Milestone Pharmaceuticals Inc.

Good day, ladies and gentlemen, and welcome to the Milestone Pharmaceuticals Investor and Analyst Webcast. As a reminder, this call is being recorded. I would now like to turn the call over to Joseph Aliveto, President and CEO of Milestone Pharmaceuticals. Mr. Aliveto?

Thank you, Keith. Good morning, everyone, and thank you for joining us today to review our new, recently presented, and published results from Rivera, our Phase II study evaluating atripamil and in patients with atrial fibrillation with rapid ventricular rate. As a reminder, a slide webcast accompanying today's remarks is available on our website at milestonepharma.com. During today's call, we will be making forward-looking statements, so we'll direct you to our SEC filings for a full disclosure of our risk factors. For today's call, We are honored to be joined by two leading cardiac electrophysiologists and atrial fibrillation experts. And I'd like to welcome Dr. John Kam, British Heart Foundation Emeritus Professor of Clinical Cardiology, the Cardiology Clinic Academic Group, Molecular and Clinical Sciences Research Institute at St. George's University of London. And Dr. Sean Picorni, Director of Arrhythmia Core Laboratory, Duke Clinical Research Institute, and Assistant Professor of Medicine, Duke University School of Medicine. Thank you both for joining us for today's call. Joining me for prepared remarks from our milestone team is Dr. David Beruccia, our Chief Medical Officer. In addition, we will be joined for the Q&A portion of the call by Amit Hesija, our Chief Financial Officer, and Lorenz Muller, our Chief Commercial Officer. I'll now provide a brief overview of the agenda for today's call. Dr. Kam will provide an overview of the positive results from our Rivera Phase II study evaluating atripamil, our leading investigational candidate in patients with atrial fibrillation with rapid ventricular rate. These data were presented at the American Heart Association Scientific Sessions just this past weekend and were simultaneously published in the journal Circulation, Arrhythmia, and Electrophysiology. Following the review of the AHA presentation, my colleague, Dr. Beruccia, will lead a discussion with Drs. Cam and Picorni for their perspectives on the Rivera data, the current treatment landscape of AFib-RVR, and the potential use case of atripamil. We will close our prepared remarks with an overview of the proposed phase three registrational study for AFib-RVR, as well as the guidance we received from the FDA to inform that trial design. In conclusion, we will open the call up for questions. Before turning the call over to Dr. Kam, I'd like to just provide a brief overview of Milestone. At Milestone, we're committed to developing and commercializing innovative cardiovascular medicines. Our two main arrhythmias of focus are PSVT and AFib-RVR, both of which are common heart conditions with a high burden on patients and on the healthcare system. We are targeting these conditions with Atripamil, our investigational calcium channel blocker nasal spray. Atripamil has been designed and developed to be a fast-acting, well-tolerated, portable, and on-demand treatment option to give patients ability to self-manage their conditions. In October, just last month, we submitted a new drug application for Atripamil and PSVT. Our lead and we look forward to working with regulators as we advance towards a potential approval. Beyond PSVT, we believe AFib-RVR represents an opportunity to expand the market for atripamil with an estimated 10 million patients with AFib by 2025 and growing to 12 million by 2030. We estimate that 30% to 40% of patients with AFib experience one or more symptomatic episodes of RVR per year requiring treatment, and we believe a trip mill can serve as a valuable intervention in this patient population. With that, I'll now turn the call over to Dr. Camp for a review of the Rivera Phase II results as presented at the AHA Scientific Sessions. Dr. Camp?

