Afternoon, everyone. Welcome to the Jefferies Healthcare Conference. My name is Anthea Li with the research team here at Jefferies. We're great to have Milestone Pharmaceuticals here with us. We have Amit Hasija, CFO, as well as Lorenz Muller, CCO. I'll leave it to you guys for a presentation on Milestone.
Great. Thank you, Anthea. Thank you to our colleagues at Jefferies for having us today. I want to welcome all of you to the investor presentation. As Anthea says, I'm the CFO. My name's Amit Hasija . I'm joined by Lorenz Muller, our CCO, our Chief Commercial Officer. For those of you who are not familiar with the Milestone story, we are developing a drug called CARDAMYST, and we're currently in the NDA review process. Today, we'll provide a little bit of an update on the application. We'll give you an overview of the drug and also some of the future indications and some of the benefit that we hope to bring to patients suffering from arrhythmias. On this first slide, you'll see a quick disclaimer. A lot of this is on our website, so if you want to read it more fully there, you can.
If you want to go to the next slide. Forward-looking statements. Again, a lot of words on this page that you can review at your leisure on our website. But let me kick it off here with an overview of Milestone. You'll see we're working on two indications. The first indication acronym is PSVT. That's Paroxysmal Supraventricular Tachycardia. It's a mouthful, but it's an arrhythmia that we've been working on. The second one that you'll see there is for atrial fibrillation with rapid ventricular rate. That's the RVR that you see. We did and have been in the NDA review process. We received a CRL on our PDUFA date, which you can see indicated there. We've also asked for a Type A meeting with the FDA to kind of follow up on that CRL.
In the next slide, I'll go through some details there, but just to give you a quick overview. Our PDUFA date originally was in March, and we were ready for promotional launch. We remain ready. As we get more information on this Type A meeting, we will pivot to the next step. You can see atrial fibrillation there. We had a phenomenal phase two data set. We were ready to start a phase three at the appropriate time. To be frank, right now, we are focused on trying to get the approval for PSVT, and that'll be our first effort here. You can see on the bottom of the page there, we have extended our patent estate out to 2042. We have a full estate, which includes composition of matter as well as formulation patents, which now goes out to that date.
We have a royalty payment, $75 million, which is due to the company upon approval from one of our investors. We can always go into that detail a little bit later. On the CRL itself, our original PDUFA date was March 27th. One of the silver linings here was no clinical issues came up. Safety and efficacy were not issues brought up in that CRL. We feel good about that because when the FDA issues these complete response letters, they are complete. They have reviewed the entire package. There were two issues related to CMC, and we have given details over time on these. They are listed here. One of those issues has to do with nitrosamine impurities, which has been an evolving piece of guidance from the FDA for some time now.
The second piece of information that was looked for was around an inspection of a lab facility. We had a change in ownership during the NDA review process, and that does trigger a pre-approval inspection. We believe that there is a simple and straightforward way to deal with this, and we will hopefully be able to clarify that with the FDA at the Type A meeting. You will see at the bottom there, anticipated next steps. We had requested a Type A meeting on May 14th. Those are usually done within 30 days. We are imminently going to hear back and have that conversation and hopefully be able to update the market soon on what the next step is.
Typically, what would happen next after you're able to kind of pull your package together for NDA resubmission, you would submit that package, and then 30 days later, you would hear whether that's accepted. There are two potential classifications that we'd learn of at that point. One would be a class two review, which would effectively be a six-month review cycle from the time that we submitted the NDA. The other is class one, which is usually around two months. We'll learn that shortly after we submit that NDA. I'll take a step back here for those of you who have been following the story closely. Again, you see the two arrhythmias that we're working on, PSVT and AFib, on this slide.
PSVT is a regular rate, but it can be characterized by very high heart rates, episodes or attacks of high heart rates going up to 250 beats per minute. On the right side, you see a quick pictogram of just what that looks like. There are two types of PSVT, and you'll see the circles there with the arrows, one around the AV node and one around one of the ventricles. These are indicating additional electrically conductive tissue. You end up with a doubling up of the signal from the atria down to the ventricles due to that extra circuitry, call it. Those can be either freezed or burned with a catheter ablation. There is a surgery available to it. Many patients do not elect to have that, and we'll talk about that further. For atrial fibrillation, a little bit different.
