Milestone Pharmaceuticals Inc. (MIST) Earnings Call Transcript & Summary

Good day, ladies and gentlemen, and welcome to the Milestone Pharmaceuticals Commercial Deep-Dive Conference Call. As a reminder, this call is being recorded. [Operator Instructions] I would now like to turn the call over to Joseph Oliveto with Milestone.

Thank you, operator, and good afternoon, everyone. I am Joe Oliveto, the CEO of Milestone, and I'd like to thank you all for joining our commercial deep-dive event, focused on the etripamil for the treatment of PSVT. Before we begin, I'll make some forward-looking statements, and we'll direct you to our SEC filings for a full disclosure of our risk factors. I'll be spending a few minutes to provide an overview of milestone before turning over to Lorenz Muller, our Chief Commercial Officer, to take you through a detailed presentation of the PSVT market and commercial opportunity for etripamil on PSVT. Excited to introduce our team who will be joining us here today. In addition to Lorenz, we are joined by David Bharucha, who's our Chief Medical Officer; Amit Hasija, our CFO and EVP of Corporate Dev; and Jeff Nelson, our Chief Operating Officer, all of whom will be available to answer questions. I'd also like to recognize Francis Plat. Francis is our Chief Scientific Officer, who will be retiring from Milestone at the end of the year following the distinguished career in pharmaceutical drug development. We've been preparing for this transition for a while, and the CMO baton has been passed to David, who will be retaining Francis' expertise in a significant, albeit in part-time consulting role, and Francis has been instrumental in milestone success over the time of the etripamil clinical development program, culminating in the highly successful Phase III RAPID study that reported out in October. I'd like to take this opportunity to recognize Francis not only for his contributions and dedication to Milestone, but also for his work along with the impressive group of key opinion leaders to advance the field of PSVT and the full expectation that his work will help improve the lives of patients living with PSVT. The investment highlights for Milestone are many. First, our compound etripamil is a novel calcium channel blocker nasal spray that potentially offers patients with PSVT, a rapid resolution of their episodes, and this can be done whenever or wherever they occur, thereby enabling patients greater control over their condition. While etripamil is a new and a novel compound, offering a unique option for patient self-management, we feel that the comfort that regulators and health care providers have with calcium channel blockers over their many years of use, offers a potentially lower risk path to market approval. And once approved, a higher likelihood of faster physician adoption. Second and foundational to the investment thesis is that PSVT is a large and untapped commercial market, affecting approximately 2 million patients in the U.S. with high unmet need and pent-up demand. The focused cardiology call point and lack of alternative treatment options allow for a concentrated sales effort with potential for high uptake. Reduced unnecessary emergency department visits as a value proposition to all stakeholders, patients, physicians and payers can appreciate and combined with a lack of competition, allows for pricing flexibility for etripamil. Our objective for today's presentation is for you, the audience, to understand the market size and the needs and desires of the 3 most important stakeholders, patients, health care providers and payers and to appreciate the opportunity we now have to change the world of PSVT management and help hundreds of thousands of patients. Third is our team and our collaborative leadership in PSVT, underlying the results and assumptions of the commercial opportunity that you'll hear about today from Lorenz lies the expertise of our team, the relationships we've built and continue to build with thought leaders and with patients. We know many patients living with PSVT, and we know them personally. And the rigor of the research that has been developed in homes over 5-plus years. We feel these relationships and this deep knowledge that positions us and etripamil well to make a meaningful impact on the PSVT market. On the development side, the Phase III data produced 3 studies in the home setting is clear, it's statistically significant, and it's clinically meaningful. This Phase III data enables the near-term deliverable of our expected NDA submission for PSVT in the middle of next year. Finally, is the opportunity for future growth from development of the second indication of atrial fibrillation with rapid ventricular rate and other life cycle management initiatives. With regard to AFib-RVR, our belief and the potential for etripamil to serve as a patient self-administered fast-acting heart rate reducing agent stems from the validated mechanism of calcium channel blockers, both IV verapamil and IV diltiazem, showing such effectiveness in prior clinical trials and being entrenched standard of care in the emergency department for many years. The mechanistic rationale combined with the heart rate reduction data already observed from the etripamil PSVT program and the existing tolerability profile of the etripamil to date, provides added conviction that there is a place for etripamil to be developed for AFib-RVR. I'll provide a little background on the condition and the drug before handing over to Lorenz to discuss the commercial opportunity. Slide 7 outlines the underlying physiology of both PSVT and Afib RVR, both supraventricular tachycardias. Well, with each different underlying physiology causing the episodes to start, the commonality of both tachycardias result in excessive signals passing over the AV node, causing elevated heart rates and marked symptoms such as palpitations, shortness of breath, chest pain, like headiness and anxiety. These symptoms drive many patients the emergency department to seek care. In the case of PSVT, approximately 150,000 ED visits annually in the case of AFib, almost 800,000 ED visits annually, many of them from elevated ventricular rates. Calcium channel blockers in IV form are approved and used in both of these indications to either break the tachycardia in the case of PSVT or slow the heart rate in the case of AFib-RVR. The available treatment options for PSVT shown on Slide 8 fall into two approaches. On the chronic or preventive side, many patients take chronic oral drugs, commonly beta blockers or calcium channel blockers in order to reduce the number of episodes. But these drugs do come with side effects such as lethargy and libido for beta blockers and constipation for calcium channel blockers and also come with uncertainty and efficacy. The second option is a procedure called the catheter ablation in which an electrophysiologist will go into the heart and attempt to burn out the accessory pathways that are creating a problem for the PSVT patient. The procedure is highly successful, however, does come with risks, for example, the potential of ablating the AV node, which if it occurs, would require a pacemaker implant. The data tells us that 85% of patients do not elect this option because of their concern over the procedure. Finally, and the area we focus on for etripamil is when a patient finds themselves in an event. They typically first attempt that vagal-maneuver. This is a bearing down procedure such as attempting to blow into a straw. Some will also try to take an extra dose of their oral medication called a pill in the pocket for which there's limited and uncertain efficacy data. The only approved intervention for breaking tachycardia involves a trip to the emergency department where IV adenosine is the current standard of care. And if that doesn't work after a few doses, patients will then receive electrical cardioversion which the patients describe as the dreaded panels. While sinus rhythm can always eventually be achieved, these are not optimal, not only is it costly, time-consuming and anxiety provoking to go to the emergency department by receiving a adenosine, which completely stops your heart for a short period as reported by the patient is very unpleasant. As a result of all these concerns, many patients opt instead to wait out episodes for long periods before taking that option. Our idea is to develop a treatment option that a patient carries with them and offers a solution to rapidly resolving the PSVT event whenever they get it and wherever they get it. Our offering is called the etripamil. Etripamil is a novel non-dihydropyridine L-type calcium channel blocker, which is the same class of calcium channel blockers that are approved in IV form for PSVT. The compound is a potent AV nodal acting agent that is formulated in nasal spray and has a very fast onset of action, and by design, a relatively short duration of action for use in the at-home setting or on supervised setting. The expected dosing regimen would instruct patients to dose themselves with 70 milligrams of drug via 2 sprays, one in each nostril. And as symptoms do not resolve within 10 minutes to take an optional second dose of 70 milligrams to provide a second pulse to break the PSVT circuit. The RAPID study with results presented recently at the American Heart Association late breaker clinical session utilized this repeat dose regimen. I will not cover those results here other than to say that primary efficacy of greater conversion compared to placebo within 30 minutes was met with high statistical significance and that etripamil converted to patients much faster than in placebo with an attractive tolerability and safety profile. The full presentation of the RAPID study top line results are available on our website, and we expect to present more interesting data from this study of future medical competes. With that introduction, I'd like to now turn it over to Lorenz to take us through an in-depth review of the PSVT market and the commercial opportunity for etripamil. Lorenz?