Thank you, Mr. Oliveto, and good day, everybody. I'm very pleased to be talking to you about this presentation made at the AHA in a featured science session. It describes a phase two study known as Rivera 201. On this slide, you will see that Atripamil is a novel investigational L-type calcium channel blocker, which is rapid in onset. You can see that from the graphs on the right-hand side of the slide. It's given with a nasal spray, which you also see illustrated. It was developed initially in order to treat PSVT. But this study concerns patients with atrial fibrillation, another arrhythmia. The bottom right of this slide shows you that the pharmacodynamic effect, at least in this slide, on the PR interval is more long-lasting than the very short blood high concentrations because the drug is destroyed by serum esterases. Let me tell you about the study. There were 23 sites, about half in Canada and half in the Netherlands. Adult patients were recruited with any type of atrial fibrillation and with a ventricular rate more than 110 beats per minute. It was a one-to-one double-blind randomization between placebo and atripamil, and ECG monitoring was performed for at least 10 minutes prior to treatment and for six hours following treatment. The primary endpoint was the mean maximum reduction in the ventricular rate within 60 minutes after administering the study drug. And the study was powered for a 20 beat per minute reduction. There were secondary endpoints such as the rapidity of ventricular rate reduction and the duration and proportion of patients achieving less than 100 beats per minute, more than or equal to 10% or 20% reduction in ventricular rate. And there was also a patient recorded outcome looking at the TSQM9 rating. Safety endpoints were also collected. The consult diagram shows that we started out with 87 patients presenting in the emergency room, not all qualified for the study. 89 patients were randomized, but between getting them randomized and setting up the study, some of them had a ventricular rate which fell below 110 beats per minute. So we had 56 entering the modified intention to treat population, which is the same as the safety population. Because we needed 60 minutes of atrial fibrillation in order to look at our primary endpoint, we lost another few patients because they converted to sinus rhythm. So our efficacy population was 49 patients. When we look at the placebo and the atropine groups, we can see that they're well balanced. The mean age was around 65. As you can see, about 40% of the patients were women. The Canadian and Netherlands sites were roughly 50-50. AF diagnosis, as you can see, was paroxysmal atrial fibrillation in about three-quarters of the cases and persistent atrial fibrillation in about between 15% and 20% and permanent in 6% or 7%. Concomitant medications, about half the patients were taking either a beta blocker or a non-dihydropyridine calcium channel blocker. These are the efficacy results as far as the primary analysis was concerned. You can see that in the placebo group, the initial heart rate averaged 135 beats per minute with a median of 135. And at its lowest, it was 130. That's a roughly five beat per minute reduction. Whereas on the atrypomole side, you can see that the baseline was 130. After drug administration, you can see that the Nadir effect was 95 beats per minute, giving us a difference between the means of 29, almost 30 beats per minute, a highly significant result. And it's very obvious from the graphs on this slide that you can see in red the effect of atripamil compared with placebo in blue. On the left, you see the first 60 minutes, and you can see the results that I've already explained to you, a significant reduction in heart rate with Atriplamil. On the right, you can see that the patients were followed on this graph up to 180 minutes. Looking at this graph, you can see that the effect is maintained for at least about 150 beats per minute. That is a meaningful difference between the heart rates with placebo and atripamil. And again, this is a highly significant result. Looking at the secondary analyses, we can see the elapsed time between giving the drug and getting to the nadir effect, that's the main effect, the largest effect of heart rate reduction, took about 13 minutes with atrypamil. The results of the placebo are pretty meaningless because there was not much change in heart rate at all. And the rest of the slide results I'm going to show you on the next slide because graphically they're more interesting and easier to understand. But importantly, the results that were obtained in the modified intention to treat group was also and the efficacy group were the same. In other words, the sensitivity analysis would be MITT population was the same as the efficacy population. Now, let's have a look at these graphs showing the ventricular rate reduction less than 100 beats per minute. You see that graphically portrayed, and you can see that within a median of seven minutes, the heart rate is reduced to less than 100 beats per minute. Very little change in getting to 100 beats per minute or less in the placebo group. On the right, we see the reductions of more than 10% in heart rate on the left, placebo in blue, atripomil in red, and you can see 96% of atripomil reached this, but only 20% of placebo. The far right, you see less than or more than 20% reduction in heart rate. None of the placebo group achieved this, but two-thirds of the atripomil group did achieve it. And the results are highly significant. We also, as I mentioned before, did some patient reported outcomes using the treatment satisfaction questionnaire for medication. You can see that this is a seven point scale. And three, a score of three is dissatisfied and a score of five is satisfied. In the middle, somewhat satisfied at four. The histograms on the right show the results with placebo, three, being roughly equivalent to dissatisfied, and with atripamil, above 4.5, approaching 5, so somewhere between somewhat satisfied and satisfied. And a movement or a difference in these scales of one or more is regarded as clinically and regulatory perspective significant. You can also see that the global satisfaction was also significantly improved with the Trefamil. Of course, convenience wouldn't change because the patients were doing the same thing with nasal insufflation. If we look at treatment adverse events, you can see that there were adverse events particularly related to nasal congestion and so on. These were short-lived problems. but quite a large number of patients reported this. There was only one significant treatment associated severe adverse event in a patient who had both bradycardia and syncope, but the patient was known to be a vagotonic, hypervagotonic patient, and it was easily dealt with by just laying the patient down. I'd like to summarize this study by saying that Rivera did show that atripomil nasal spray demonstrated substantial reduction in the ventricular rate, about 30 beats per minute, and significantly different to placebo. The median time was 13 minutes to achieve this. The mean duration of this effect Getting less than 100 beats per minute was 45 minutes in the first 60 minutes. The majority of adverse events were related to the drug administration site. Atripomil was associated with a significant improvement in symptoms and in treatment satisfaction. And I think that these results indicate that there is a potential role for atripomil nasal spray to reduce the ventricular rate in patients who present with symptomatic atrial fibrillation with a rapid ventricular rate. Obviously, we need to do more studies to document this further. So, thank you very much for your attention.

Dr. Kam, thank you very much. This is David Baruccia, the Chief Medical Officer of Milestone. So, thank you, Dr. Kam, for presenting. the Rivera data on behalf of the co-authors. I'm now very pleased to be joined by both Dr. Kim and Dr. Sean Picorni so they can share their perspectives on the Rivera data as well as their thoughts on the current treatment landscape of atrial fibrillation with a rapid ventricular rate and of course their views on the potential use cases of atripamil. So Dr. Picorni, if I could start with you. What is your overall reaction to the Rivera data that Dr. Cam just presented? And specifically, what are your thoughts about the magnitude of reduction in ventricular rate that was observed? Are these reductions of a meaningful amount?