Atrial fibrillation is an irregular heart rate. When patients have episodes of rapid ventricular rate, they tend not to be as high as PSVT, but they're still high and uncomfortable. The symptoms are very similar. You can see a list of the symptoms at the bottom of the page, but patients do feel like they're running a marathon when these episodes happen. They have palpitations, shortness of breath, lightheadedness, oftentimes feeling like after they resolve, they're fatigued and feel like they have been running on a treadmill for some period of time. These are quite debilitating. Most patients can't do daily activities while they're happening. There are some treatments for this. You can see both chronic and preventative treatments on the left-hand side and the right, the acute treatments that are possible. From a chronic perspective, patients are sometimes prescribed oral beta-blockers or calcium channel blockers.
Chronically, these are meant to suppress episodes. If a patient is having dozens of episodes a year, these will reduce that number, that burden on the patient. There is not a lot of data around how effective these are, and they do come with side effects. Oftentimes, younger patients would elect to or try to avoid not having some of these additional drugs. The second chronic or preventative treatment is to have a catheter ablation. Very effective for PSVT. You can burn, as I said, or freeze that additional electrically conductive tissue. Some patients it does not work for. Some patients elect not to have it because it is heart surgery. On the right side, you will see the acute therapeutic options. You can take a calcium channel or beta-blocker, not just chronically, but also to alleviate a particular episode.
Not a lot of data on whether that works. It is oral, so it takes time regardless of whether it works. On the right-hand side there, you'll see some patients just can't wait these out. They're so uncomfortable, they say that they need to go to the emergency department where they're given an IV bolus of something called adenosine, which will stop their heart and then restart it at sinus rhythm. Or they'll be given something like verapamil, which is a calcium channel blocker in kind of IV form. That oftentimes can solve the issue. The third option is to give them cardioversion, electrical cardioversion, DC paddles. Many patients have attacks despite these chronic therapies, despite the preventative therapies, and are forced into the acute therapeutic area, which is where etripamil comes in.
On this slide, you'll see a little bit of the characterization of the disease. I would say that it is a chronic condition. If you have this condition, it happens from time to time. You cannot predict when. You cannot predict how long they will last. It's often anxiety-provoking. Patients feel like they need to manage their life around the disease. They may make changes in how they travel. They may not travel at all. Imagine having something like a 250 or 200 beat per minute rapid rate on a train, on a plane, while they're driving. People really change the way that they interact with society and how they have these kind of public interactions. We've seen that with the patients that we deal with.
You do see there a list of the patients, the types of interventions they seek out, but greater than 500,000 patients every year are looking for some kind of treatment for this. And some of them elect just not to get anything as a result because there are not adequate treatments out there. There are about 2 million patients in the United States that are costing the healthcare system about $5 billion annually, whether it is in the form of some intervention or hospital visits. You will see up there on the upper left that about almost 500,000 patients are visiting the emergency department every year. And 1/4 of those on the upper right are ending up in patient admissions. So they are going into the hospital and being observed for some period of time.
On the bottom, you'll see about 100,000 ablations, which is a small number compared to how many patients actually have the disease. We think a lot of patients are electing not to have it, either due to age or fear or whatever it may be. A lot of patients are looking for some sort of treatment. Up to 1 million patients are looking for some sort of treatment, which I mentioned previously. CARDAMYST was actually designed specifically for these types of arrhythmias, both PSVT and AFib with RVR. It's a new chemical entity. I mentioned the patent estate earlier. We do have composition of matter formulation patents, as well as other patents around the drug. It's a short-acting calcium channel blocker.
It was meant to create a very quick Cmax, so kind of replicate an IV bolus of a drug, and then come off quickly so any sort of side effects would not last very long. The things we are kind of really concerned about with calcium channel blockers are blood pressure drops and that sort of thing. Because it is a calcium channel blocker, it is a really well-understood mechanism. Doctors are comfortable with it. They know what those side effects could be. The FDA is comfortable with it. They have seen this drug over many, many, many years. We feel like that is a nice type of product to give to patients to treat themselves with at home. We have really tried to empower the patient here. You will see a little picture in the middle, a mockup of the actual drug.
