CARDAMYST: New FDA-approved Nasal Spray treatment for PSVT heart arrhythmia.

Hi, thanks for joining us for episode #140 of the Doctor Podcast Show, and I'm your host, Doctor Robert Sichert. Please subscribe to and follow Doctor Podcast. We're on every video social media platform, including the three most popular ones, which are YouTube, Spotify, and X. Please also like and repost this episode so that we can continue to be leading provider of reliable, accurate medical information from top physicians and medical companies. Today's topic is a heart issue that affects about over 1,000,000 people in the USA but has not received the attention it deserves.

It's a heart arrhythmia or regular heartbeat called paroxysmal superventricular tachycardia, or we call it PSVT for short because it's easier to say that it causes sudden, extremely rapid heartbeats which can cause other heart problems, shortness of breath, fainting, and sometimes even land you in the hospital. Today we have two excellent cardiologist guests who are experts in PSVT and other heart conditions as well. We'll be discussing a new life changing treatment for PSVT as well. Our guest today, Doctor Bruce Stambler and Doctor David Berucha.

Thank you both for appearing on doctor podcasts and sharing your expertise with this important heart condition. We appreciate it. Thank you for inviting us, it's a pleasure. Thank you. All right, So first I'd like to introduce Doctor Stambler. He's a leading cardiac electrophysiologist formerly at Piedmont Heart in Atlanta, and he's an expert in heart rhythm disorders, including PSVT or paroxysmal superventricular tachycardia, other types of heart arrhythmias, and also catheter ablation, which was a treatment for this.

Also we have Doctor David Berucha. Dr. Berucha is the Chief Medical Officer at Milestone Pharmaceuticals, which makes a new drug for treating PSVT and he's been the Chief Medical officer now since February of 2022. He directly overseas the clinical development and the FDA approval of cartomist, which is the drug we're going to discuss, which is a new drug for treating PSVT. He's also a cardiac electrophysiologist, which we'll define in a moment. With deep clinical practice experience in arrhythmic care and ablation procedures and extensive global drug development experience across cardiovascular diseases of various type.

He earned his MD and pH D in biochemistry and molecular biology at the University of Chicago. Complete internal medicine residency at University of Pennsylvania and cardiology and electrophysiology at Mass General Hospital and Harvard. He's a formerly faculty member at Mount Sinai School of Medicine, Jefferson Medical University, and he's a fellow of the American College of Cardiology. So Doctor Stambler, let me ask you first, can you tell us what a cardiologist, electrophysiologist is, as I mentioned in the introductions, and for someone who's never heard the term before, can you explain in simple terms what this PSVT arrhythmia is and what it feel like, feels like when an episode hits?

And which part of the heart is abnormal and why is it called paroxysmal? Sure, for my pleasure. So First off, a cardiologist is a physician who specializes in diseases of the heart and the vascular system. I trained in cardiology. Within cardiology there are different subspecialties and cardiac electrophysiology or electricians of the heart, I like to say because my dad was an electrical engineer. I became an electrician of the heart, I like to say, and I trained additionally in electrical disturbances of the heart, which always fascinated me, the EKG's and rhythm disturbances, one of which as you alluded to is PSVT, paroxysmal super ventricular tachycardia, a mouthful there.

But in any event, that's a clinical electrophysiologic syndrome that's associated with episodes of very fast heart beating tachycardia, we call it 100 to 250 beats per minute. The heart is racing off characteristically the electrical requirements of this tachycardia that involves an electrical structure in the heart called the atrio ventricular node or AV node for short. And this is a necessary part of the reentrant electrical circuit in the two types of PSVT that we see commonly, one of which is known as AV nodal reentrant tachycardia Avant, which is the most common and AVRT or AV reciprocating tachycardia due to an AV accessory connection.

And these are very common. They importantly, they occur suddenly and abruptly. There are other types of SVT that many people I'm sure have heard about, especially atrial fibrillation or atrial flutter or atrial tachycardia. But these are not dependent on this structure, electrical structure called the Avenue node. We're focusing here on the Avenue nodal dependent tachycardias. What people experience who have PSVT is typically, as we said, a rapid heartbeat, a feeling that their heart is racing off suddenly palpitations.