Yeah, no, thanks so much. You know, John, really nice job going through that data. I think the data is really exciting from a clinician perspective. You know, I think when I'm approaching my patients who have episodes of AFib with RVR, really what I'm targeting if I'm adding oral agents from home is I'm really trying to get the heart rate down to around 100 beats a minute or less. And again, that was the magnitude that we were seeing in this study. We were seeing, you know, significant reductions with a large portion of the patients getting down to a heart rate of less than 100 beats a minute with the average heart rate being in the mid 90s. And so, you know, that's really the heart rates that we're targeting clinically. And that's the goal of what we're trying to achieve in order to avoid having patients end up in the emergency department. So I think that the data is certainly clinically significant. And I think that the duration of the effect is also really important. You know, obviously we saw an effect out to 60 minutes, but really we saw an effect out to 150 minutes, which really, you know, provides time for either the rapid ventricular response episode to fully pass or allows time, you know, potentially to add in an oral agent if you're concerned that there is going to be a rebound effect after that, you know, two and a half hour mark. And so, you know, I think that, again, you know, really at the end of the day, all of the focus of these patients is to maintain better rate control, again, targeting a heart rate really ideally less than 100 clinically. And we see that that has an impact in terms of the symptoms as well. As Dr. Kam went over, you know, I think that seeing those significant symptom improvements are critical because it's the symptoms that more than anything else, that drive fear and anxiety and land patients in the emergency department. So I think, you know, again, really impressive results from all of those standpoints. I think to me, you know, one of the things, and Dr. Kam went over the PK data for Atripamil, you know, one of the things that I was most surprised by from the study was the fact that we did see this durable effect out to 150 minutes, out to two and a half hours Dr. Kim, do you have any thoughts on why we saw such a durable effect based on that PK data?

Well, the PK data, of course, refers to the plasma concentration. It doesn't say anything about the concentration of the drug in the myocardium. And in particular, it doesn't say much about the concentration of the drug on the receptor itself. And I think it may well be the drug does not escape from the receptor, detach from the receptor as quickly, particularly during rapid heart rates. So I think that we've seen this effect previously. We know, for example, from the EP studies that were done on the original clinical investigation of the drug, that the effect on the AV node was more long-lasting than the very brief effect that we had anticipated originally. So, for example, Winkibar periodicity was at a slower heart rate for quite a long period following the administration of the drug. So we had an idea that it might last longer than the AV node, half an hour or 60 minutes that we thought originally. But I think we're all surprised that it lasted quite as long as it did. And obviously, we need to document that further and look into it further. But it's a very interesting finding.

Thanks, both of you. Dr. Kam, if you could also tell us your thoughts about the magnitude of reduction in ventricular rate that was observed in this study. and your thoughts as to the clinical meaningfulness and the potential impact of these types of reductions.

The guidelines all tell us, David, that we should try and reduce the heart rate to less than 100 beats per minute in atrial fibrillation. And I think, therefore, that this is a clinically effective dose. And indeed, from my own experience, it obviously is effective. If you start off with a patient, say, let's just say 130 beats per minute, and it's a rapid and irregular rate. Just imagine you can tap on your chest a rapid rate like that, and you can imagine how patients react to that. If you slow the heart rate below 100 beats per minute, and it happens in a fairly quick fashion, seven minutes or 13 minutes, we have the two measures of efficacy in this study, then the patient will immediately feel very relieved. So I think there's no doubt that it is a dose which is clinically very meaningful and clinicians as well as their patients would be very pleased to see that effect.

Thank you, Dr. Kim. If we could add on to your last point for the effect or the impact that might be expected, how would you see kind of the use case of atripomel? And specifically, if you have any particular patient types in mind that would benefit from this, the types of reductions, the rapidity of reduction that you just mentioned?

Well, I think Patients are alarmed and highly anxious when their heart suddenly goes rapidly and irregularly. Imagine everybody listening to this can reproduce these sorts of symptoms that I mentioned just by tapping on their chest at that rate and irregularly. Now, many patients, particularly with paroxysmal atrial fibrillation, at the onset of the arrhythmia, they have a rapid rate And that rate will tend to decline as the hours go by. And that's because of the production of endogenous so-called glycoside-like compounds. But it takes hours to happen. Now, if you have a patient who has a paroxysm of atrial fibrillation, many of these paroxysms will only last an hour or less. And if under those circumstances you give a drug that will rapidly and effectively slow the heart rate you might cover the entire duration of the arrhythmia and it becomes a definitive treatment in itself so i think we have to think of that kind of patient they may have these episodes several times a week or several times a month and it would be a very valuable therapy in itself just just to cover these moments of very rapid heart rate

It sounds like the point in which a patient initially goes into atrial fibrillation with a rapid rate is a prime time to take action. Would that be correct?

Absolutely. That's when they want the therapy. That's the moment of the greatest anxiety. And it's also a very anxious concept when you suddenly get your heart racing away like this of trying to plan what to do next. What to do about it? Should you just sit it out and hope that it goes away? Should you call your doctor and discuss it with him? Should you get in the car and drive to a hospital? Should you get somebody else to drive you to an emergency department? How should you handle it? And that creates another level of anxiety. And so if you had something that you could immediately do, which would have a noticeable effect quite rapidly that you would associate definitely with the treatment, then that would give you a lot of relief so that waiting for any subsequent events, if you knew you had a therapy like this, you're inclined to be much more tranquil about the arrhythmia when it starts. So I think that, uh, The secret of this therapy will be the rapidity of the effect. It will allow the patient to very quickly get on top of the first crisis that develops when this arrhythmia starts. Thank you.

Dr. Pokorny, a similar question to you. Your thoughts on the main or main use cases for an acutely acting drug like a trypamil nasal spray. What are your thoughts about the different use cases, and what are your thoughts about the importance of intervening very early?