Thank you, Joe, and good afternoon to everyone, and happy holidays. Thanks for making the time today and your busy calendars to learn more about the commercial opportunity that etripamil represents in PSVT. I'm going to start today with the disease burden so that you can better appreciate what PSVT means for patients, both during an episode and in terms of the emotional impact of the disease between episodes. I'm then going to move on and translate the clinical findings from the RAPID study into the value proposition that we will be taking to market to communicate to all the different relevant stakeholders if etripamil is approved. Next, we're going to dissect the PSVT market and its size because this is a complex issue. We believe that we have the most robust understanding of exactly how many patients are diagnosed with PSVT. And I want to share those insights because they're fundamental to the investment thesis. Then lastly, and perhaps most importantly, I want to translate all these insights into an actionable plan for how we're going to commercialize etripamil and how a company like Milestone, launching its first product, can do that successfully. Let me start with some historical perspective on what we've been doing over the last number of years. For a small company, you might be surprised to learn that we've been exploring the commercial opportunity for etripamil for the better part of a decade. I joined in 2017 as the Commercial Officer, but the company had already done 5 to 6 years' worth of research prior to that. Qualitative and quantitative work, some initial claims analysis, a really robust work for a company very early on, even before Phase III. Since I joined, we've ramped all that up. And as we got into Phase III, we've complemented what we had already understood about the market with additional robust quantitative work, looking at the patient journey, which is fundamental to understanding what etripamil could be for patients. We realized even for market research, there were some limitations to what patients could recall about the impact of their disease. So we commissioned a gold standard longitudinal observational study to really understand what's going on with these patients. We've supplemented that on the physician side with multiple rounds of quantitative research to understand how they perceive the disease, and how they would use a product like etripamil. And we've gone out and complemented that with a lot of claims analysis that I'm going to show you which helps us understand the size of the market and gives us insights on health care resource use and costs as well. We've translated a lot of this considerable work and those analysis into publications that you can find on our website. Most recently, we've also been doing much deeper, we've also been going much deeper with payers and understanding the value proposition and some of the dynamics going on in the marketplace right now. Underlying all of that, for the better part of 5 years, we've been engaging with KOLs in both North America and Europe on our standing advisory boards. So in aggregate, we've garnered insights from well over 2,000 stakeholders in this marketplace. Patients, physicians and payers and feel like that gives us a foundational understanding that allows us to claim thought leadership in PSVT. So let's now explore some of the key learnings from this large body of work. One of our early realizations from market research with patients with PSVT was that they weren't able to communicate the full burden of the condition on their lives because they were generally only remembering the most severe episodes they experience, something known as recall bias. To address this 4 years ago, we commissioned a gold standard study to really understand the impact that a condition like PSVT has on patients. We recruited about 250 patients in the U.S. and the U.K., make sure they had a smartphone and asked them to initially complete a baseline survey to understand the impact of PSVT on their lives currently. And we went back and said, every week or 2 weeks, please check in with us, fill out a short 5-minute survey. And if you had an episode, document that episode for us, tell us what the duration of the episode was, what the symptoms were, how severe they were, what kind of treatments you sought for example, if you go to the emergency department. For those patients who didn't experience one or more episodes between check-ins, we ask them to fill out a quality of life survey just so we'd have balance and ensure because we're providing a little bit of remuneration in this study that we wouldn't have any bias toward patients wanting to fill out one survey or the other. As a result of this effort, over the course of the year, we collected data on over 5,000 episodes of PSVT. And that gave us incredibly unique insights into what this disease means for patients, both physically during an episode and emotionally between episodes. This slide shows some of the key findings from this observational study. On the left, you'll see that 60% of respondents had multiple longer episodes of PSVT and that they self characterized as moderate or severe in intensity. In addition, almost half the patients had on average episodes that last more than 30 minutes. To put this into perspective, imagine for a minute that you're on a treadmill and you get your heart rate up to 170 beats per minute. Now you step off the treadmill, but rather than slowing down, your heart continues to race along at that high rate. That's what patients tell us, it feels like when you're in an episode of PSVT, like they're completely out of control, and there's nothing they can do to make it slow down. This is in part the reason why patients often feel compel to call 911 and go to the emergency department. In this observational study, we found that over 20% of the patients experienced one or more episodes, which required medical intervention, mostly trips to the emergency department for treatment. In addition, patients in the study reported a median frequency of 12 to 15 episodes per year annualized depending upon how long they were in the study. Here, over 1/3 of these annual episodes lasted at least 30 minutes and more than half were recorded by the patient is either moderate or severe intensity. This burden is further exacerbated by the underlying uncertainty of when episodes will start how long they will last, how bad they'll be and will they require medical intervention to stop them. These data are very important because they help us to define the size of the target addressable market of patients that are diagnosed with PSVT. On the right-hand part of this slide, you can see our conclusions from the study. First, we believe that 40% to 60% of patients diagnosed with PSVT have episodes each year that are sufficiently burdensome that they would welcome a therapy like etripamil. And second, these data allow us to estimate the percent of an average patient's episodes each year that are likely to be burdensome enough that they would reach for a product like etripamil, which we believe is 4 to 6x per year. Now let's look at symptoms from the same study. This is also very important because symptoms are the things that patients experience that makes them feel bad during an episode. It's the things that they remember and truly dread and so it's what will make them want to seek treatment. In the totality of the episodes here, you can see almost all episodes are characterized by palpitations and rapid heart rate. About 1/3 include difficulty breathing, about 1/4 dizziness and about 17% chest pain. On average, respondents reported that they experienced about 3 symptoms per episode, but as the patients perceive that the episodes were more and more severe, you can see the number of symptoms that they perceived went from 2 with a mild episode to 6 with a severe episode. The more concerning symptoms, including difficulty breathing, dizziness and chest pain went up significantly from 18% to 80%, for example, between mild-to-severe episodes on the symptom of difficulty breathing. This gives you a sense that patients really do attribute the number of symptoms and the types of symptoms with how bad that episode is. And again, that will strongly correlate with their desire to seek a treatment or perhaps to go to the emergency department. In summary, the data I've shown you on the last few slides give us conviction in the target addressable market for etripamil and likely frequency of use. Specifically, that 40% to 60% of patients with PSVT have sufficient disease burden to want to use a therapy like etripamil. And that on average, and etripamil user will treat 4 to 6 episodes per year with the drug. Another very important aspect that we learned from this study is that a big part of the burden of PSVT is not just the symptoms that patients feel when they're in an episode, but also the fear between episodes. Never knowing when it will happen, along the episode will last and how they're going to manage it or feel. One of the foundational findings about PSVT is that the episodes are highly unpredictable and highly both across the patient population and even within a given patient. This slide taken from a very insightful publication by Kathy Wood at Emory illustrates that living with uncertainty is a huge part of the burden of PSVT. The uncertainty starts when they're not diagnosed quickly, typically taking 2 to 3 years and oftentimes getting a prescription for an anti-anxiety drug or a panic drug because the physician was not able to successfully diagnose PSVT. Even once they're diagnosed, the concern patients feel about symptoms and having to cover them up are feeling embarrassed when they're in an episode because they can't get it to stop or searching for what's causing all of this. All of this suggests to us that a patient will likely want to if they find a treatment that works for them, use it on many of their episodes. We believe that this dealing of empowerment and control over their condition that etripamil could provide will motivate patients to both initially try etripamil and then use it again and again on future episodes. Let's now look at the results from the recently completed RAPID study through the lens of a target product profile, and how we're going to define the value proposition for patients, physicians and payers. Looking at the clinical data then, these are the primary Kaplan-Meier cardiac outcome results from the RAPID study, showing roughly 2/3 of patients converted on etripamil of 30 minutes, which is more than double the number that converted on placebo. That went up to almost 3 quarters in an hour and over 80% at 90 minutes. So a very robust efficacy finding. Also, if you look at the medium time to conversion and the speed of conversion is important messaging to patients and physicians, patients converted more than 3x faster, taking etripamil than placebo. This rapid onset of action leading to a robust resolution of symptoms is key to the attractiveness of this drug. Very importantly for all stakeholders, the 40% difference in ED visits that we saw in the pooled analysis of our studies is very impactful because everyone wants to keep patients out of the emergency department or hospital. Patients certainly don't look forward to going there, spending the time and money and getting adenosine, which is a very uncomfortable experience. We've also consistently seen improvement in symptoms in our clinical program, which is an important part of the profile of etripamil. Importantly, as I mentioned earlier, it's a well-tolerated drug with minimal side effects. In the clinical program, we saw virtually no concerning adverse events. We expect to have labeling that would suggest less than 1% of patients observed any sort of blood pressure or conduction mediated issues in terms of dizziness or anything like that. The majority -- the vast majority of AVs were mild, transient and localized to the administration of the drug through their nose. Now let me give you a little bit of a perspective on how we think about translating some of these perceived benefits of the drug into a value proposition. I'll start with the patients. When we show them a profile of etripamil based on what we saw in the RAPID study, it consistently tell us that the benefit of etripamil to them is the rapid and reliable relief from the symptoms and duration of an episode. With etripamil, they associate a feeling of empowerment and control of their disease, which is something they do not feel currently because there are no viable options where they can count on it, helping them stop their episodes consistently and feel better quickly. In addition, if patients are feeling in control and have