We're close enough to commercial that we really know what this is going to look like. You see that little package there almost looks like an iPod carrier or AirPod carrier case. It can carry two devices. Why that's important is we allowed in our phase three trial for patients to try once, just try to spray and then break that tachycardia. There is another device available to them in order to try a second time if they're not able to break it, which is very consistent with how patients will be treated in an emergency department, for example. Electrocardioversion, if it does not work for the first time with the paddles, they'll try again. True for IV adenosine and other drugs that are given in bolus, they'll try once, two. We've even heard of three or four times.
We have sort of tried to replicate that for the patient at home. We feel like if the patient has this kind of device and a backup to kind of break that tachycardia, it can really empower them to think, "I can treat this on my own. I do not have to change my lifestyle as a result," and hopefully alleviate some of that anxiety they feel and go on with their lives as would any normal person without this kind of disease. Just a brief overview of our clinical endpoint to kind of give you a little consistency behind what we are thinking the product can do for patients. You will see the endpoint in that little blue box there is showing a 30-minute endpoint where we saw 64% of etripamil patients had returned to sinus rhythm from their arrhythmia and 30% of placebo.
I think what's even more impactful about this graph, as you read across that blue line for the etripamil patients, you can see that first point kind of around 15-20 minutes, nearly half of the patients had already converted on etripamil, and it was much less in the placebo arm. Now, placebo patients do spontaneously convert. You're not seeing some action of the placebo here. It's really just people having a normal kind of return to sinus rhythm. Over that 90-minute period on that graph, you see that 39% of those patients on the placebo arm still hadn't converted, while over 80% of the etripamil patients had. That delta actually goes out to five hours, and we were able to observe that.
You're actually getting some patients who just don't even convert over that long period of time but have the chance to convert with etripamil. The last point I'll make on this slide is on the bottom right-hand side, which is we did follow the number of ED visits that patients had, and it was about 40% less with the CARDAMYST or etripamil arm. I think this slide's a good slide to really elucidate the comfort we have around giving patients this for at-home use. No SAEs were observed during this trial, no syncope events, which was one of the issues that we looked for, and no second or third-degree AV block. Quite safe to use at home. What you do see is really the result of nasal administration.
A little nasal discomfort, congestion, some bloody nose, and not like a very bad bloody nose, very simple type things to deal with. We did see some of that, but things that people can definitely deal with at home and can feel safe taking the drug at home. We think that's a hallmark of this drug. That's the PSVT and etripamil story to this point. I'm going to hand it over to Lorenz, our Chief Commercial Officer, to give you a little bit of the commercial opportunity ahead of us, how we're preparing for that, and also atrial fibrillation.
Thanks, Amit. Thanks to everyone for joining us after a long conference here and also those of you online. I'm Lorenz Muller. I'm the Chief Commercial Officer. I've been now with Milestone going on eight years.
A long time preparing to launch what we think is a really important drug. We are very close right now, we feel. On this slide, I wanted to start by talking about you have heard a lot of the features of the drug and how we have studied it. I want to turn it now to what is the value proposition. Specifically, when we have the opportunity to launch CARDAMYST, what is it going to mean for patients or physicians or payers. First and foremost, for patients, it is a story of empowerment. You heard Amit talk about the uncertainty around this disease, how the symptoms are bad during an episode, in between episodes, the uncertainty and the unpredictability of when you will have your next episode.
We feel CARDAMYST, in the same ways you see in migraine or in asthma or in some other disease states, we have non-fatal disease, but it's very annoying, and you want to be able to control this. That's the idea with CARDAMYST. You have it in your pocket. When you feel an episode, you're not beholden to the healthcare system. You're not powerless. You can do something yourself most of the time to control that episode and get back to your life. That self-administration, the lack of disruption, the lack of reliance on the healthcare system, and specifically the emergency department, and less fear about when the next episode will happen, how bad it will be, leads to an empowerment that is critical, I think, to patients feeling better about their disease.