Yeah, no, great question. I mean, I couldn't agree more with all of Dr. Kam's points. I guess I would just add a couple things, especially to the importance of the early onset and the rapid timing. that again, Dr. Cam talked about the level of anxiety that these patients experience, and the level of anxiety drives adrenaline, essentially, and to some extent that it becomes sort of a downward spiral for these patients. They have an episode of AFib. They start feeling more anxious. It drives the heart rates higher. They get more anxious. It drives the heart rates higher, and that's what leads to number one, emergency department visits for many of these patients, and also potentially may prevent these episodes from terminating. And there's some thinking, and I'm at least one of the people that share this thinking, that when patients get to lower heart rates and their heart rates are better controlled and they're less anxious, they don't have that adrenaline, they're maybe more likely to self-terminate their episodes. So I completely agree with Dr. Kam about the fact that the medication atripamil may be sort of a self-terminal treatment for these patients, may really treat them for the duration of their episode. I think that in addition, what, you know, what we often see in, there's sort of two other groups of patients that I think about in my practice. One group of patients is the group of patients that are taking pill-in-the-pocket antiarrhythmic medications. So some of these patients, when they have an episode of atrial fibrillation, they'll take an antiarrhythmic medication to try to bring them back into normal rhythm. And for most of those medications, we want them on some type of AV nodal blocker. And many of the patients that are doing that pill-in-the-pocket strategy are not on daily AV nodal blockers because of symptoms that those avinodal blockers will cause. So from my perspective, from a safety perspective, getting a rapid-acting avinodal blocker in place, such as atripamil, would allow me to feel even more comfortable treating some of these pill-in-the-pocket antiarrhythmic medication patients in an outpatient setting, again, sort of more effectively and more safely. And then the final point that I would make is, that for the patients that don't convert, one of the goals is really keeping these patients out of the hospital. When these patients show up in the emergency department in atrial fibrillation with a rapid ventricular response, they don't receive the treatment that they're expecting. They don't receive the treatment that probably many on the phone are expecting. Generally, what they get is a rate control strategy until they can get a cardioversion. So for example, at Duke, if a patient comes into the emergency department at 3.30 on a Friday afternoon with AFib with RVR, they're going to get some rate control strategy, probably IV diltiazem, and they're going to be sitting there over the course of the weekend getting rate controlled until they can get a cardioversion on Monday when the cardioversion lab is sort of back up and running. And so for those reasons, we really try, I try my best to keep my patients out of the emergency department and out of the hospital. And I think that having a trypamil would allow me to control their heart rates at that target heart rate of less than 100 to the point where we can calm them down, again, potentially add in some oral rate control on the back of it and layer that in to keep them rate controlled until we can get an outpatient cardioversion if that's the definitive therapy that's needed.

Okay. That's great, Dr. Pokorny. Thank you for those insights. Dr. Kam, one of the last topics I'd like to hit on this morning is the quote unquote subtypes of atrial fibrillation. The disease, as we know, is sometimes subdivided into those with paroxysmal, persistent, or permanent atrial fibrillation. In this study, we enrolled patients across that spectrum. Is the array, so two questions. Is the array of patients that we saw in the trial representative of patients that you see or hear from? And also, what would be your expectations for how these different types of patients might present, meaning the frequency of presentation? How amenable would each patient type be to treatment with an acute agent like a trip mill?

Again, very good questions, Dr. Borussia. I think everybody appreciates that atrial fibrillation has various so-called temporal patterns. The term paroxysmal, as you might expect, means that the atrial fibrillation comes in attacks. And these attacks are defined usually as lasting up to two days or up to seven days sometimes. But the majority of them are fairly short acting, just a few hours or a day or so, but rarely going up to seven days. The next kind is called persistent atrial fibrillation, which as you might expect from the terminology is atrial fibrillation that doesn't go away unless you do something to treat it definitively, such as, for example, a cardioversion. And the third kind of atrial fibrillation is so-called permanent atrial fibrillation. And that essentially means that the patient or the doctor has refused any further attempt to get the patient into sinus rhythm now having said all that it sounds pretty clear the distinction between these three groups but if you actually put a monitor on these patients and look at their rhythm continuously for days on end you'll find that the relationship between what I've defined as paroxysmal etc and reality can be very different and doctors often put patients in these subtypes when they don't really belong or they have a mixture of several of these subtypes. Now, having said that, you said, do we hear from or see them in the proportion that we had in this trial? Well, we certainly hear from them in the proportion that we have in the trial because the paroxysmal atrial fibrillators are probably much the more symptomatic of the subtypes. On the other hand, if we sort of catalog each case of atrial fibrillation on the books, we'll find there are far more permanent atrial fibrillation than we had in the study and more persistent types. And I think for that, the reason for that is quite simple. It's the onset of the arrhythmia, which is generally the problem. When it first starts, it's very abrupt change from sinus rhythm suddenly going into this arrhythmia, and that's when the patients seek emergency treatment to try and get their arrhythmia under some form of control those with persistent atrial fibrillation have probably got a much longer history with the arrhythmia know it much better and generally only occasionally relative to paroxysmal atrial fibrillation will they have new episodes because the episodes are so long lasting and permanent atrial fibrillation We don't really see as an emergency unless, for example, they've forgotten their tablets. They've gone away on a week's holiday, forgotten their tablets, and their heart rate gets faster and faster, and then they may present in the sort of way that we saw in this study. Also, as I say, some of the so-called permanent atrial fibrillation isn't really permanent, and they do have episodes of sinus rhythm and then lapse back into atrial fibrillation. So I think the main issue is the sudden onset of the arrhythmia. And sudden onsets are going to be much more common in the paroxysmal group than in the persistent group, than in the permanent group. And that's exactly what we saw when we recruited patients into Rivera.