something in their pocket that can terminate episodes, they're going to feel more confident to be able to do the things and not be anxious or concerned wondering when the next one will hit them. That will allow them to get back to their lives and pursue more active living. These are the 4 foundational hallmarks of what we think would be fundamental elements of a value proposition for patients. The elements of the value proposition of etripamil for physicians are a little bit different than for patients. As Joe mentioned, the calcium channel blocker mechanism that they understand and have used for over 30 years is foundational to their familiarity with the drug right at approval. The fact that they trust it and that we've demonstrated the safety profile in clinical programs makes them much more likely to prescribe it quickly and to a broader group of patients. They want to prescribe it because they feel like it has a rapid uptake, it's well tolerated and it's reliable in the sense that it helps most patients convert within an hour. They love the idea that it's an at-home sort of an on-demand treatment and that can be used in a number of ways, including as a bridge or alternative tubulation. Lastly, all stakeholders, including physicians really do care about keeping patients out of the emergency department. So these are the 4 foundational elements of the value proposition that we can build now for physicians based on the results we've seen in our clinical program. Finally, let's think about the value proposition of etripamil to payers. Researchers have shown that payers do clearly understand that there is an unmet need here, and that there are no approved therapies for patients with PSVT to use at home once they're in an episode. Here they see the clinical data and they hear from cardiologists that the RAPID study results are clinically meaningful outcomes. And that is important because it means payers are going to perceive that there will be utilization, which means they will need to cover the drug. Payers also clearly care about ED visits. Even if we don't get into a label claim, it gives payers a reason to want to review the drug quickly because of the perception that there could be economics that are favorable for them in terms of reduced emergency department and hospitalization costs. The fact that tripling is not a reformulation of an existing product, but a novel molecule makes it more interesting to them because it means it's not just an incremental innovation, but it's actually a potentially paradigm-changing treatment for their patients. Lastly, I'll make a few comments about payers and what we're thinking about in terms of a market access strategy. We've done interviews now with well over 100 payers, both regional and national, commercial and Medicare. And very consistent that you've heard them say that while they're not currently actively managing PSVT, they understand it. They do ask for education that they haven't had anyone talk to them about this for probably the better part of 30 years. but they pretty quickly understand the burden and intuitively understand the value proposition anchored in reduction in ED visits. From these observations, we understand the importance of educating payers early, even pre-approval with compliant information exchange to help them understand the disease state, the unmet need and the value proposition that etripamil presents. Payers tell us that they don't see PSVT as a heavy -- heavily budget impacting disease in the way that they think about oral anticoagulation or hypercholesterolemia, for example. They tell us that as long as we're not irrational in our pricing strategy, they don't want to actively manage this category, which is good for us in terms of reducing the likelihood of onerous utilization management or tier placement, they would impact that would impact the hassle factor for physician prescribing or the willingness to pay for patients. Secondly and probably equally important is the fact that this is a noncompetitive market, unlike diabetes or the NOACs. Noncompetitive market means there's no one to bid against each other and drive up rebates over time. Now let's go into detail about how we estimate the market size for PSVT. In markets where there are existing therapies or where there's a lot of competitors in many prescriptions that you can track, it's a lot easier to do this. For example, think about diabetes or the novel oral anticoagulant in case of AFib patients or even lipid disease. There's not a lot of debate about how big those markets are. Those are all understood to be big markets because there is many products that have been adopted, there's lots of prescription volume and readily available to the go to assess that. In the case of PSVT, because there has been no innovation for over 30 years, you can't rely on those sources, especially because many of the drugs that are used to treat PSVT currently, ineffective as they are, are generically used to manage other diseases as well from hypertension and heart failure to angina. So you can't go to the prescription data to estimate the market size. I'm going to give you a quick summary here of what we've learned, and then we'll come back and support all of these different points. We've employed a standard approach for this type of incidence prevalence modeling. And I use the concept of an iceberg to help communicate that because it's often used when we think about an epidemiological approach to estimating market size. So first, the patients at the top of this iceberg goes above the water line, what we call our initial target market are those that we've identified with a confirmed diagnosis of PSVT and have sufficient disease burden where they're in the health care system annually, billing claims being treated, whether that's going to the emergency department, filling a prescription, going to their doctors for an appointment or even having an ablation. As I'll show you, we've identified roughly 650,000 patients in any given year, engaging in the U.S. health care system that we have high confidence of diagnosed with PSVT, which we see as our initial target market. But that only represents a small part as the iceberg analogy suggests that the total market. We have identified another 1.4 million patients who are also are diagnosed but are inconsistently engaged with the health care system. We're not showing up in the claims data every year, and it's primarily because they're just engaged. They're not satisfied with existing treatments or some of them might have insufficient disease burden, where they're not having long enough or severe enough episodes where they feel like they needed treatment. Our research suggests that most of these are patients that are just not happy with existing treatments and are sitting at home, topping out episodes because they've been told by their physician that SVT episodes will not kill them and all episodes will eventually stop. So they really shouldn't go to the emergency department unless they've endured an episode for at least an hour. That's at least what physicians tell patients. As you can see, most of this market is underneath the water, accessible to us, but not as readily accessible as the 650,000 that are above the water line. Lastly, I'll show you that there's around 300,000 patients a year that are newly diagnosed or incident patients. On average, taking 2 to 3 years to get a diagnosis from symptom onset to actual diagnosis. Doing the math on that, there's up to 1 million patients in this market that are currently in the process of being diagnosed but not yet even aware that they have PSVT. There are other tactics over the life cycle of the drug, which I'll discuss later, where we could activate some of these patients, help them get diagnosed more quickly and thereby add them to the pool of diagnosed patients available for treatment with the etripamil. The punchline is that there is a large market of over 2 million patients who have been diagnosed with PSVT with more than 30% or 650,000 of them engaging with the health care system each year because their SVT episodes are burdensome enough that they seek treatment. Let me now show you how we got to these numbers. First, we analyze claims data to identify patients from a 9-year period between 2008 and 2016, using the unique ICD-9 code for PSVT, which is 427.0. We then identified how many patients were present in a given year that conform to the rigorous definition of PSVT that you can see at the bottom of the screen. Specifically, patients that present with one or more inpatient codes like an ED visit or hospitalization or 2 or more outpatient codes for PSVT, such as a doctor's visit or a prescription refill. Based on this definition, we found almost 650,000 patients in the index year that met this criteria, which is intended to remove patients who might be miscoded based on only having one outpatient PSVT code in the medical record. In any given year, you can imagine that's how many patients that are seeking care for their PSVT. We then run further and identified in the following or second year, another 417,000 patients who met the criteria for PSVT, but were unique from the patients we identified in year 1. That means these 417,000 patients presenting in the health care system in year 2 did not engage with the health care system in year 1. Along the same lines in year 3, 379,000 unique patients were captured but were not present in years 2 or 1. You can see the pattern here for year 4, another $345,000 showed up in that year, but not in the 3 prior years. By the time you get to year 5, you're down to 312,000 unique patients who showed up in year 5 in these claims data, but not in the previous 4 years. We begin to see how the year 5 number is an approximation for incidents since if you show up in claims data in a year, and you don't have any claims in the previous 4 years, that's a good estimate of a newly diagnosed patient because they are not visible in the health care system for the previous 4 years. You can imagine going on for 5 or 10 or even 15 years with this analysis, but the sample size gets rather small. So this is the data set that we chose, which is pretty standard. You also see over this 5-year analysis that the numbers sort of asymptotically approach around 300,000 patients, which is ultimately perhaps the steady-state estimate of incidents. Since these patients are all unique in all 5 years, you can also add them up, which gives you a point estimate of a 5-year prevalence for diagnosed patients of 2.1 million. The analysis I've just walked you through is the subject of a recent publication in the Journal of Clinical Electrophysiology by group of electrophysiologists at Duke, with experience doing health economic analysis using longitude patient claims data. Their conclusion is that the diagnosed prevalence of PSVT in the U.S. is between 1.3 million and 2.1 million, depending upon how you account for patients who also have atrial fibrillation as a potential comorbidity. If you do a PubMed search on PSVT, you will find 2 additional publications, one from the 1990s called MESA and a more contemporary one called PREEMPT published by Kaiser. While both papers offer valuable demographic and clinical characteristic data on PSVT, they're not very good for predicting prevalence or incidents. This is because their methodology is limited to identifying only patients that present in the acute health care setting in an episode that is actually adjudicated on ECG by cardiologists. Not to say that these aren't validations, but they represent the very tip of the iceberg of patients who make it into the ED or hospital and get their SVT episode captured on ECG. I'll remind you, in the RAPID trial in the placebo group, only 25% of patients actually sought medical intervention for their SVT episode. This means that fully 75% of patients in the study resolved their episodes without seeking medical intervention. So 3/4 of the market, if you use the MESA or PREEMPT methodology is not visible because those patients never saw treatment for their PSVT. Another very important finding for MESA is that -- it is that of the patients in the study that they captured and adjudicated having PSVT, less than 40% actually had a PSVT 427.0 ICD-9 code in their medical record. The other ones that they actually demonstrated adjudicating [indiscernible] SVT had some other codes in the claims data. But that means that the analysis that the Duke physicians did, which are based on PSVT ICD-9 codes, are likely quite understated, potentially missing as many as 2.5x the total number of patients that are in this market. So not only are we confident in our examination of prevalence, but there's potential upside too.