For physicians, as I mentioned, this is not life-saving, but we think of it as quality of life sparing. It is a trusted mechanism. It is something physicians will be comfortable prescribing for patients to use at home. Let's face it, cardiologists—I have been working with cardiologists for the better part of 30 years—they love new tools. They love evidence-based tools that they can give their patients that they have confidence will work for them. In this case, it will work without the physician having to intervene. They can focus their energies on other types of patients that they treat: the heart attacks and the strokes and the heart failure, et cetera. It frees up their time and their resources, which in this day and age is a very important part of the positioning to docs. Payers are genuinely intrigued. First and foremost, this is not a reformulation.
This is a new chemical entity. This is a drug that's been specifically engineered and designed to treat this disease state and AFib. Let's face it, you don't often see cost offsets in cardiovascular drugs. They're usually fully cost additive. In this case, we've demonstrated in our clinical program a 40% cost offset. Not to mention that 25% of patients that we've documented, when they go to the emergency department with an episode of SVT, end up getting admitted, at least for observation, if not for other reasons. That adds significantly to the cost.
Our goal here in deploying a strategy, a launch strategy, and in launch tactics, a sales force, all of that is to make the drug easy to use for patients, to make it easy to prescribe for the doctors, and to really limit the desire of the payers to actively manage its use. Let's talk a little bit about--you heard Amit talk about kind of the burden of this disease on patients. On the right-hand side of this slide, you really see that vicious cycle of literally millions of times a year in the United States. Patients have an attack. They did not expect it. It is not predictable. It is very variable. Sometimes it is not very bad. Sometimes it is really bad. Most of the time, it is not infrequent and moderate or severe in intensity. That is our target addressable market.
At that point, once they're in an episode, they can either—and most of the time, what they do is they sit at home and they tough it out. It's all they can do. Not trivially, 100,000-plus times a year, they go to the emergency department because they just can't tolerate the symptoms. Right now, what physicians are doing is they're prescribing chronic meds. They're prescribing pill-in-pocket. They're, in many cases, doing no treatment, or they're trying to convince the patient to have an ablation. What's unique for our value proposition is CARDAMYST can be used in every one of those treatment paradigms. It can either be added on as a therapy to chronic prophylaxis, or it can be switched. Like a patient that's on pill-in-pocket can then now be given CARDAMYST, or you can leave it up to the patient to decide.
There's even an important use case in ablations. As a physician has finally convinced the patient to have the ablation, they can schedule it six, eight, 10 weeks out. They want to make sure that patient has a good experience leading into that surgery as they're weaning them off their chronic meds, which they have to do before the ablation. That's a use case where these important influencers, the electrophysiologists, can get experience with our product. We have a diversity of use cases within the disease state of PSVT. What that results in is a significant stated adoption from physicians. We've done research now with literally thousands of physicians over the last seven or eight years. What they tell us is, on the left-hand side, here's how we currently manage. About 1/3 of the patients get a script for pill-in-pocket. About another 1/3 are on prophylaxis.
About 1/5 get no treatment, either because their disease isn't symptomatic enough where they needed treatment, or more likely, they've tried treatment and they can't tolerate the side effects. As Amit pointed out, a minority of patients, literally 10%-15%, get an ablation. Highly successful procedure, pretty manageable safety profile, yet most patients elect not to have it. Why? It's an intervention. Nobody wants to have their heart frozen or burned, unless they absolutely have to. As we put a profile of etripamil in front of docs, like what we expect to get in our labeling, they suggest that in many of these use cases, the majority of their patients would be offered a script of CARDAMYST, leading to a roughly 50% stated adoption.
What is particularly compelling about the commercial opportunity that I'm here presenting to you all today for CARDAMYST is represented on this slide. If you ask me what kind of a product, if I could have any product that I could launch, I would choose something that ideally has no anticipated branded competition, which is the case for CARDAMYST, which gives me a 100% share of voice. Every detail that goes in is not counter-detailed. It also, and people do not often think about it this way, when you do not have a competitive marketplace, the pressure to offer incrementally higher and higher rebates to payers to cover it just is not there. We have the ability not only to generate demand, but also to be able to bring more of that to the bottom line.