Thank you, Dr. Kam. Dr. Corning, before we move on to the next topic, Any last brief observations on what Dr. Kam just mentioned about the different subtypes or amenability to treatment within each of those subtypes?

No, I think that, you know, that was a really nice overview and discussion of it. I would say that at least for me, you know, in my clinical practice, I would say that the proportion of patients represented in the study, 75% paroxysmal and 5% permanent, I would say that probably in clinical practice, there's a larger number of permanent AFib patients and probably a smaller number of paroxysmal patients. But I do think that the patients included in the study, the proportions represent the proportionality of the patient's conditions who will likely benefit from atripamil, meaning I think that the majority of patients that will end up that we'll use the medication in will be the paroxysmal patients to a lesser extent, the persistent, and then, you know, to a far lesser extent, the permanent. So I think that the patients that are represented in Rivera are representative of how we would likely use the medication in clinical practice and are representative of the patients that should be included in the phase three study.

Okay. Thank you both very much, Dr. Kam, Dr. Pokorny. All of your insights are brilliant, and we also truly appreciate your presenting the data that were presented at a featured science presentation, Dr. Kam. Now I'd like to direct our attention to Milestone's proposed Phase III Registrational Study in AFib. First, to give this some context, over several studies, there's been a growing body of evidence demonstrating the potential of atripamil in AFib RVR. For example, at the Heart Rhythm Society meetings just earlier this year, Dr. Paul Dorian and colleagues presented data from open-label administration of atripamil and showing on the left-hand panel there a prompt reduction in ventricular rate. In the Rivera data reporting that Dr. Kam just summarized, we are very pleased, this is on the right-hand panel, very pleased to see first significantly superior efficacy in ventricular rate reduction. And this clarity is present over the course of at least 60 minutes, truly out to at least 150 minutes or two and a half hours. The third element that we're very pleased to see is the demonstration of symptomatic improvement with a known PRO. And the last element among many that we were very pleased to see were the favorable safety and tolerability results and data that are consistent with the known profile of atripamil from prior programs. The totality of this evidence supports further evaluation of atripamil in a larger Phase III study, we had the opportunity at Milestone to meet with FDA earlier this year, the Cardiorenal Division, regarding planning for a registrational program. To report out on that, FDA concurs that proceeding with a single Phase III study with self-administered at-home setting would be appropriate to gain a labeled indication via a supplemental NDA route. The FDA also concurred that we can utilize the safety database from our prior extensive PSVT program. The primary endpoint in this inquiry would be a reduction in ventricular rate akin to what was already successfully shown in the Rivera study. Please take note. FDA was very clear that the secondary endpoint must be based on benefit on symptoms via a PRO. This key secondary endpoint would need to be reported with a p-value of less than 0.05 in order to gain approval, and that analysis would need to be performed in an ITT population. In other words, all patients self-administering study drugs. An important recommendation by FDA was also to use for the PRO a seven-point anchored scale, similar to what was done in the Rivera study. And there's an expectation of us needing to show a one-unit improvement in a target population, or those patients with verified AFib-RVR. Last and importantly, The FDA review division gave us latitude as to the specific PRO that might be used, and they're certainly going to look at the data obtained from the TSQM-9 as presented already this morning. So the proposed phase three design is summarized on the slide that's about to come up. The key inclusion criterion would be history of symptomatic episodes of AFib-RVR. Patients would self-administer the drug at home for perceived episodes at a dose 70 milligrams, which is the same dose used in the PSVT program, including a repeat dose regimen. The primary endpoint, as I already alluded to, would be maximum reduction in ventricular rate, same as Rivera or similar to Rivera, The key secondary endpoint would be symptomatic relief utilizing a PRO. Our objectives would be to show a p-value of less than .05 for both the primary and key secondary endpoints. No alpha spend is anticipated in the statistical design that we're beginning to formulate. We would need to show a meaningful PRO-based change in the target population, a minimum of a one-point change on a seven-point scale, I'll remind people that we observed in Rivera a 1.55 unit change on a seven-point scale. Our estimated study size with the powering calculations detailed on the written slide in front of you, the estimated study size would be 150 to 200 total events for patients with patients self-administering the drug for perceived AFib-RVR. The timing that we anticipate is speaking to the FDA to get formal confirmation on our protocol within several months. That would enable us to start the study in the middle of 2024 and report out top-line data approximately two years later in the middle of 2026. With that, I'll turn the call back over to Joe Oliveto for his final comments and to open up the lines for Q&A. Joe?