Mr. Lorenz, can you pause there and maybe go back to that previous slide? I have -- following our last KOL call, I had investors ask me about that very point. And I just want to make sure we emphasize it here. So all the work done by the Duke group and published was on the 427.0 code. So in essence and this is important that investors want a confirmation on all of the work that we use in the analysis of our sizing of the market, which gets us to about 2 million patients is done on 427.0, meaning that we're working on the 40% of patients that were identified in MESA, not the 60% that weren't, right? So that's where you get the potential for maybe an underestimate. So I wanted to just emphasize that also because the call came in to make sure people hear that.

No, that's exactly right. And in fact, if you look at the manuscript from MESA or PREEMPT, they actually identified 7 different codes including AFib and other dysrhythmias and tachycardias that are the ones that actually are often used when they don't quite know what the diagnosis is or for other reasons. So you're exactly right. We are probably underestimating the size of this market by using a 2 million number. So let me now come briefly back to the image of the iceberg that describes the prevalence of PSVT to illustrate one additional characteristic to this market that is important to understand. While there are currently 650,000 patients being treated annually for PSVT in the United States, as I've mentioned, many patients by our estimate upwards of 160,000 per year become dissatisfied with currently available treatments and disengage from the market. Etripamil if approved could bring some of these patients back into the market each year either because they heard about it from their physician or because they saw a direct patient advertisement or something that made them curious enough to go to their doctor and ask about it. Either way, over a 5-year period we estimate that the annually treated patient population for PSVT. That part of the market above the water line could grow to over 1 million patients. Not only is this great for patient care, meaning more patients with PSVT satisfied with their treatment, but it also increases the denominator of patients who are more likely to get etripamil. Based on these analysis, we have conviction that at least 2 million patients in the U.S. are diagnosed with PSVT, 650,000 treatment for their episodes each year and 300,000 new patients are added to this population each and every year. So let me now translate all of these insights into how we think about commercializing entripamil to help fill the need for patients with PSVT. Let me come back again to the analogy of the iceberg and the patients that we think are readily accessible in the initial target market compared to those that we think represent opportunities for a future target market or market growth, either bringing them back into the health care system or helping them to get diagnosed more quickly because there's new novel interventions or novel diagnostic tools. The opportunity to go after the initial target market is really one of hyper focusing on those patients that are in the health care system every year, identifying the physicians that are treating them, finding those physicians that are early adopters and targeting them at launch in terms of a go-to-market strategy. We also think it's foundational in any strategy to establish quality reimbursement quickly and make sure there's appropriate copay support so that patients can truly feel comfortable using etripamil on any episode where they feel sufficient burden. As you've heard me say before, this is a patient-driven market. And so it will be very important that patients not only have a good experience with the etripamil, but they have the product support, and it's not difficult to access for them. In order to bring patients that are not annually treated back into the market, we'll do a lot of direct-to-patient work and ensure that we establish expanded access across commercial payers and into Medicare and other channels of reimbursement. Also expanding into primary care from cardiology, which is where we would focus at launch will be important. There's also a market opportunity, although it's probably a little later in the life cycle of the drug, to go into the institutional setting and perhaps using etripamil ahead of adenosine, but perhaps even in the ambulances where adenosine currently is being used. We're not targeting adenosine as an initial opportunity because it's not nearly as big as the retail opportunity that I've described to you, but it is an area that should be part of the life-cycle plan for the drug. Finally, to address and help those patients that are struggling with an unclear diagnosis of their condition, we would invest in deliberate market development, leveraging ongoing advances in digital diagnostics, whether it's algorithms to help diagnose PSVT or just helping patients to capture rhythms through a Fitbit or an iWatch and then taking that data to the cardiologist. This would increase the rates of diagnosis and therefore, help bring patients into the incident pool and get treated with etripamil. Additionally, doing some DTC work down the life cycle of the product and help patients know that there are new therapeutic interventions and that -- if they're feeling certain kinds of symptoms that they perhaps should go back to their physician and get diagnosed. One of the other foundational insights for understanding how to commercialize etripamil into this market is that it's a very focused market. I mentioned earlier on that, that we would target cardiology at launch, and that's because most patients who have PSVT are managed by that specialty. We've seen this in multiple rounds of market research. 60% of these patients are managed by clinical cardiology, about 10% by electrophysiology and the remaining 30% by primary care. That gives us a core cardiology market to go after, whereby we could deploy 150 to 200 reps and target 60% to 70% of the revenue opportunity for etripamil in an efficient manner. It also gives us an important use case for electrophysiologists, who are not the bulk of the volume in this market, but they certainly are influential. Having them use etripamil as a bridge to an ablation or perhaps as an alternative to an ablation for patients who refuse the procedure will give them critical experience with the drug and thereby enable them to become advocates over time. Another important consideration is that the physicians we would need to target etripamil the largely overlap those at existing pharmaceutical companies target for their approved cardiovascular drugs. We estimate the overlap to be anywhere from 50% to 60% with PCSK9 drugs or heart failure drugs to 100% with novel all anticoagulant. This is important because it means that if we eventually want to find a partner to maximize the U.S. opportunity with etripamil, we should not have a difficult time doing that. Let's talk a little bit about how physicians view at etripamil based on the results we had from the RAPID study. Specifically, how would these physicians use it and how are they adopt? What this slide shows is from a quantitative study of around 250 cardiologists we completed a few years ago. This stacked bar chart shows how physicians say they currently manage patients with PSVT. Starting from the bottom with the 19% that they prescribe pill in pocket to, not because it's effective or quick, but because it's now unfortunately, the only outpatient drug option. Overall, about 40% of the market currently is getting pill in pocket and about half of them are getting it in combination with some sort of prophylaxis. Another 40% of the market are getting chronic medication, but not being prescribed pill in pocket. So fully 80% of the patients are currently being treated in some shape or form with prescriptions and roughly 20% are not being treated at all. We then ask physicians based on the results that we received in the RAPID study, how would you now prescribe. And that's what you see on the right-hand side of this slide. You can see from this that physicians said, for the patients that I treat as a physician previously prescribed pill in pocket to roughly 39% and that's going to be only 14% once etripamil comes to market. For the patients that are being chronically prophylaxed with beta blockers or calcium channel blockers, but not getting a pill-in-pocket prescription, that's going to go down to 24% or again, roughly half. Even the patients that are receiving no treatment, roughly half of them are going to continue to remain not treated probably because they have relatively mild disease burden and short episodes. The punchline is that overall, 53% of the market is going to receive a prescription for etripamil, either alone or in combination with chronic medications. When at the type of patients in whom physicians would likely want to try etripamil, they respond with 3 basic archetypes. Patients who are newly diagnosed with PSVT, patients with a history of emergency department visits and patients who are dissatisfied with their current treatments for PSVT. Let me bring all these days together and show you how we assess the full U.S. market opportunity for etripamil PSVT. I've shown you that 2 million patients is the diagnosed prevalence and growing this by about 1% a year to 2030, which we estimate as the peak year, gives you 2.6 million patients. I showed you the longitudinal observational study we did that clearly identified that 40% to 60% of diagnosed patients have sufficient burden where they would want to seek treatment based on both the duration and severity of symptoms experienced. That gives us a target addressable market of 1 million to 1.6 million patients. I just showed the stated adoption from physicians who were shown exactly the profile of etripamil that we got in the RAPID study, and from that, we estimate a 50% stated adoption at peak, which gets you to about 0.5 million to 800,000 patients treated. From the same observational study of the 12 to 15 median episodes that patients report as experiencing, we think about 5 of those 12 or 15 are going to have sufficient burden, but they're going to want to use a product like etripamil. Therefore, we estimate around 5 episodes treated per year for a patient that is prescribed etripamil. That mathematically gets you to 2.5 million to 4 million episodes treated per year at peak and dollarizing that assuming a price of $500 to $1,000 per prescription for episode treated and a presumed annual frequencies of 4 times a year will get you to a peak net revenue of over $2 billion in the United States. We've taken you through a lot of information here and hopefully have learned something about how we think about the commercial opportunity, how we model it, and how we might go to market and be able to realize that opportunity. I want to leave you with these 5 key takeaways as we finish up our time together. First, PSVT represents a large, underserved and actionable population with a clear place to start engaging and with room to grow over time. Second, most patients in this market at one point or other experience episodes or multiple episodes that would benefit from etripamil. There are certainly types of patients that physicians can readily identify, which we would target following approval as well as target physicians that are more likely to prescribe etripamil quickly. All of this is enabled by the RAPID study results, which contributes to a very attractive product profile and value propositions that are appealing to physicians and patients without overly burdening payers. The market dynamics allow for both early success without overburdening our P&L with excessive operating expenses an opportunity to expand as we establish coverage and broaden into other types of physician audiences. Finally, over the last 10 or more years, Milestone has built a unique and foundational market understanding and has the commercialization expertise to implement and if approved, to leverage this understanding to successfully launch etripamil in the U.S. Thanks again for your attention today. With that, let's open the call for questions. Operator?

