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

Ladies and gentlemen, thank you for standing by, and welcome to the IW-6463 clinical program top line results update conference call. [Operator Instructions] I would now like to hand the conference to your speaker today, Bill Huyett, Chief Financial Officer. Please go ahead, sir.

Thank you, Jorel. Good morning. Thank you for joining us today. You will have seen our 2 press releases that crossed the wire earlier today. This morning, we'll be discussing the exciting top line findings from Cyclerion's translational pharmacology study, IW-6463, for treating CNS disorders. From Cyclerion, Peter Hecht, our CEO; Chris Wright, our Chief Medical Officer; and Cheryl Gault, our Strategy and Business development Leader, will cover further remarks. Dr. Andrew Budson, an independent expert in cognitive and behavioral neurology, will also participate in the call. We'll be reviewing slides that are available from the Investor and Media section of our website during these remarks and encourage you to follow those slides alongside today's discussion. Before we start, I'd like to remind our listeners that remarks made during this call may state management's intentions, beliefs, expectations or projections for the future. They are forward-looking statements that involve risks and uncertainties. They are made pursuant to the safe harbor provisions of the federal securities laws. These forward-looking statements are based on Cyclerion's current expectations, and actual results could differ materially. As a result, you should not place undue reliance on any forward-looking statements. Some of the factors that could cause actual results to differ materially from those contemplated by such forward-looking statements are discussed in the periodic reports that Cyclerion files with the SEC. These documents are available on our website and on the SEC website. We encourage you to review them. With that, I will turn the call over to Peter Hecht, our CEO. Peter?

Thank you, Bill, and thanks to all of you for joining us on the investor call this morning to talk about the 6463 top line translational pharmacology data. As Bill mentioned, we issued 2 press releases this morning to announce the top line data for both the Phase II sickle cell study and the 6463 study in healthy elderly subjects. Before we get to the 6463 study, let me express my gratitude on behalf of our whole team, to the patients, caregivers, clinical trial partners and investors who work with us so that we could evaluate both of these treatments. I'd like to acknowledge the people on both of the teams, both in our shop and our collaborators, who have worked tirelessly and passionately under very trying conditions, with COVID and all, to deliver such high-quality data. We all know that discovering and developing novel medicines for high-need patient populations is not for the faint of heart. And we're very fortunate that our teams delivered unambiguous high-quality information. We should be clear we're very disappointed not to be advancing our much-needed treatment option for patients with sickle cell disease. We've built many trusted relationships with the sickle cell disease community over the last few years, and we'd really hoped to be part of the solution for their devastating disease. However, while olinciguat was generally well tolerated in the STRONG study, it didn't demonstrate adequate efficacy on key endpoints of potential differentiation that would further warrant internal clinical development by Cyclerion. And meanwhile, as I think you're going to hear from us, we're highly encouraged by everything we've seen from our 6463 development program overall and especially by the data that we're going to be discussing with you this morning from this translational pharmacology study in healthy elderly subjects. If you'll turn to Slide 4, and the slides are available on our website, you can watch along with us directly. On Slide 4, you'll see that we were able to confirm and extend data that we'd seen in our earlier single and multiple ascending dose study showing quite favorable in safety and tolerability data that we were able to cross the blood-brain barrier at desired levels to have good exposure in the brain. We have clear evidence of target pathway engagement both in the periphery and in the CNS. And most exciting, and we'll take you through this in some detail this morning, we observed significant impacts on several neurophysiological and objective performance measures that are associated with age-related cognitive decline and neurodegenerative diseases. And to see such clear biomarkers of activity in this small and short study with a single dose was highly encouraging to us. To provide some context on these novel findings, as Bill mentioned, we have the good fortune to have Dr. Budson. If you'll turn to Slide 5, you'll see his bio. I won't read it, but he has a great deal of depth and experience in this field, both in the clinic, in treating Alzheimer's patients and clinical development and in developing drugs for dementia and cognitive decline, and as well in the areas of electrophysiology and some of the clinical measures that we're going to be discussing with you this morning. So he'll be an active participant during the question-and-answer session. If you'll turn to Slide 5, just briefly -- sorry, Slide 6, just to orient you on the call, I'm going to turn the call over to our Chief Medical Officer, Chris Wright, to take you through the data. And then we'll have brief remarks from Cheryl Gault, our Head of Strategy and Corporate Development, on our focus. And then we'll open it up for what I hope will be a vigorous question-and-answer session. With that, let me turn it over to Chris. And Chris, you may be on mute.