As I mentioned earlier, and Amit mentioned, calcium channel blockers have been around for 30 years. This is a new chemical entity, custom-made to treat this disease, but it's a familiar and trusted mechanism. We believe, and physicians have told us, that the bar for prescribing here is relatively low. Importantly, in this disease state, and frankly, in any disease state for cardiology, it's evidence-based. Randomized placebo-controlled studies that clearly show a statistically significant reduction in the primary endpoints versus placebo. The opportunity is significant. Millions of patients, you heard Amit say, every year, north of 500,000 patients are already in the healthcare system in the United States seeking treatment for PSVT. I don't have to deploy a bunch of expensive tactics to get patients to be activated and go in and ask their doctor about CARDAMYST.
They're already going to be in the offices. I just have to be in front of that physician so it's top of mind, so they're willing to offer that patient that option. In many cases, the patients have told us they will gladly take it. Also, for a launch in this day and age, having half the patients be under the age of 65 and commercially insured gives me a chance to demonstrate demand early on in a launch, given sometimes the longer or more protracted contracting cycles for Medicare. Where are we? As I think everyone knows, and you heard about the CRL, we were fully ready to launch CARDAMYST on March 27th. We had already recruited the entire commercial and medical affairs leadership team. The MSL team was already out engaging customers. We had hired and trained the entire sales management team.
We got a CRL. We did not hire the reps. We stopped short of that. That entire team, I am happy to say, is still intact and doing productive things to prepare for the launch. In the event that we have not a very protracted delay with FDA, we are ready relatively quickly to go re-engage and actually launch CARDAMYST. On the access side, we have negotiated. This is going to be a retail distribution strategy, consistent with the easy-to-get-the-product that I mentioned earlier from a strategic standpoint. We have negotiated and completed all the distribution contracts. We have had account managers, national account managers in the field for well over a year now, engaging with payers, PBMs, Medicare, IDNs.
There's a significant level of interest I can report in wanting to see the benefits of these potential cost offsets and in, frankly, filling a void where there have not been other products, along with all the different reimbursement support programs you need appropriate for a retail product and patient support services. Because once a patient's on therapy, we want to have a relationship with them. We want to be able to encourage them to get refills or anything else we can do to ensure that they stay on therapy, as well as the appropriate copay mitigation that we'd use to be able to pull through some of that demand in a launch year. We are ready to go. We just need the nod from the FDA, and we should be able to be in market within a couple of three months with substantial demand generation.
I'll just spend the last five minutes here talking a little bit about the second indication that Amit alluded to, which is atrial fibrillation with rapid ventricular rate. On this slide, you can see it's a much epidemiologically, it's a much bigger challenge. More patients have this, and it's growing at a much faster rate. It's still showing potentially a doubling of the prevalence of AFib between 2020 and 2030. You've got six times as many patients therefore going to the emergency department every year. It's probably over 1 million now. This was data from 2016, 1 million patients a year going to the emergency department with a rapid rate that's symptomatic. Physicians do not want to see these patients in the emergency department unless they're hemodynamically unstable, which the vast majority are not. They'd rather they treat themselves at home.
They just do not have the tools to rapidly and safely slow their rate so that they can be managed in whatever way they want to manage rhythm or rate control. We estimate here that the TAM for the target addressable market for atrial fibrillation with rapid rate is on the order of 3 million-4 million. Already you can see it is 3-4 times the size of PSVT. I want to spend just a minute here. This is really important on the use case of CARDAMYST in treating AFib with rapid rate. In PSVT, it is empirically clear to everyone. You have a patient with a 200 beats per minute rapid rate. You take our drug. You are back in sinus rhythm. You go about your day. Very clear how that would have a benefit.
In atrial fibrillation, a calcium channel blocker or a beta blocker, but in our case, a CCB, is not used to convert them to sinus rhythm. There are conversion rate agents, class 1C antiarrhythmics, flecainide, propafenone, generic agents that are specifically designed to convert a patient from the arrhythmia, AFib, to sinus rhythm. In order to do that, the treatment guidelines say you've got to slow them down first. If you go to an emergency department, and many of these patients, as you saw, showed up in the emergency department, the first thing you do, once you figured out they're in AFib with rapid rate, is to slow them down. Our idea is, let's take that treatment paradigm, same as in PSVT, by the way, and take it out of the acute care setting and into the at-home setting. Let's empower these patients with a tool.