[Operator Instructions] The first question comes from Chris Howerton with Jefferies.

I guess 2 for me. One would be maybe just kind of a curiosity, Lorenz, I noticed that when you were presenting the physician perception survey that was after the initial data cut but not the most recent or the footnote was wrong. So I guess I was just curious how you're thinking about the 2 doses and how that could affect physician's perception. And then the second question I have is around kind of the commercial rollout from a strategic perspective. How is it that you're thinking about the different segmentations of the population, building up a commercial sales team and winning things like cash needs and potential business development.

Lorenz, I think that's ideal for you to take right off the bat with regard to the profile...

Yes. No worries. And Chris, thanks so much for the question and for calling in. So the first, I think you were referring to the physician quant research show toward the end there, where we showed the initial current market and then how they would prescribe stated adoption once etripamil is launched. Is that correct? That's the...

Yes. Yes. Just because on the footnote, it said it was conducted June to September of 2020. So I just wanted to know if that was wrong or yes, anyway go ahead.

No, no, it's actually not wrong. In fact, right after we conceive the rapid study and we're getting at to launch it, we did market research with a bunch of different profiles for RAPID. On the lower end, we assume just 301 life results and even we had a scenario below that, and then we incrementally increased efficacy of conversions of 30 minutes and other variables to try to create scenarios for potential outcomes from RAPID. And it was literally 2 years before we reported it out. As it turns out, the profile we actually got in the RAPID study was exactly the high end of those different scenarios. So we have come up with a scenario, frankly, that we thought was a stretch but we wanted to have one that was on the high side and that was ironically exactly what we got in the study. So I'm able to report with confidence literally right as we got the results that we know what physicians are going to think about the product because it includes the 2-dose regimen. It includes the exact results of rapid to the decimal point that we actually achieved in the studies. Hopefully, that clarifies that question. On the...