Yes. Thank you, Peter. Just -- I'd like to start off by saying, as a clinical neurologist and neuroscientist, I'm particularly excited to share our new 6463 data with you today. Patients continue to be desperately in need of new and meaningful therapies across the spectrum of severe neurodegenerative diseases. We're hopeful that 6463 might be able to make a difference for these patients given the CNS activity we'll discuss today. If you can go to Slide 7, as we've shared in the past, including at our investor webinar, we're following a biomarker data-driven clinical development approach for 6463. We believe that for CNS compounds, this is an efficient risk-reducing process. We met our first goal, which was to demonstrate safety and tolerability as well as CNS exposure to ensure 6463 was actually crossing the blood-brain barrier. We achieved this in our first-in-human study, which enrolled 110 patients and read out at the end of last year. We next aspired to demonstrate that 6463 had CNS activity in a translational pharmacology study that we will cover in more depth today. Having met the next-level criteria of impacting CNS activity, as I will review with you shortly, we're now poised to take 6463 into key CNS disease trials. We'll use a biomarker-driven approach to efficiently understand the potential of our mechanism in severe neurodegenerative diseases. We'll also look for future opportunities where relevant, to use a biomarker approach for accelerated regulatory approvals. Slide 7, let's see -- slide 8. So with regards to our translational pharmacology study, I'd like to first review with you our overall findings with 24 healthy elderly subjects treated over a 2-week dosing period. A robust and rapid effect on CNS activity was observed, which we believe speaks to the potential of this mechanism in CNS diseases. In this study, 6463 was safe and well tolerated with no discontinuations in this elderly population. We demonstrated that 6463 crossed the blood-brain barrier and achieved target exposure levels based on our preclinical work. We confirmed mechanism engagement via blood pressure and cGMP, CSF monitoring. We did not see effects on CBF or metabolism, but we did see clear positive signals on brain neurophysiology and quantitative performance measures that were strong, consistent and rapid in onset. We're especially encouraged by the mutually supportive nature of the findings. On this basis, we continue to advance our planned CNS development programs in MELAS, and we are refining our plans for ADv based on the recent results to ensure an optimal study. Slide 9. The translational pharmacology study enrolled 24 elderly patients, 65 to 79. This was a crossover study in which subjects were randomized to 6463 or placebo in the first period and treated for 15 days. There was then a washout period, and subjects received in the second period whatever treatment assignment they had not received in the first period. Because of COVID, half of the subjects, 12, completed the second crossover period. As mentioned, we were assessing several defined objectives, including safety, blood-brain barrier penetration, mechanistic target engagement and cerebral blood flow as well as several exploratory objectives assessing their inflammation, bioenergetics, neuronal function via EEG and cognitive and behavioral testing. You can go to Slide 10. We found robust effects on the 15-day time frame in measures of neuronal function, including ERP, EEG and eye movement reaction time testing. In particular, we saw significant increases in alpha frequency on the EEG; improvements in N200 latencies on the ERP; and a faster saccadic reaction time, all cohesively indicating a positive effect on CNS neurophysiology and performance. We did not see effects on cerebral blood flow. We expect that we might see this based on the mechanism. These subjects also had lower blood flow as is typical with aging. There may not have been sufficient NO deficiency or pathology to be able to overcome the natural cerebral blood flow autoregulation in this healthy population. We also did not see changes in CNS metabolism. We look forward to assessing this further in MELAS, which is a serious disease with mitochondrial metabolism and bioenergetic defects. We have several CNS biomarkers of inflammation tending and look forward to seeing if we have an impact on modulating these. I'd now like to return to our key results that indicate improvements in the neuronal functioning with 6463 on the next slide, Slide 11. Sorry, Slide 12. No, sorry. If I go back to -- it's Slide 11. So we identified 3 complementary areas of CNS biomarker improvement. I'll cover these 3 areas in more detail. One, EEG alpha power improvements; two, positive effects on the ERP N200; and three, enhancements in saccadic eye movement as a measure of performance benefit. On Slide 12 -- now on Slide 13, you'll see that we performed quantitative EEG recordings and look to assess EEG spectral power. That included analyzing several distinct frequency bands. We were particularly interested in alpha and gamma frequency, which are associated with attention and cognitive processing. These rhythms are improved by some approved drugs that are cognitive enhancers. Alpha, in particular, as you can see on Slide 12, is associated with aging and neurodegenerative diseases with cognitive impairment. In the coming slides, I will focus on our alpha finding. We also had supportive trends in gamma. Slide 13. We demonstrated a significant improvement in alpha EEG power at day 15 versus baseline in treated subjects with 6463 versus placebo. What you see are spectral power maps that depict the percent change in alpha power. We're kind of looking down on the head, and you can see the nose at the top and the ears on the side. The blue color represents decreased alpha power, while the red color represents an increase. As you can see on the left, there was little change from baseline in the placebo group. In contrast, in the middle map, you can see a significant increase in alpha power in the 6463 group. On the right, you can see the difference between these 2 maps. That's the 6463 versus placebo treatment effect, which shows significantly increased spectral power for 6463 treatment versus placebo. It's really remarkable that given such a short treatment duration and a small number of subjects, we're seeing such powerful effects. Slide 14. So this effect was robust and consistent within the experiment. We collected 2 EEGs on day 1 pre-dose. You can see those in the left-hand panel on Slide 14. We also -- and as you can see in that panel, there were minimal changes in baseline EEG, but clear and reproducible effects if you look on the right-hand side for all 4 post-dose sessions for 6463 relative to placebo and relative to baseline. Those are the upper 2 rows in the day 15 measures box, where you can see strong effects on power. What's very nice about these results is that we see similar effects across all 4 sessions, indicating that there's a stability for the effect. And similarly, we saw a lack of consistent effect