Thanks, David. And before we close out the call and accept questions, I'd like to extend my deepest gratitude to all those who participated in the study, including the patients and, of course, the healthcare professionals. I'd also like to thank the entire Milestone team for their dedication. and commitment to bringing atripamil to as many appropriate patients as possible. This quarter was transformational for our company. We believe the combination of the submission of our first new drug application for Cardamist and treating PSVT and the release of the positive results from our Phase II study evaluating atripamil to treat patients with AFib-RVR demonstrates that we are on track to advance our clinical development program And we are approaching 2024 with a well-defined strategy and even greater confidence around the potential of our lead asset, atripamil, to help people living with these serious heart arrhythmias. We've now demonstrated the potential of atripamil to address significant unmet needs in patient self-management in two different serious arrhythmias, PSVT and AFib-RVR. And with our new drug application recently submitted to the FDA for PSVT, and a potential approval in the fourth quarter of next year, we are focused on commercial preparations in anticipation of a potential launch. In AFib-RVR, the results we've discussed today demonstrate potential of the triple mill to serve as a meaningful intervention in this patient population. And with these results in hand, we look forward to working with you to finalize a registrational program to evaluate a triple mill in the at-home setting, which we expect to begin in 2024. So as we move here to Q&A, before we get there, I'd like to thank Drs. Kam and Pokorny. I appreciate them staying on the phone here during the Q&A portion. And open up the call for the Q&A. Keith?

Yes, thank you. At this time, we will begin the question and answer session. To ask a question, you may press star, then 1 on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. At this time, we will pause momentarily to assemble the roster. And the first question comes from Ritu Barao with TD Cowan.

Hey, guys. This is Athena Ahn for Ritu. Thanks for taking my question. My first question is, how will the maximum ventricular rate reduction be assessed in the proposed phase three study? And what do you expect to see in rate reduction for the effect size needed on the primary endpoints? And secondly, can you please fully define the target AFib population that needs to show meaningful PRO-based change? Thanks.

Sure. Athena, good morning. Thanks for your questions. This is David Baruccia. We will be assessing ventricular rate reduction in the Phase III study very similar, if not identically, to the way that we did it in our PSVT programs. Patients upon experiencing an episode in the at-home setting will set themselves up with a very feasible, very easy to use EKG device. It's about the size of the palm of your hand. It was used very successfully in the PSVT program and allows very high fidelity recordings of EKGs for the duration of the recording. That will be more than sufficient to yield very clean data to assess this endpoint. Athena, if you could remind me of your second question. I think it was about the target patient population that we would be looking towards.

Yes, but I did ask a question in between. What do you expect to see in the rate reduction for the effect science needed on the primary endpoint?

Well, it's hard to always make predictions, but based on the strength of the Rivera data, and the strength, I'm not only talking about the p-values, I'm talking about the extent of treatment effect. We saw such a robust treatment effect in several different measures of ventricular rate reduction. We showed a very robust treatment effect in the difference in the TSQM9 PRO scores that I'm optimistic that we'll see at least discernible, if not vigorous, treatment effect as we translate this program to the outpatient setting.

Got it. And my third question was to please define the target population that you would need to see to show meaningful PRO-based change.

For a PRO-based change, just about every patient with Atrial fibrillation and a rapid ventricular rate who's symptomatic would benefit from heart rate reduction and therefore would benefit by showing symptomatic reduction. Heart rate reduction and symptomatic reduction really go hand in hand. Does that answer your question, Tina?

Yes, thank you. I'll hop back to the queue.

Okay. Thank you. And the next question comes from Leland Gershaw with Oppenheimer.

Great. Good morning. Thank you for holding this event and taking my questions. Just a question for our physician experts, Drs. Kim and McCorney. Given the ability of triple mil to work effectively in all patients with AFib who may experience rapid ventricular rape, One could ideally think this should be in the pocket or the handbag of any patient at risk. At the same time, it's not an ideal world, and certain patients may be more prone to be prescribed this versus others. I wonder if you could speak to to what extent would you prescribe this in your patient populations as you think about patients who would be more at risk versus less? Would it be reserved for patients who tend to have more frequent episodes of RVR? Would it be for patients who have more longstanding AFib? Maybe just some more color as we think about how this product may see uptake into the marketplace, presuming approval.

Thank you. Dr. Kim, would you like to comment on that first, and then Dr. Pokorny?

Thank you. Yes, I will say a few words about that. Obviously, the drug will be more valuable in patients who are more symptomatic And we do have to recall that some patients have very few symptoms associated with their arrhythmia. So the symptomatic patient is much more likely to have a treatment of this kind. Also, as evidenced, I think, by the Rivera study, the patients who are more symptomatic are usually patients with paroxysmal symptoms. atrial fibrillation because they have so many more events usually than those who have persistent atrial fibrillation. And it's relative rarity for permanent atrial fibrillation to present with a rapid ventricular rate if they've been in the system and have their management already under control. So I think it's likely to be the symptomatic patient with paroxysmal atrial fibrillation who will have the best results from a treatment of this kind. Having said that, there are other considerations. Some patients find giving their own treatment more difficult than being treated by somebody else. And clearly, they need to have the confidence to use the therapy Now, this therapy is pretty easy to use, particularly when the patients get used to doing this. In the Rivera study, of course, the medication was administered in the emergency department. But in the phase three study, the patients will administer it themselves. But they will already probably have had experience with either receiving the drug or certainly being trained with a placebo form of the drug so that they are comfortable with nasal insufflation. Once they are comfortable with how they can do it, then I think that there should be no particular problem unless they have sensitivities to calcium antagonists or something of that sort. Obviously, not every patient will take a therapy like this because some of them will have arrhythmias that are so infrequent that they're not going to remember to keep the therapy with them. It's really for those patients who anticipate having treatments months apart or days apart or weeks apart, not years apart, in the sense that they forget about the arrhythmia and they forget about the therapy, which they probably leave at home rather than put it in their handbag or their pocket. Fortunately, the therapy is very small, and it's very possible for patients to carry it around without any difficulty at all.