Let me start the second -- so the second question, Chris, you have 3 kind of sub parts. One is differentiation with regards to targeting, and how we would approach that. Two part of that, building the sales team around that. And three, all in the context of business development. Maybe I'll start with the third and then shift it over to Lorenz for the first 2 on targeting and building of a team over time. So we've been public, obviously, that we are going to focus on the U.S. We've been active interacting with other parties for ex U.S. rights. We've already licensed China and are expecting to be speaking to people about Europe, for example, and many of those conversations do include wanting to have discussions about the U.S., obviously, we entertain those discussions. There is opportunities over the long haul to approach partners about expanding out maybe into primary care and getting to the full potential of this product. So it's a unique asset in that it doesn't necessarily require a partnership for the U.S. opportunity, but has nice components to it, where we feel we could dial in partnerships to get to the full opportunity. And that's whether it's with large pharma partners or even players on the diagnostics side, who you may be aware Chris, are actively coming with new tools and wearables, specifically around cardiovascular and arrhythmias. So that's the part on the BD side, but I'll turn it over to Lorenz to talk about segmentation and approach and sales build.

Yes. It's a really great question, Chris, and Thanks, Joe. So the way to think about this, and you've heard me say this in the past is we think the majority of this market is managed by cardiology and in fact, there's probably around 20,000 to 25,000 targets, adding in the most important cardiologists, the electrophysiologists and some small amount of primary care that look and behave like cardiology based on their prescribing of cardiovascular drugs. So ultimately, you'd imagine trying to get to 60% to 70% of the revenue opportunity, you need 150 to 200 reps, they would target those 25,000 doctors. And that's ultimately where I think we'll get to. The question really is, when you get approved and you're at launch and you haven't optimized the market conditions for uptake. In other words, you haven't established broad access perhaps you haven't fully established the relationships with doctors and post-COVID, some of the access challenges there. So there's more and more literature and case studies on doing a sort of a staged launch. And so I'm not saying necessarily what we're going to do, but it is something we're strongly evaluating and it would look something like this. You can imagine that I could go into the kind of data you can get now, and we've done this and identified of those 25,000 doctors, a subset of, say, 10,000 to 15,000 that have certain characteristics that make them very attractive to target initially. For example, they write a lot of AV nodal blocking or antiarrhythmic drugs. They are early adopters. They see a lot of patients with PSVT, and we can literally do that now from IQVIA or other data sources, matching up prescriptions with actual patients. And importantly, also perhaps that they have a disproportionate number of younger patients since commercial coverage will likely precede Medicare coverage. So by doing all that, I'm pretty confident that we're going to be able to identify a subset of physicians that would represent the best targets have launched and that would, in turn, allow us to deploy perhaps less than 150 to 200 reps right at approval, perhaps even something in the range of 80 to 120, targeting those 10,000 to 15,000 doctors be able to demonstrate utilization while we're expanding access and that would make the whole launch process a lot more efficient from a cash perspective. So that's a little bit of how I think about a strategy potentially for commercializing in an efficient manner while still achieving those goals we would set for ourselves at launch.

Okay. No, that's also I really appreciate it. I guess. I mean it's got me to thinking, Lorenz, what is the opportunity, I think, in terms of using digital approaches. I think you kind of mentioned a little bit in terms of data. Just I cover another company that's launching a drug right now and using a CRM system from Veeva. And so I guess I'm just curious what is your view on those kind of digital approaches, if you can comment on that at all?

I'd love to, and thanks for the question. I think there I use the word foundational an awful lot in his presentation as to listening to myself, but it is literally the core of how you go to market nowadays, meaning certainly, you have to deploy reps. There's no replacement yet for a face-to-face interaction, but so much of modern-day marketing now, whether it's to physicians or patients is related with sort of CRM tools, patient engagement tools, physician engagement tools, digital marketing which sort of provides that omni-channel that surround sound to the sales reps detailing the doctor. And so we are currently exploring with physicians, all the different types of ways that we can engage with them digitally that would include everything from a sales rep that calls on doctors also makes digital calls through Zoom or other. And most of the data I've seen suggest that especially within cardiology, roughly 1/3 of calls currently made on cardiologists are done through Zoom and other techniques and 2/3 are in cursive still as well as CRM tools to engage and figure out which of the sales messages we're delivering are the most impactful on positions, and that's available through a system like Veeva that you suggested. And on the patient side, also having an engagement tool where we would support prescriptions of etripamil and the patient experience with optimal patient support, where we would follow up with text messaging or other tools to ensure that they're having a good experience with the drug. And they perhaps remind them to refill and all that stuff is available not completely off the shelf, but pretty darn close nowadays to make it accessible for a company like us launching our first drug to be able to do. So I think this is essential to a successful launch. It's something we will be doing extensively as we get into the launch and beyond.

Next question comes from Ritu Baral with Cowen.

I wanted to ask about the low-hanging fruit, the population that may sort of merely be the bridge 2 ablation population. As you've done your market research on these patients, how long to ablation after diagnosis do they tend to wait or a corollary of that might be, how long do these patients stay under the care of that cardiologist before moving on to the electrophysiologist. And then I have a follow-up.

Sure. I can take that. So yes, certainly, the bridge 2 ablation is an interesting use case, as I mentioned during the presentation, because it provides the electrophysiologist, which is such an important influencer in the antiarrhythmic market, with the opportunity to actually use the drug, see the experience, talk to patients, and that is just very important for them to become advocates. Within the realm of where they're -- recognize that represents less than 10% of the total opportunity. But within that 10%, it's important. And specifically in the United States to answer your question, Ritu, we have talked to, as you mentioned, a lot of electrophysiologists. And you can imagine in the United States, it takes anywhere from a couple of weeks to a month typically from the time that a physician decides to ablation to actually schedule it. So the use case is about the rate where they would prescribe a prescription for -- when they're coming off their chronic meds to be able to make sure that they're in a good -- being well managed before they have that ablation. Within the total population, to answer your first question, we see that for the 15% or so of patients that actually get an ablation, the majority of those get it early, meaning in their year of diagnosis just about. So you can imagine, I don't remember the exact numbers, but it's roughly 60% or 70% of ablations that happen in the year of diagnosis. So almost by definition, that's a younger population. And then the remaining, call it, 30% or 40% sort of get it 6 to 7 years later. So it's sort of a bimodal distribution of either Okay, I get what I have, I want it to go away, I'm a young person, I'm active, I want this to stop. I'm going to have an ablation or -- and this is the majority of the patients, I'm just not ready for this. But eventually, the burden becomes enough and even 6 or 7 years down the road, they'll go back to the electrophysiologist, say, I really had enough now. It's either gotten worse or whatever, and I want to have that ablation. But it's definitely that split of 70-30 for a younger [indiscernible].

Got it.

You have a follow-up?

Yes. And it's a payer-related follow-up. As you've had your conversations with payers, have you been able to present to them a sort of cost savings calculus in so far as the percentage of reduction will either clarify for them their sort of personal cost of emergency department visits related to PSVT and the reduction based off of the RAPID data that, that could mean for them?

Yes. So where we are in our engagement with payers is more -- at this stage of the game prior to RAPID data was more on the disease state, understanding the burden, understanding the kinds of controls they're using, et cetera. So we haven't actually, in all Canada, in which you've done a lot of work with specifically around the impact of the RAPID data as it relates to budget impact modeling or global effectiveness and that sort of stuff. All that work starts in earnest now. We're still solid 1.5 year 2, 2.5 years from approval. So now is the right time to put together the dossier with the data and start to do that work. Having said that, a year ago, we built a budget impact model. So we've done all the computational work to actually have a working model that has placeholders for a lot of these assumptions that will now populate and be able to use that. So we're in a position to pretty quickly mobilize do that analysis and build that tool so that when we do hire our account managers later next year, and have them start to engage with payers, they'll have real data, real evidence real tools to be able to help payers understand the potential cost offsets that the ED reductions might represent to them.