in the placebo subjects as can be seen in the last row on the right. So for those first 4 -- those 4 measurements that we obtained on day 15 that were the last day of treatment, there's very consistent effects for each of those measures in the context of looking at 6463 versus placebo or a change from -- or a 6463 change from baseline, the top 2 rows. And in the bottom row, you can see that all of those measurements, the 4 really show no effects consistent with that being the placebo arm. It's known that alpha power declines with aging and the neurodegenerative diseases with cognitive impairment. There's also a substantial literature related to alpha power -- relating alpha power to a cognitive decline and risk factors for Alzheimer's disease, such as the APOE-4 genotype. And also, if alpha power has been linked to lower -- lower alpha power has been linked to increased CSF levels of the abnormal proteins that are seen in Alzheimer's disease. What's also interesting about this finding and which suggests its robustness is that we know that 6463 has a long half-life, and so we see a nice effect on the -- on day 15 even before we give a dose because the exposures are still in a good range, and then also on the next 3 measurements, after which subjects have received a dose. So that's very consistent with a long half-life and the favorable peak to trough of 6463. Lastly, interestingly, when we compare our data to a normative alpha database, it looks like that 6463 is reversing the alpha power aging effect by about 2 years in only about 2 weeks of treatment. So very interesting and exciting findings. Slide 15. In this slide, you can see the magnitude of the effects across the group and the consistency of the individual subject responses. The bar graph on the left shows that the alpha power treatment effect is approximately 17% increased with a p-value of 0.02, rounded up. This is a substantial effect for any CNS biomarker. In the individual subject change from baseline plot on the right, you can see that the majority of participants, 13 of the 18, have a positive effect, whereas only about 5 of the 18 in placebo have such an effect. It's clear from this data that there was a consistent effect across subjects and that it was not driven by outlier findings. Slide 16. I'd now like to turn to our ERP effects. ERP waveforms are affected in aging and neurodegenerative diseases with cognitive impairment. To record these ERPs, participants wear our EEG cap and headphones and are presented with repeated auditory tones. Some tones are deviant or different, and the subject is instructed to press a button when they hear that different or deviant tone. The key waveforms are N200, which is an initial negative deflection, which you can see in the bottom left figure. It's in the N200 box going down. And there's a later wave form, which is the P300, which is associated with cognitive processing capacity. And that's following the N200 there in the adjacent box. N200 is associated with stimulus identification and distinction, and both measures may be impacted by aging and the neurodegenerative process. And they also may improve using treatment with cognitive enhancers. We didn't find improvements in the P300 in our study, so I will focus on our N200 results. We assessed the latency and amplitude of N200 and the response to 6463 after 15 days of treatment. We found significant effects on the N200 latency with positive trends on amplitude, and I will dive into these interesting latency effects in the next slide. Slide 17. In the left panel, which shows the effects of 15 days of 6463 on N200 latency, you can see improved latency relative to the untreated state. Latency is reduced, so it's faster. In addition, on the right-hand panel, we observed a very strong interaction effect between 6463 and aging on the N200, such that older subjects had quite a bit bigger latency improvement than the younger ones in this older age range. And interestingly, as you can see also in the right-hand panel, in the older subject, there's quite a narrowing in the variability, which, to us, is very supportive of a drug effect impact. Slide 18. We examine the effects of age in more detail. Looking at the size of the effects of 6463 treated subjects and how that related to their age. So you can see the latency value here is on the y-axis in milliseconds. And then on the x-axis is the age of our individual subjects. Consistent with the earlier data I presented you, you can see that the effects of 6463 increased with age. That's kind of going from right to -- sorry, left to right on the graph. And in fact, at the older ages, the latency improvements reflect up to a 10-year reversal in the N200 age latency effect, again, over just a 2-week period of treatment. If we go on to the next slide, 19, finally, we observed improvements in an objective functional measure of motor activity using an eye movement task. Saccades are short, fast eye movements when you move your gaze directly from one position to another. A number of brain areas are involved in this activity as well as the nerves going to the eyes and the muscles. Saccadic movements measure -- saccadic movement measures are thought to reflect attention and arousal and are impacted by interventions such as sedatives or cognitive enhancers. Saccadic performance measures are also impacted by aging and neurodegenerative diseases. In this study, we examined the reaction times and velocity of saccadic eye movements in an alternating visual fixation task. We looked at latency, which is the timing to begin the movement; and peak velocity, which are the key parameters for the saccadic eye movements. Slide 20. We observed shorter or faster saccadic reaction times for those treated with 6463 compared to placebo, as you can see in the left-hand graph. Similarly on the right, we saw a trend increase in saccadic velocities. These results indicate that 6463 has the potential not only to substantially improve CNS neurophysiology, as I showed you with our EEG findings and ERP findings, but it also has the potential to have positive impacts on CNS functional performance. Slide 21. So before I pass the floor back to Cheryl, our Head of Strategy; and Peter, our CEO, to conclude, I wanted to say how excited we are to move our clinical trials in serious CNS diseases forward. With the data we have showing 6463 shows robust CNS activity over a short time frame of 2 weeks, along with confirming the safety profile and the blood-brain barrier penetration, we're very enthusiastic about advancing our MELAS clinical trial, which we expect to begin later this year. In addition, we look forward to initiating our ADv study in 2021 and to refining the design of that study based on our current results and ongoing analyses, including the biomarkers. We have a really great opportunity here to use these rapid and robust findings to design faster and more efficient studies to assess the potential of 6463 in these very high unmet need areas of neurology. Thank you for your attention. And with that, I'd like to pass the mic on to Cheryl.