Thanks, Dr. Kim.

Yeah, no, so I would agree. Again, I think Dr. Kim has sort of nicely summarized that I think that it'll be particularly useful in the symptomatic paroxysmal patients. I think that, you know, some of the, just to maybe add additional thoughts in separate groups, separate specific groups, that I think it may be particularly useful in the post-ablation patients. You know, a large portion of our patients get ablation for atrial fibrillation, and we know that the recurrence rates are really, you know, as high as as 25% at one year and out to 40% at five years. You know, many of those patients are patients that are getting ablation because they're looking to stop taking chronic medications. And so, you know, those are patients that are going to have high rates of recurrence and are likely to have rapid ventricular response when they do have those episodes. And they're going to be patients that are particularly symptomatic, which is why they underwent the ablation in the first place. And so I think that that's one example of a group of patients, a large group of patients that I think would be particularly useful for the medication. I think that another group of patients that I think is really important is, you know, to me, one of the big benefits of atripamil is the ease of use. And Dr. Kam talked about this, you know, to some extent, ease of use of the patient, but there's also ease of use from the provider perspective. You know, when you look through the PSVT data, there were really no concerns with high-grade AV block. There were no concerns with hypotension. And so the safety profile is really extremely favorable. And so particularly for patients who might have heart failure with reduced ejection fraction, patients that may have sort of marginal blood pressures on whatever rate control strategy they're on at home, including among persistent patients. You know, those are patients that having atripamil available to them would be, I think, particularly useful because if they do have these episodes where for a short time their heart rate accelerates considerably, I would be comfortable as a provider with those patients using atripamil to rapidly reduce their heart rate without having concerns about inducing a heart failure exacerbation, which you might induce if you give large amounts of additional oral medications, as well as, you know, not being concerned about having periods of hypotension or passing out low blood pressure that would similarly land patients in the emergency department, again, because we haven't seen any of those effects with the medication in the PSVT population.

Great.

Thank you both for your perspective.

Thank you. And the next question comes to Ted Henthoff with Piper Sandler.

Great, thank you. Can you hear me okay?

We got you, Ted.

So thanks for this update. Really, really exciting. And I just look at how this medicine is progressing. It's great to see. So kind of a question on both PSVT and AFib. PSVT, can you tell us a little bit about the commercial prep that you're doing and how you're planning on distributing Atripamil in that indication. And when it comes to the larger indication of AFib, do you think you'd still be able to do that, or do you think that would require a partner? Thanks.

Thanks, Ted. I'll start, but ask Lorenz to contribute, especially around how we're going to plan to distribute. We're very proud to have built out the full commercial team here with the exception of our VP of sales that will come probably early next year. So we've been built out now probably for a good six months or so. And we've also been starting to work on informing and educating the market around PSVT. It's a very well understood condition in the eyes of the cardiologists and very well characterized. but I think the message that we're trying to get out there is the patient need and bring that to life. And we've had MedAffairs out on the ground now probably for six to nine months or so. So we're starting to build that. Hopefully you and the audience are seeing more publications coming out on PSVT. You're seeing us more prominent at conferences. You're seeing this type of data, and that's the start of the progress here and the process. And we do feel confident that we as a small company can deliver on that PSVT indication, and partially because while it is a new calcium channel blocker and a novel way to think about treating PSVT, it is very well established and understood by Doctors Pokorny, Kam, and their colleagues. They have a long history with calcium channel blockers, and we've heard from colleagues like them, and also treating physicians, not just key opinion leaders as they are, that they're very comfortable with that. So we feel very confident that we can bring that to life. With regard to distribution, we're going down a standard retail route. We would like this to be readily available to people and not have any special needs or requirements to be able to get the drug. We will price it that way such that it's not a burden for physicians or to go through a lot of steps to get it for their patients and for patients to have pain in paying for it. So that's our approach. And lastly, with regard to AFib, the people that treat PSVT largely are very, very, very high overlap with those that are treating AFib. So the approach would be the same for us. And just for clarity, our approach is to really launch this ourselves. In the U.S., we can think about partnering as we get towards the primary care portion of the population that manages condition. We think that's in the range of about 30% all in. But at launch, we're going to focus on the experts, which are the cardiologists in the area. And then when AFib were to come to the market, if we are successful, we're thinking that happens, call it two to three years after the PSVT launch. And we think by then, we'll have a very good understanding of the drug itself and PSVT and would warrant maybe a little bit more promotional effort to bring AFib and expand, especially as we get towards the primary care group. That's super helpful. Thanks, Joe.

Thank you. And the next question comes from Patrick Trucchio with HCA Wainwright.

Thanks. Good morning, and congrats on the data. Just a couple of follow-up questions. First, for Drs. Kam and Pokornyi, I'm wondering if you can discuss the learnings that emerged from the Phase 2 Rivera trial as regards to Phase 3 design. And can you comment on your thoughts on the Phase 3 design, including dosing along with the primary and secondary endpoints and potential for success based on the Rivera outcome? And separately, can you also comment on the anticipated enrollment with the study start in mid-2024? Is it reasonable to expect top-line data from this trial could be achieved by mid-2026?

Sean, do you want to start with this one and then Dr. Camp? Sure.

