology, as you can see outlined here in the yellow boxes. So really excited about the breadth of this mechanism in this population. And we're excited that we may have some meaningful relief for patients that are suffering from not only the CNS symptoms, but also potentially the systemic symptoms. Next slide, please. So there's really strong supportive scientific rationale for using a centrally penetrant-sGC stimulator to target MELAS and other mitochondrial disorders with CNS features. So there's clinical precedence, as we discussed, for NO precursors, such as arginine, which are used in practice acutely as well as chronically, primarily targeting the stroke symptoms. However, the effect of NO donors or the precursors is expected to be narrower than 6463, as I described earlier, and the utility beyond stroke for other symptoms may be limited. So from the pathophysiology of MELAS, what we really like in terms of the match is that it features the CNS metabolic dysfunction as well as the CNS vascular pathology. And really both of these areas are areas that we know this sGC mechanism can have an impact. So -- and in addition, we have a very detailed preclinical pharmacology move -- support from 6463, some of which Andy outlined for you earlier. But we've seen that the 6463 can increase and normalize ATP production in human mitochondrial disease cell lines. We also have data showing that it increases the expression of genes that are beneficial to mitochondrial function. And of course, as he showed you, it increases blood flow to the CNS and vascular health as well. The next slide, please. So on the basis of all this information, we designed an open-label study to evaluate once-daily 6463 for up to 29 days in up to 20 patients with MELAS, using an objective CNS biomarker approach in a well-defined population. We expect this study to start later in Q3. And as Marni mentioned earlier, it's really important that we identify a homogeneous population, as heterogeneity in mitochondrial diseases is known to be a challenge in this area and it's the reason that many programs did not meet their goal. So with the advice from experts such as Dr. Falk and others, we were -- we've carefully selected genetically and phenotypically defined MELAS population with CNS symptoms and that is also required to have elevated lactate levels, which is one of our key biomarker endpoints. And as was mentioned, lactate elevated, it's a required aspect of the MELAS diagnosis, it's part of the abbreviation, lactic acidosis, and so it's directly related to mitochondrial dysfunction, and also it's correlated with symptom severity and disease progression. So there's both a mechanistic and a clinical connection to that as a biomarker, making it quite attractive. So we're working with several centers of excellence, such as Children's Hospital of Philadelphia, MGH, Columbia Children's National, Johns Hopkins. And our planned study evaluates safety, tolerability and utilizes the biomarker approach to understand the impact that 6463 could have in these patients in need. And so changes in lactate levels from baseline sort of treatment effects would be a key assessment. They're closely related to the underlying pathophysiology of the disease. And so if we were to see changes there, that would give us very strong evidence that we're having an impact on the underlying cause of the disease. We'll also look at cerebral blood flow as this is dysregulated in MELAS, and it's one of the key disease domains. But we'd expect 6463, as an sGC stimulator, to have an impact. And then further, we'll assess neurofilament light chain and perform some cognitive and behavioral tests. It's a relatively short study to see changes in these measures, but it will provide us with some experience in this population. And if we did see some changes in neurofilament light chain or cognitive functioning, that will be very promising and exciting, too. So -- and if we saw this improved lactate, as I mentioned, with increased cerebral blood flow, that would indicate that we're having an important impact on the underlying mechanism of the disease and also could support us moving forward rapidly with biomarker registration approach, given this is an orphan population with no approved treatments. Next slide, please. So for the next section, I'd like to move on to discussing Alzheimer's disease with vascular pathology. And again, we're quite fortunate to have Dr. Eric Smith joining us today. Dr. Smith is a neurologist with a focus on the vascular contributions to dementia. He's a Professor of Neurology at the University of Calgary, and he's also the Katthy Taylor Chair in Vascular Dementia. So I'd like to pass the floor on to Eric. And if you could please unmute, that would be great.

Thank you, Chris. Yes, it's Eric here. Can you guys hear me okay?