Great. Thank you, Chris. So before we wrap up, let's turn to Slide 22, and I want to spend just a few minutes talking about how these results relate to our overall corporate strategy. With these data from the translational pharmacology study, we now have evidence that IW-6463 is a biologically active molecule, that it crosses the blood-brain barrier at the desired concentration, that it engages the target and that it impacts relevant biomarkers known to be important in CNS diseases. These data indicate that IW-6463 is a very promising molecule that warrants further development. We look forward to advancing it from healthy volunteers into patients, where we believe it has the potential to provide meaningful clinical benefit to patients suffering from serious CNS diseases, particularly in the area of cognition. And for a drug that has the potential to impact cognition, the opportunity in front of us to positively impact patients is both broad and exciting. As a result of these data and our enthusiasm for pursuing indications in the CNS, we are concentrating our future efforts on CNS exclusively. We have a really talented team of CNS experts across our organization, including in research, in translational science and in clinical development. And we are eager to continue on this journey to make important new medicines in the CNS. Over time, we will, of course, take a long-term view, and that will include exploring adjacent indications in the CNS as well as building and advancing a portfolio of CNS assets. But in the near term, we are very focused on advancing IW-6463 specifically and intend to focus on a few key areas. One, deepening our understanding of the biology and pharmacology as this is a novel scientific area, and we have lots to learn; two, moving beyond healthy volunteers to gain clinical data in patients, which will come from our 2 planned Phase II studies in MELAS and ADv; and three, exploring a strategic partnership that will allow us to fully prosecute the opportunity. As we move forward as a CNS-focused company, this means that we will allocate our capital to CNS development as we fund a risk-reduced development approach for IW-6463 and also that we will shape our organization size and capabilities to best support that CNS focus. CNS is an exciting therapeutic area as the unmet needs are immense, and we look forward to advancing to patients and hopefully creating important new medicines. So with that, we can turn to Slide 23. And I will say thank you very much for joining the discussion today. And I'll now turn it over to Peter to lead the question-and-answer session. Peter?