They can be anxious, they can feel chest discomfort, they can be dizzy, they can be lightheaded. They can get shortness of breath. That's the typical presentation of PSVT or AV nodal dependent SVT. There's basically an abnormal electrical current or circuit that's going on inside the heart, but it starts suddenly out of the blue. Exactly. It's circuit. I would emphasize there in what what you had to say for sure. It's a electrical circuit. Right now, Doctor Barucha, how common is PSVT in the USA?

For example, who typically gets it? Is it young people, older people? Is it men or women or both? And does it usually mean that there's something structurally wrong with their heart? Let me answer the second question first. It does not necessarily mean there's something structurally abnormal with the heart. Some of the abnormalities or issues that Doctor Stambler just mentioned are microscopic electrical pathways that can lead to what you essentially summarized correctly as being a short circuiting of the heart.

Those are do not have a basis of structural heart disease, do not have a basis of valvular disease, and do not mean the patient has had a previous heart attack. Just to amplify one other aspect of what you just mentioned, it's not only the distress of the episodes themselves, it's the uncertainty that patients feel among the episodes, between the episodes. And we can get into more of that later when we start talking about the patient experience. To answer your other question, Doctor Seikert, how common is this?

It's a lot more common in the United States and worldwide than people think. It's estimated that over 2 million patients in the United States today have diagnosed PSVT. In addition to that, that unfortunately results in reasonably frequent emergency department visits for PSVT. Estimates are anywhere from 140,000 to over 500,000 emergency department visits annually in the US alone for PSVT. That's that's a huge number. That's a lot of healthcare dollars also spent on this condition. Yeah. Absolutely.

Now, Doctor Stambler, what triggers PSVT since there's no structural abnormality, or is this a possibly just a genetic defect in the electrical circuitry of the heart? And are there things that can trigger it? For example, stress, anxiety, exercise, caffeine, alcohol, things like that? Well, first of all, it's, it's not a genetic condition, but it is something that is inherent to the heart. That is, you have to have this electrical substrate that I talked about before. The heart is not structurally abnormal, but there is an electrical circuit either what we call dual AV nodal pathways or two pathways in the AV node or an extra electrical circuit call called an AV connection or a connection from the atrium to the ventricle outside the AV node.

And this allows this short circuiting that we already talked about. You have to have that. So if you don't have these extra electrical circuits, then you're not going to get PSVT. As the first thing to understand, if you do have the appropriate electrical circuit, and most people don't know it, the truth is that it's entirely unpredictable when it will occur. It can occur anytime and it's quite variable in onset. In some people it occurs at rest, and in fact most people it occurs at rest, but it can occur with exercise.

And this unpredictability about it makes it somewhat disconcerting and anxiety provoking for patients because it can occur essentially at any time in any place. It turns out that although we often tell people don't drink caffeine or coffee when they have PSVT, it turns out that caffeine does not in fact trigger PSVT based on the evidence that we have. If in fact the evidence suggests that people who drink coffee have less PSVT and less A-fib as well. So you can drink your coffee if you have PSVT.

There's no impact and it's completely unpredictable. And I tell people with PSVT is don't, don't think that you did something or didn't do something to 'cause this episode of PSVT because you're just going to create a greater sense of anxiety and there's no way one could predict what causes it. What we have looked at some data and there's some interesting tidbits that I might share. It's more common during the daytime versus night and it's more common in colder months in winter versus the summer.

Interestingly, likely we think related to a higher of adrenaline or sympathetic nervous system stimulation. We think in the EP lab when we study and induce this tachycardia in patients who have a history of it before we do an ablation procedure. For example, if we can't bring on the tachycardia in the EP lab, we frequently infuse it via a vein, a medication called isopertaranol or epidephrine, which is like adrenaline that the body puts out. And this makes it much easier to induce this tachycardia and people who have the appropriate electrical substrate.