The next question comes from Edward Tenthoff with Piper Sandler.

I love [indiscernible] add on a model like this. So this has been fun. One just kind of housekeeping question. What does the assumed growth rate that you're using for the PSVT population? And then I think maybe more relevant, and we've talked about this a little bit, but how would you actually package and sort of, I guess, group different nasal sprays. So here's kind of the heart of where I'm going to get. So like would they have -- would they get 2 prescriptions at one just in case episode was so great that they needed to use it twice? Or would they have maybe a 5-pack or a 10-pack, such that they have one in the office, one at home, one in the car. I'm trying to get a sense for maybe how the ultimately package is presented to patients. And is that something that actually gets discussed with the FDA.

And let me answer the first one on the growth rates for the PSVT population, I'll give you some numbers to tell you how we model this. So you heard me say we see the PSVT population is growing about 1% per year roughly. And the majority of that is just organic growth, meaning we have our -- a group that's in the prevalent population. We're adding about 300,000, 310,000 from the data I showed per year is newly diagnosed. And then we're losing patients. You've heard me in the past say, roughly 80,000 a year getting ablation. The majority of those are successful, and therefore, they're no longer having PSVT, if you will. We calculate about 60,000 a year actually die because half of our population is elderly and they not dying from PSVT, but they are dying. And then you also heard me during the presentation refer to the 150,000 patients a year that are disengaging because they're not happy with the existing treatment options. If you do the math on all of that, you're basically putting about 10,000 or 15,000 more patients into the market than you're taking out, and that calculates to about a 1% growth. We'd also think a little bit as we engage with the market, we also estimate a little bit of growth through improvement in diagnostics, and that will bring more new patients in, but that's a very small part of that 1% because that requires a significant effort that we haven't yet completely committed to.

And with the packaging, maybe compared to launch versus over time?

Yes, exactly. So I couldn't have answered that question right before the RAPID results because we weren't really sure whether we would go to market with a single dose or a 2-dose or repeat dose regimen, clearly from the RAPID results, we're confident that we will submit a package that will advocate for a 2-dose regimen. So at a minimum, we want any patient that has PSVT and get a prescription to be given a 2 dose and to have -- and we'll package it in a plastic container likely which will allow them to have in a prescription 2 doses available. Not all of them will use both doses on every episode, but they'll always have it available. And presumably, even if they don't use both doses on an episode, they'll -- we'll encourage them to go and get another prescription. To answer your question specifically, at launch, we would expect to have a prescription be for a single dose -- repeat dose regimen, so 2 doses in a package to treat a single episode. That's partly because when we launch physicians will likely want to prescribe it for their patients and then have them come back to them before they refill it just to make sure they tolerate it and everything worked out. So that's just a logical way to package it. Also from a pricing standpoint, we have to really think through, if you put more than a single dosing regimen into a prescription that will drive up the cost and that could potentially have some implications for how payers would see covering it or are the kinds of utilization management or tiered structure they put us into. So long story short will start at a single episode treated equal to prescription. And then I suspect over time, physicians would start to add more refills, which means the patient could get electronically refilled without going back to the doctor, and I do see eventually down the road that we might package it as 2 or 5 episode equivalent treatment into a single prescription. But at launch, we would not plan on doing that.

The next question comes from Patrick Trucchio with H.C. Wainwright.

Just a few follow-up questions. Just the first is on Slides 24 and 27, where you show the potential addressable patient population I'm wondering what it would take to convert the diagnosed, not annually treated patients to diagnose an annually treated patients, specifically from a sales force marketing KOL outreach perspective, such that you can increase from that 650,000 treated patients to the 1 million treated patients that you know is possible. And do you have an idea of what annual rate you believe that conversion could occur following the launch -- potential launch?

Yes. Thanks, Patrick. So the way to think about this is that you -- the easiest ones to get to the patients that are most actionable or the ones that are being -- or already in the health care system because we don't have to drive them into the health care system, we just have to get in front of their physician before they're treated or we have to get messages to the patient where they're going back to a visit anywhere they can easily get a script. So that's the top of that pyramid. The ones that are below the waterline in the slides you referenced are the ones that are diagnosed, and they're being treated to be clear, they're not completely lost to follow up, but they're not being consistently treated. So the extra energy you have to put in, in terms of tactics is to get awareness of those patients that, frankly, aren't planning in the upcoming year to go see their doctor talk about PSVT to have them take that step. So that's sort of a little bit in part to the previous question from Ted, to think about the kind of tactics where we do direct-to-patient marketing. Now this is not to scare anyone away and say it's direct-to-consumer, which I think of STV. I'm not suggesting that at launch at all. But there's plenty of digitally enabled direct-to-patient tactics that you can get messages out through social media, through search engine optimization, through websites, where they can become aware when they normally wouldn't have gone back for treatment in the next year, which is the population you're talking about, to drive them back to see their doctor and ask, "hey, doc, I heard there might be something new for my PSVT." It's gotten a little worse, I'm having longer episodes, what is it? That's that patient, and that's that growth that I suggested that goes from 650,000 perhaps now we're in a launch year, up to $1 million. And I'm embarrass to say, Patrick, I haven't done a calculated the CAGR, but literally, what I'm suggesting to you is that we think we can drive that market from 650,000 to 1 million over the course of 5 years. And I think that's somewhere between a 5% and 10% CAGR, but don't hold me to that.

Yes. That's helpful. And then can you talk more about the diagnostic tools? What can you do on that front to expand the number of patients diagnosed in that 600,000 to 900,000 bucket of undiagnosed patients?

Yes. So there's a couple of broad areas, and I mean, there's a ton of different things you could do here, Patrick. But the main ones we think about are, can we leverage existing technology, so the devices that patients already have, whether it's on their wrist or whether they purchase a live or they'd be open to purchasing one of those on Amazon or whatever, so that they can capture the rhythm that they're feeling when they're in an episode that they don't yet know they have PSVT you literally only need to capture 30 seconds of a single lead ECG, which is available on -- I'm wearing a Fitbit right now and it has an ECG, if I hold the bezel for 30 seconds, I can capture a rhythm. That could be digitized sent to my doctor and that doctor, if it's Dr. Bharucha for example, sitting here with me, he could look at that and diagnose that as PSVT if in fact that's what's happening to me. So one angle is just to make patients aware that there are these tools, whether they already have them or that they need to spend $50 or $100 buying one to be able to capture that rhythm. The other part of this that we're excited about is that there are more and more companies evolving that are developing FDA-approved algorithms to actually diagnose "PSVT." You've seen a lot of activity recently in the AFib space where iWatch and others and Apple are looking at to be able to do that. We believe, and in fact, we've identified some companies that actually have already approved algorithms for a number of different SVTs, including PSVT, and we think there's some investments we can make to explore that to see if we could ultimately get an algorithm that could be licensed to a bunch of different device manufacturers, to be able to help patients more quickly get to that diagnosis. And those are just 2 are probably a half dozen we could come up with that will be prudent investments to make to over time, shorten that period of diagnosis, alleviate that anxiety from the patient and then ultimately get more patients on etripamil.

And Patrick, if I could add to that. The other kind of obvious area that I think will evolve over the next few years is there are these device/wearable players who are out there now posting the market, advertising for their wares, I think of a live core as being on TV and selling their product on Amazon. And they need a reason to use that product. And our alignment is great here. We have the reason as to why people may want to know if they're an in fact tachycardia or not and specifically in PSVT. So we see that as an opportunity to engage these types of players and collaborate with them. We're thinking a little bit more after we get the approval, but it's on our radar screen.