When they feel the symptoms of AFib, they can take something that's going to work rapidly, lower their rate, and then they're going to follow their doctor's instructions as to whether that's sufficient because they're going to spontaneously convert relatively quickly anywhere. Not spontaneously, but they're going to convert naturally without taking additional drugs. Or if they have more protracted disease, maybe they take a chronic rate control agent or a chronic rhythm control agent. Up to the doctor. Depends on the patient. In all those cases, you're going to want to slow them down quickly. Because if you don't slow them down quickly, they're going to get more and more worked up. A million times a year, they're going to go to the emergency department. What's the first thing they're going to get in the ED? IV rate control agents.
This graphic simply shows the idea of, rather than going to the emergency department or sitting at home waiting for pill-in-pocket to work, which is to take an extra tablet of a rate control agent, we should be able to do it much faster. That is going to lead, we believe, to many fewer patients having to go to the emergency department. Those are the use cases. You can either take it alone to rapidly lower rate in patients that tend to have shorter episodes where they would naturally convert after an hour or two anyway. You can use it as a bridge to chronic rate or rhythm control. EPs have even told us, electrophysiologists have told us you can use this peri-ablation in that sort of storm period after an ablation, ideally, again, to keep them from having these symptomatic episodes.
There's even options potentially to use it in an acute care setting ahead of using IV agents. That's kind of getting ahead of ourselves. Those first two use cases are the majority of the market opportunity for CARDAMYST in atrial fibrillation. Let me just quickly show you a little bit of the data that Amit was alluding to that we were very excited about. We presented this at AHA a few years ago. We took an acute care setting. We always study our drug first in a new disease in an acute care setting where we can control everything, measure heart rate and blood pressure and all that stuff. We took patients that were in AFib with rapid rate, and we randomized them to either get placebo or etripamil. This was a single dose of etripamil, 70 mg . We followed them for an hour.
They weren't allowed to take additional drugs during that hour. At the end of the hour, they were able to take other meds for the ones that were still rapid rate. The vast majority of patients on placebo, for example, were still at a very rapid rate. We saw we were looking to try to get the rate down quickly, and we were trying to figure out how far down would it go, how quickly would it get there, and then how long would it last. That is sort of the real currency here about the value of CARDAMYST. What we saw in this data, you can see we dropped rate by 35 beats a minute. Clinicians, by the way, will tell you anything more than 20 beats a minute is clinically significant in AFib.
We dropped it by 35 beats per minute absolute, or about 30 beats per minute relative to placebo adjusted. We did it within 10 minutes. On this graph, you saw it easily lasted to an hour, which is interesting considering the pharmacology. You would think it would wear off, but it does not in AFib, at least not by this data. There is another data we have shown publicly that suggests that this effect is durable out to two hours plus. That is on a single dose. That was exactly the profile we were looking for. We were very excited about it. In addition to that, we also looked at symptom relief. You will see in a minute why that is important. We saw a statistically significant reduction in patient-reported outcomes related to symptom relief, specifically how satisfied patients were with the symptom relief offered by the drug relative to placebo.
The reason that latter point is important is because in order to get an FDA-approved indication for temporary rate control in AFib, the FDA has said on the good news side, they've said, "Hey, if you get PSVT approved, you can follow an sNDA pathway. You can benefit from all the safety data. You have to do one randomized study, p<0.05, show efficacy, and have nothing bad go on in safety, and you're good to go." That is the study we've now designed. The primary endpoint would be rate reduction, very similar to what I just showed you. Importantly, the FDA said if you want an indication, you're going to have to demonstrate as a key secondary endpoint symptom relief via a PRO.
That finding in the phase two study is very supportive of us being able to size a study and do a study in phase three that would demonstrate a label-enabling result. We estimate that this study, by the way, not to belabor it, but it would be roughly similar to the size of studies we have already done in PSVT. Many of the sites we have already done research in are excited to do this study. It is ready to go. The protocol has gone through the FDA. It is on hold, as Amit told you a minute ago, for financial reasons, but we can spin this thing up really quick once we are ready to go. With that, we will talk about our financial situation.
Now, I'll put this up just for a second, but we did have cash and short-term investments of $56 million at the end of the last quarter. We have a royalty agreement with RTW that's listed here at $75 million. If anybody has any questions, we're happy to handle them afterwards since we're kind of out of time. We can talk to you individually. Thank you very much.