Yeah, no problem. So let's see. There's a lot to unpack there. So just I'll try to make sure that I hit each of those items and then maybe we can make sure that I really did. So I think in terms of of the approach to enrollment. I guess we'll start with your last question first. I think that, you know, the nice thing about the AFib population is that it's a large and highly prevalent population. And the patients that have symptomatic AFib with RVR are patients that are looking for solutions and interested in engaging many of these patients, as I mentioned, we have large populations that are younger and healthier and don't want to take daily medication. So I think that the clinical trial will enroll actually pretty rapidly. I think it should be a relatively easy population to enroll because you're going to have sort of an active and engaged cohort of patients who are looking for this type of short-term at-home solution to avoid going to the emergency department. So I think that piece You know, that's sort of the first piece. In terms of the dose administration, you know, I think that obviously we've seen great results with the 70 milligram dose. I think the 70 milligram dose, from my perspective, is the right dose because, again, what we don't want to have is we don't want to have too much bradycardia in these patients. So we certainly want to get their heart rates less than 100. there's not a great need to drive their heart rates down to 60 or 70 beats a minute. And so I think that the dose that was studied in Rivera, I think, is the appropriate dose to continue forward with in the phase three study. I think that in terms of the outcome, certainly we're going to care about heart rate. You know, for me, one of the key endpoints is really going to be heart-related or cardiovascular hospitalization or emergency department visits. I think that's really what the payers are going to care about. That's what patients are going to care about. And that's what providers are going to care about. Certainly heart rate is sort of a proof of concept component, and it's going to be important to look at that as well. But I think it's really these emergency department visits and cardiovascular hospitalizations that are going to be the most critical. What other things did I miss from the question?

You know, I think you touched on everything. Just, I think just, you know, based on what we've seen in the Rivera outcome, just the likelihood of success on the primary endpoint in this.

Yeah. Got it. Perfect. Yeah. And then I'll turn it over to Dr. Kam. Yeah, I think that, so again, I think that what we see clinically is that the patients that go to the emergency department with AFib, by and large, are patients who are experiencing rapid ventricular response. That's what, as Dr. Kim said earlier, produces the anxiety. That's what drives these emergency department visits. So I think that by reducing the heart rate to that target heart rate less than 100, number one, I think patients are going to feel dramatically better, as we saw from Rivera with the symptom score. And I think that reduction in symptom score is going to drive less of a desire to go to the hospital. I also think that you know, with education of the patients, of the safety of AFib, with heart rates less than 100 beats a minute, since that's in line with the guidelines, I think we can get more and more patients comfortable. They don't need to visit the hospital. So I do think that the endpoint will be achievable. But again, interested to see what Dr. Kam thinks as well.

Thank you very much, Sean. That's a really good question, because the Rivera showed us that there is definitely a clearly demonstrable effect on the heart rate and I don't expect that to be any different in the definitive study but I do think that we learned one or two important lessons from Rivera one that I would definitely try to correct for the phase three study is to hold off from randomizing the patient until they're already hooked up to a the ECG, and they've recorded their original 10 minutes of ECG and randomize them at that point, because then we would not have dropouts between the randomized population and the efficacy population or the MITT population. So I would think very carefully about that. I'd also like to think about whether we should stratify the population in some way, particularly with regard to whether they're taking already AV nodal blocking agents such as beta blockers and non-dihydropyridine calcium channel blockers. With regard to endpoints, I think our endpoint should probably remain a 60-minute endpoint. But I think that we should obviously, given that the study is going to be out of hospital, have endpoints that relate to what other healthcare facility usage there is in the phase three study because that would be a very critical component. And I think we have to have very solid PRO data. system that we used in rivera was pretty good but i think you could also argue that you could back that up with some other pro material because i think that's going to be a major regulatory issue whether i think it's feasible to do this and have it all done and dusted by 2026 certainly i think it's possible to do that and i'd have no doubt about it thank you

Yep, that's great, and thank you. That's very helpful. Just one follow-up then from Milestone on slide 23. I'm wondering how a potential approval in PSVT could impact the clinical development pathway for AFib, and if there's a further streamlining perhaps of safety data or other aspects of the supplemental NDA that could be modified or accelerated post that potential approval in PSVT.

Right. Yeah, thank you, Patrick, and thanks for hitting on that. The FDA clearly guided us to the understanding that they are thinking that it would be an SNDA pathway, so in that definition, if you will, you are leveraging the safety data set from SVT. As Dr. Cam had mentioned before, we'll obviously be evaluating this in a phase three comparative trial in AFib where we'll look at safety as well, but we feel like that's an important leverage point for us to take advantage of. And, you know, that allows this fast pathway to a potential AFib-RVR filing shortly after you get that top-line data. So our view is single study to deliver efficacy largely, although we'll measure everything, of course, and be able to deliver that for our S&DA approval. Yeah, terrific. Thank you so much. Thanks, Patrick.

Thank you. And this concludes the question and answer session. I would like to turn the floor to Joseph Aliveto for any closing comments.

Thank you, Keith. And I'd like to thank everyone for taking the time out to hear the milestone story and especially our guests and experts, Dr. John Kam and Dr. Sean Picorni for their outstanding comments today. And we'll look forward to seeing everyone as we speak at the end of the quarter today. Take care.

Thank you. The conference has now concluded. Thank you for attending today's presentation, and you may now disconnect your lines.