And then maybe just one last question, just a follow-up on Slide 32, which outlined the peak potential revenues per year of more than $2 billion. I'm wondering what would have to happen prior to and during the initial stages of the launch that would give confidence that this is, in fact, the trajectory of etripamil. And what are some of the things that you're aware of that can go wrong during these early stages of the launch that you plan for now to avoid that scenario?

Yes. Great question. So you heard me in a previous answer alluded to this idea of maybe a stage launch where we target a certain group of physicians with a smaller number of reps. And that would not to be clear, that resourcing would not put us on the -- without -- in and of itself allow us to get $2 billion in peak net sales, but it could put us on a trajectory to that point. The question is to your very good question is how do we know if we're on that trajectory. And the way we would set that up is we would identify that group of physicians, how much of the market they represent. It's a subset of cardiology, you heard me say. And what are the appropriate KPIs or performance metrics that we would expect out of those physicians in the launch year or 2, consistent with awareness about what level of coverage existed and patient support and all that programs that we do as well as all the DTP work to get patients into physicians to either get diagnosed or to become aware of etripamil. And all of that together then would -- if we could define those KPIs and do that in a launch year or 2, and say, this would put us on a trajectory to a certain amount of revenue, but you can multiply that by 2 or 3 or 4 or 5 or whatever number because we're only technically promoting to a subset of the overall market, that would give me confidence that I'm on a path that if I then invest more resources at a certain point in the launch, perhaps once we have really broad coverage and then again expand as cardiology is adopting perhaps into primary care, those additional resources plus investments in diagnostics, plus eventually probably direct-to-consumer TV type work, all of that significant investment would ultimately get us to that -- confidently to that $2 billion in peak net sales. And your last question was what go wrong, which is -- sorry, which is a very important question. And there, I think it's actually in the same answer I just gave, which is you've got to really think about who you're targeting at launch, what are the critical KPIs you need to measure, what's the performance you expect out of those targets, whether they are patients or physicians and being able to track and measure those accurately. So you've got to have a robust data strategy. You've got to be able to get those data. You've got to be able to analyze them, you got to be able to report them frequently enough so that people can track with you as to how you're performing to put you on a path with a series of inflections over time as you put more resources in. So the way you get it wrong is if you don't make the investments in infrastructure data strategy, analytics, so that you don't know what's going on in your launch or you had not tracking the right metrics or you don't even have data to track those metrics and report out on them. I think that's a pretty quick recipe for disaster. And that's what some of these white papers that are coming out now about stage launches strongly advocate for repeatedly, which is to make that investment early on, on which to reassure you, we are, of course, doing.

The next questioner is Rohan Mathur with Oppenheimer.

This is Rohan. I'm speaking on behalf of Leland Gershell at Oppenheimer. I really appreciate this event you guys did and the work Milestone has done to provide the stuff of detail on the commercial landscape for etripamil. I just have 2 questions, if you don't mind. So for one, for some of the patients considered to be underwater in the model, that you had given? And they're not really approaching treatment methods or using them on a regular basis? Will there be some form of containing from the company following regulatory approval, to increase awareness among those patients even physicians we can pick up on patients not attempting to treat these episodes. And additionally, could you maybe go into some of the incentives for cardiologists to prescribe the etripamil for their patients given that there isn't as much of a financial incentive, maybe doctors are more hesitant to have patients self-administered the medication during an episode of PSVT? And do they see -- so the potential liability for their practices? And would they prefer that this is maybe received with some form of medical supervision in the ER?

Thanks, Rohan. I think I'll give Lorenz a chance here to think about those questions. But I just want to just reemphasize one of the things about the 1.4 million and give a general comment before you get some specifics as to how we would move them above the waterline quicker. But over the course of time, over the course of 5 years, they will naturally be coming into the system at some point in time. So while they're under the waterline in any 1 year per se, over a 3-, 4-, 5-year period of time, they'll be seen in the system. Obviously, our goal is to bring them to the system sooner. And one of the things of just simply having a new intervention come to the market, this is often -- there are other models of this where a new intervention comes and then the market wakes up because it's been kind of dormant and ready for a new opportunity, which we believe we have that dynamic here. So one point is that just bringing a drug to the market will bring some of those people above the water line. sooner than they normally would be. But I think Lorenz could maybe speak to some of the specific items before we go into the view of the cardiologists and EDs versus ClinCards.

Actually, I think of it almost the opposite way, Rohan, is I'm so encouraged that there's a big chunk of this market that I don't have to energize to get into health care system because they're already there. So imagine a scenario where we're going into PSVT, we're launching, and the entire population is disengaged and you have to drive them back into the market to get a single prescription. So I don't focus as much at launch on the people that are underwater because as Joe said, in the year 2 or 3 or 4, they are eventually inevitably going to come back in. But I focus my energies to answer a little bit of the previous question about how are you successful at launch. To be able to get to these patients that are already in the health care system that are motivated. They have enough burden because they're literally taking the time to get into the health care system and to receive treatment. I think that's the low-hanging fruit, that will allow us to be successful quickly. And there will be some spillover, even though we're really trying to hyperfocus and target on a certain audience by -- almost by definition, we're going to -- some of those messages through digital strategies and social media, we'll get to other patients and get to other physicians, and that will sort of start to bring some of the market together. So I don't worry about that group as -- and the rate at which we take patients from being not annually treated to annually treated, to me is not as a terminant of our success at launch, but it does provide a lot of opportunity for growth 3, 4, 5 years into a launch. And then maybe just to transition to the last question because I think this is -- I didn't emphasize this as much during the formal presentation. So Rohan, I appreciate you're asking. One of the clear things we see from physicians is a very low bar to describing etripamil for 2 main reasons. Even though this is not a life-threatening disease, physicians really do care about their patients and they're frustrated for 30 years that they haven't been able to give them something that's effective that allows them to manage the disease at home. And they haven't been able to do that because the existing treatments, whether they're on or off label, are either ineffective, they take too long to work or there's potentially some concerns about safety, especially with like antiarrhythmic drugs like Flecainide. And so physicians actually knowing [indiscernible] to calcium channel blocker, a mechanism like known for 30 years, knowing it's safe from the data that we hopefully would bring to market if we're approved by the FDA and knowing that all that is going to make them -- basically want to give this to just about anyone who would have it and who they perceive as having sufficient burden, obviously, not with the contraindicated patients but for most patients, and that's really attractive to them. So we really don't see them as needing a whole lot of motivation, and they tell us, we don't need a lot of motivation to write this for the majority of our patients.

And Rohan, I think underlying one of your questions was maybe a difference between clinical cardiology and electrophysiology when you mentioned financial incentives. We are aware that electrophysiologists many of them largely do ablations and only do ablations. They don't necessarily manage patients outside of that. And there are electrophysiologists who believe that ablation is the best answer for everyone. We think actually there will be more inflations as we bring awareness to PSVT likely. But the fundamental benefit we have is that even those patients, I believe ablation is the answer, they have enough patients typically 10% or 20% of those patients that won't want to be ablated or I want to wait for an ablation and just thinking about it. And even there, the ability to utilize etripamil to help them keep those patients in their referral pattern, get a good experience for etripamil. We feel that's a great benefit for us to engage with electrophysiologists and help overall support the drug to really the larger population of physicians, which are clinical cardiologists who manage the vast majority of these patients.

This concludes our question-and-answer session. I would like to turn the conference back over to Joe Oliveto for any closing remarks.

All right. Well, thank you, operator. And of course, thank you all for the attention today. Thank you for our analysts for their questions. And we look forward to seeing you in the next upcoming investor conference. Take care.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.