Thank you, Cheryl, and thanks, Chris. And Jorel, if you can open the lines up, we have several members of management, the 3 of us who have spoken, and the rest of our leadership team. And we also, as I mentioned in the opening, have Dr. Andrew Budson for his independent expert input as well. So Jorel, do we have questions on the line?

[Operator Instructions] Our first question comes from Charles Duncan with Cantor Fitzgerald.

Peter and team, thanks for sharing these observations, and thanks for taking our questions. I had a few -- yes, so I had a few. I'll just start with the first one. In terms of the strong SCD study, can I assume that you saw, in addition to a lack of efficacy or sufficient efficacy, were there any surprising observations due to on- or off-target effects that may make you wonder about the safety or tolerability of modulating this pharmacology?

Chris, do you want to take a crack at that one?

Sure, sure. So overall, the safety profile and the tolerability were as we would expect for this mechanism. We didn't see anything different than our earlier studies. It was really quite well tolerated with only 2 subjects discontinuing across the entire study due to an AE. And one of them actually discontinued before starting their first dose study drug. So overall, we were quite pleased with the safety and the tolerability profile.

Okay, okay. That's helpful. And then moving on to more germane questions with regard to today's call. On the MELAS study, can you help us understand some of the observations that you've made with regard to quantitative neurophysiological measures and how that relates to MELAS, perhaps getting some insights from Dr. Budson? I'd also like to know your thoughts to management on the dosing and duration for the planned MELAS study.

Great. Chris, maybe you can start and cover the technical issues and then turn it over to Dr. Budson?

Sure. So I think what we see in the study and we find quite encouraging in the sense that we see effects that are quite rapid over a short time frame. And also, they're in measures that are closely linked to the cognitive function. And one of the areas that's importantly impacted in MELAS patients that they really suffer from the most is exactly around cognition and cognitive fatigue. So I'll let Dr. Budson comment a little bit on the clinical manifestations and his focus is primarily on Alzheimer's disease. But I have had the chance to speak with some KOLs that are working with us on our MELAS study, and they were quite encouraged and excited about taking a closer look at cognition in MELAS, in addition to the other measures that we were looking at based on these results. Andrew, I don't know if you have any additional comments on this.

I don't actually have comments on MELAS. That's not my area of focus.

Okay. Maybe I can expand the question to one that asks Dr. Budson about the predictive value of some of the measures that we're seeing the changes in neurophysiology chain measures. And I'm wondering how that relates to cognition for neurodegenerative disorders.

Sure. So we have, in our lab, we have done a number of ERP studies that have used a similar paradigm. And we also find that the most sensitive and repeatable findings are in the N200. The variability in that waveform is relatively small, so it actually is a good one to be able to pick out effects. To be able to see statistically significant differences after a drug is used for -- with only 24 subjects is actually quite remarkable. As you probably know, most of the studies that are testing compounds for Alzheimer's disease, for example, use between hundreds to several thousand subjects to achieve statistical significance. And here, we're seeing it with 24 subjects. And I do think the N200 is where you would expect to see it. And we have seen differences, for example, in the N200, when we compared both individuals with mild Alzheimer's disease, dementia or mild cognitive impairment that are thought to be due to Alzheimer's disease pathology and also even in one study that we did where we looked at people in the Colombian South American kindred that were carrying the presenilin-1 mutation, which means they were all destined to develop Alzheimer's disease in the future, but we could see differences in their N200, even before they developed any cognitive symptoms and even before their neuropsychological test results showed any abnormalities. So I do think that the N200 differences that they see with a decrease in latency relative to placebo is a meaningful and an expected finding. In other words, if you expect to see anything with 24 subjects, it would be in this N200. The one other thing I'll just comment on that, when Chris first shared these data with me that I was particularly intrigued about is what's on Slide 18, in that the effects seem largest in those subjects who were oldest. And I do think that it sort of makes sense to me that if you have a treatment that is going to be working because people's brains are not functioning as well as we would like, that you would begin to see these effects to be greater as people are older, as people increase over the age of 70. Even if they have no symptoms and no detectable abnormalities and neuropsychological tests, they just statistically, epidemiologically, they are building up cerebrovascular disease. It's often very small cerebrovascular disease, but it is building up. And they may even be building up beta amyloid pathology. So I'm just very intrigued and excited by these data as a potential treatment for either cerebrovascular and/or Alzheimer's pathology.

That's very helpful, Dr. Budson, addresses my questions about predictive value. Last question for company is related to 6463 and the broader platform. This is a single clinical stage candidate. I'm wondering if you have backup and/or follow-on compounds, which have perhaps differentiated, call it, additional chemistry behind them and how broad the IP is around this -- modulating this pharmacology.

Thanks, Charles. Mark Currie, can you take that one? Mark, you may be on mute. We may be having a technical difficulty. Mark? Well, I can take a crack at it. We do have second-generation compounds coming, and they're different in their structure and different in their IP. And both 6463 and the next-generation compounds are wholly-owned compounds by Cyclerion with long IP that they have published. And in the case of 6463 issued patents on broadly covering both the composition, and we're generally very good on IP. So we have a quite good picket fence around the molecule and I'd say IP out, without patent term extension of a good 20 years.

Okay. That's helpful, Peter. So that could enable a divergent business model of -- focused on rare central nervous system diseases as well as more prevalent diseases in the future?

That's right. Exactly, exactly. You got it. Thanks, Charles. Do we have more questions?

Our next question comes from Justin Zelin with B. Riley Securities.

First, I'd like to offer my congrats on this very interesting and objective data set. It's great to see this encouraging data from such a short and small study held during a very difficult time for clinical trial execution. I'd like to ask a question to Dr. Budson on these promising biomarker data. What gives you confidence that these biomarkers could be affecting the underlying pathophysiology? And specifically, APOE was mentioned. If you could extend on the understanding of how these data could be translated from engaging that target or others.

Sure. So I believe the APOE, which, as I'm sure you know, is the major autosomal dominant genetic risk factor for Alzheimer's disease that in individuals with APOE-4 allele, you can actually see slowing on ERP measures, including the N200. And I think in terms of what makes me think this could be helpful for disease states like cerebrovascular disease and beta amyloid, of course, the "healthy" subjects who were tested in this study did not have their quantification of their white matter nor did they have beta amyloid measured by either PET scan or CSF. So I don't, of course, know for sure. But we do know that these types of ethologies tend to accumulate in the brain as people get older. It's, of course, not true in every single older subject, but the prevalence even of clinical disease, which represents the accumulation of a large amount of pathology approaches 50% by the time people are of age 85. And it's estimated that people are accumulating beta amyloid and/or cerebrovascular disease at least 15 to 20 years before they're showing clinical manifestations. So it's for those reasons that I'm just presuming, again, just from a statistical standpoint, that it's likely that the older these individuals are, the greater amounts of pathology they likely have. And if you want to flip it around, that's one of the reasons that the untreated group is showing increasing latencies. The fact that, again, we're seeing improvements in the older individuals, but not in the younger individuals, to me, resonates with all sorts of drugs that we use to treat CNS diseases. So for example, if you give L-dopa, Sinemet, to Parkinson's patients, it improves their symptoms. But if you give it to healthy individuals, it really doesn't do much of anything, except possibly cause side effects. If you give donepezil, Aricept, to an Alzheimer's patient, it improves their cognition. But if you give it to healthy elder without Alzheimer's or another dementia pathology, it doesn't do much of anything. So the fact that we're seeing improvement in the N200 latency for older individuals, but not younger individuals, again, it sort of fits with my understanding of how drugs work affecting pathophysiologic CNS disease processes.

That's very helpful. And if I could just ask one more follow-up question, probably directed to either Chris or Peter. So I understand you didn't see significant differences in cerebral blood flow. But I'm just curious, did you see any changes in perhaps blood pressure, which could be tied back to the underlying mechanism of action here?

Chris? Chris, you're on mute.

Great. Yes, I was just trying to get off mute. Yes. So in fact, we did -- and then I pressed the wrong button on my phone. So anyway, but we did, in fact, see small changes in blood pressure peripherally. And what's interesting is that those remained all within a normal range, but there were a few millimeter of mercury differences that we saw in treatment versus the placebo group. And we didn't have any discontinuations or other AEs relating to that. There were -- so it sort of gave us an indication that we're hitting the mechanism, the target mechanism, and without having any other consequences peripherally. And then we also did see cGMP decreases -- sorry, increases in cGMP in the CSF. So we monitored both blood pressure and CSF, the cGMP to understand if we had effects on target engagement.

And if you don't mind, could I just ask Dr. Budson? This change in blood pressure, would you, Dr. Budson, find that a drug that has this kind of an effect would be helpful for patients with vascular Alzheimer's diseases?

Are you asking me if it happens -- the drug happens to have a sort of a side effect of lowering blood pressure if that might be helpful in patients with vascular disease?

Yes. My question is for patients who have vascular disease, if a drug that could lower blood pressure would be helpful for their underlying disease state. And these patients typically are at risk for other vascular diseases as well, be it that they have smoking comorbidities and what have you.

Sure. The -- several studies, including the SPRINT MIND study, showed that decreasing blood pressure even somewhat lower than primary care doctors normally reduce it to, in other words, to 120 over 80 or lower does reduce the development of mild cognitive impairment. And, most likely, dementia, as you may know, that study was terminated early because the findings were so positive. But then, of course, they didn't have time to reach all of their endpoints. So yes, I do think that a drug that lowers blood pressure a little bit, but not to a clinically, sort of potentially dangerous level, could only be beneficial when you're trying to manage disease. With blood pressure, essentially, as long as all your end organs are functioning normally, lower tends to be better.

[Operator Instructions] Our next question comes from Marty Auster with Crédit Suisse.

Yes, happy to see the improvements in the neuronal function. And I was hoping we could discuss a little bit more kind of the proposed mechanism of action for 6463 was to improve cerebral blood flow and reduce neuro-inflammation and enhance the cellular bioenergetics. And I guess I was curious about a couple of things. One was when you thought you might have more information on some of the neuro-inflammatory markers you're looking at. And secondly, maybe if you could review how you selected the dose for the study and the dose going forward. And maybe if it wouldn't make sense to explore a higher dose range, if possible, given you didn't observe some of those benefits on blood flow and what sort of neurofunctional data looks like. And then I have a couple of follow-ups on the neuro function data as well.

Okay. Great. Let's start with those first 2 questions. I think those are both to you, Chris.

Great. So let's see. So I would say that maybe -- could you just remind me of the second question again?

Yes. The second one was about dose, Chris. And just kind of, because you didn't observe some of those findings, and we'll see what the inflammatory data looks like, but I was curious if you thought it made sense as to look at a higher dose cohort looking forward.

Got it. Okay. Got it. So first question, I think, was around the mechanism and kind of how do we think this is actually working. And what's -- maybe it would be great, if Mark was here, he would tell you a lot about this. But what's really interesting about this pathway and what was first described about it was actually -- at least one of the main things that was described early on in the brain was that it actually has an impact on brain physiology. And in particular, it's known to have the NO pathway, is well known to induce LTP and enhance LTP. And we have a number of preclinical experiments that show that 6463 can improve LTP and by working through sort of ion channels, modulating channels to have an effect on that. And it's also ion channels that really impact the EEG. We did see interesting EEG effects across the brain as well in our preclinical experiments, kind of in support of what we're seeing here today. So I think there is certainly focus on the vascular effects because that's a known effect of sGC. I think -- and we've spoken to a few other experts in the area, in addition to Dr. Budson. And I think there's a sense that the vascular reactivity changes in the elderly may not have been far along enough to see an impact a little bit towards what you mentioned about the more you have a disease, the more you can see an effect. And cerebral autoregulation may not have been overcome in the context of this particular study. And then to cover your metabolic question. So we did see clinical terms that we had a strong effect on, improving the ATP levels, bringing them back to normal in mitochondrial cell lines from humans with mitochondrial disease. And so in this context, we didn't -- we were exploring it, but we didn't necessarily expect changes in the MR spectroscopy metabolic findings. I think, in MELAS, you have a severe metabolic defect with increased lactate, which is not something that you see in normal healthy individuals. And that's kind of the target that we're assessing in that MELAS study. So we're quite interested to see how, in the context of truly disordered metabolism, how we have an effect from that perspective. So that's kind of to cover that first question. With regards to the dose, we did a pretty extensive first-in-human dose-ranging study. And we went to doses that were quite a bit higher than the doses that we gave in this study. And what we saw overall is that we reached a very nice level of CSF or blood-brain barrier penetration and the concentrations in the brain with this particular dose that is -- that gets all the patients above our highest threshold dose for activity in our preclinical experiments. So we believe this is the right dose moving forward and gives us the right level of blood pressure change and also has a strong effect in all of our preclinical experiments based on the exposure level. So at this stage, we believe this is the right dose going forward. We can -- we'll have to do some PK/PD analyses to understand more how exposure specifically relates to the effects that we're seeing. And maybe that will help us to understand if it would make sense to go higher or lower, but we feel pretty good about the dose we're at right now.

And do you think of the data on the kind of impact on cytokines and adhesion molecules and other inflammatory markers will be available?

We have -- we're planning on kind of putting all the information together, and I'm looking towards meetings in the next -- in the coming months in terms of abstracts or presentations and publications. So I think once we kind of get together, get the data in and have a chance to look at it, I can give you a bit more of a detailed timing of that.

Okay. And then just finally on the neuronal functional improvements that were observed. I was curious if the volunteers had depressed alpha power at baseline. And I was curious if you'd measured beta power as well. I know in cognitive disorders, that can be in decline as well. If you can help the elderly patients, I think, or volunteers, I think that would be normal. So I was curious about that. And then also curious on the cognitive behavioral functions. You showed a few measures. I think you were doing the entire NeuroCart battery. And I was curious if the other measures just were not -- no meaningful changes or if there's any more detail kind of around the entire battery.

Sure. So what we're talking about today is really our top line data and so -- and that we've analyzed kind of to the greatest extent. And so what I -- I guess what I can say is that the baseline alpha levels were typical for the age range. And so we're increasing above or improving above the typical kind of age range alpha. And then from the beta perspective, we didn't see any changes in beta. So it was kind of selective really to gamma and to alpha is what we saw in this particular study. And then let's see, your last question, what was that one again?

Sorry, I was just asking because you mentioned that you were evaluating the NeuroCart battery for any behavioral changes. So just, yes, of the other kind of check from there were just kind of no change what the overall....

Yes. We're looking into the cart in more detail, and we're taking all the behavioral measures and relating those to the responses to see if there are relationships there. In the basic analysis, we didn't see strong effects.

Okay. Got it. And sorry to be hogging up all the microphone time here, but if you could comment on kind of -- is there any kind of proposed hypothesis from your perspective on the alpha/gamma selectivity on the EEG?

That's a great question. I'm not -- I don't know. I mean, I could speculate in the sense that like there are some cyclic nucleotide responsive channels in the brain. And they actually are important for regulating cells that also impact specific EEG rhythm. So maybe there's like a cell-specific cyclic nucleotide-responsive ion channel that regulates one or another rhythm. It's speculation. It's a really interesting question. That's what's really interesting about this entire area, is that there's so much unknown, and we have a chance -- a greater chance to learn a huge amount about how things work. So...

So Chris, I'll just jump in. And the way that I think about it is how it would sort of fit together with some of the ERP finding, is it sort of facilitates subjects' ability to pay attention. And the alpha power increase is sort of -- you see it in sort of a wakefulness, but a mindfulness where people are sort of ready to attend to a stimulus and to do a response. So I sort of see it as a sign that people are ready to pay attention.

I'm not showing any further questions at this time. I would now like to turn the call back over to CEO, Peter Hecht, for closing remarks.

Okay. Thanks very much, and thanks, Dr. Budson for your time and to the questioners for their time and interest, and to all of you for participating this morning. If you look, just in closing, at Slide 23, just to remind you, what we had hoped to see from this translational pharmacology study, I think, we've seen and more. We were hoping to recapitulate what we had seen in our early studies in terms of safety and tolerability and target engagement and penetration in the blood-brain barrier. And we were looking for some measure of evidence that the drug was having activity in the brain. And I think we have some very interesting and intriguing biomarkers and some great hypotheses to follow up. And I think the question Marty asked about specificity in the different wavelengths in power is one of many questions that are now rattling around in our shop and those of our key collaborators. We have a lot of work to do to follow up on these initial findings. And importantly, we have a very focused development effort to deliver on. We have the MELAS study, which is initiated, and we're hoping to enroll our first patients very soon; and our ADv study to fine-tune with our collaborators and to initiate in 2021. And we'll be focusing our time and effort there and working very hard to build a CNS company together with you. So thank you for your time. We'll be available for follow-up questions throughout the day and going forward. You can reach out to Bill Huyett or Carlo Tanzi. Their contacts are on the press releases. Thank you so much. We appreciate it.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.