So there's no obvious triggers, but we do think that excess levels of adrenaline or sympathetic stimulation does provide the trigger in an appropriate substrate. What about the alcohol? I I have some patients who have this condition and tell me if they if they have a drink of alcohol or two, it sometimes will trigger it. Is that just a coincidence or is that it's probably? Just coincidence in particular for PSVT. Now that's in distinction to atrial fibrillation, which is very common and alcohol clearly is a precipitant for atrial fibrillation, which has a different mechanism and alcohol, no evidence that it can trigger or reliably triggers PSVT.

Now if somebody has an alcoholic drink and every time they drink alcohol they go into SVT, that's common sense. But the medical evidence basis is that the onset of these episodes is really unpredictable and that creates A considerable amount of anxiety for people. Right now Doctor Barucha, since we don't know why these episodes start and stop so suddenly and they cause a lot of anxiety. Is there also an association with with having strokes with this with PSVT as there is with atrial fibrillation or the PSVT arrhythmias don't really cause the blood clots in the heart and the strokes?

The simple and reassuring answer is no. There's one qualifier that people do need to be aware of, and generally a a diagnostic evaluation from a cardiologist can clarify this. In some cases, as many as 20% of the cases, PSVT and atrial fibrillation might coexist. So the answer to your question is PSVT alone is not associated with an increased risk of embolic events or stroke. However, sometimes the two may go hand in hand. So it's just a reason to have one's cardiac ailments, be they PSVT, Afib, or something else, be thoroughly evaluated.

Right, because if you have a fib, then you need to go on blood thinners or anticoagulants. But I I take it from what you're saying, if you have PSVT, you don't need to go on the anticoagulants or blood thinners, right? That that's accurate. For PSVT alone, that's accurate. OK, now Doctor Sandler, before we discuss the newly FDA approved drug cardamist, what were the main ways that doctors treated APSVT episode when let's say a patient arrives in the emergency room and their heart is racing and they're short of breath and they're anxious and they think they're about to die sometimes.

Sure, sure. So the way the way we try to terminate an episode acutely of PSVT that's ongoing, that's sustained. The first approach is have the patient try what are called vagal or Valsalva maneuver. Valsalva maneuvers where we try to stimulate the vagal nerve in the body, which is sort of is in a position or opposes the sympathetic system. So it's the fright or flight response. This is the parasympathetic component. We ask the patient to sort of bear down, raise their legs through all these sort of maneuvers to increase vagal tone.

And this can have an effect on the AV node that I talked about before and can interrupt these circuits. Unfortunately, vagal maneuvers are not overly reliable and effective in terminating ongoing PSVT. The data suggests that in no more than 20% of episodes kind of vagal new over terminate it. Most time in people who have PSVT, they are instructed or heard about vagal maneuvers or Valsalva maneuvers and they've already tried that before they get to the emergency room. So when we looked at this in the Atripamil database, which we'll talk about in a moment, only 5% of episodes terminated with a vagal maneuver before they had to use the spray.

When the patient gets to the emergency room, what happens typically is an IV is inserted after an EKG or at the same time as an EKG is obtained in. The diagnosis is confirmed on the EKG. And then intravenous medicine typically is infused either a medicine called adenosine, which works very, very quickly and they get one or more boluses of this medicine. Or sometimes they get an intravenous calcium channel blocker such as diltiazem or verapamil, or possibly sometimes a beta blocker like metoprolol IV.

In rare cases when the patient is hemodynamically unstable, that is, the blood pressure is very low and the patient feels horrible, we might resort to an electrical shock on the outside of the body after the patient is heavily sedated to try to terminate this episode. But a shock is almost never, or I should say very rarely, required for PSVT termination. Most of the time, in the US at least, a patient will get a bolus of intravenous adenosine which acts quickly and will terminate PSVT most of the time.

Right, that's good to know. Now, Doctor Burucha, if, if this is an elderly patient who let's say has clogged coronary arteries and high blood pressure and high cholesterol and maybe diabetic, are they at risk of getting a heart attack triggered by this PSVT because their heart is racing so fast? That's a complex question, but it's more or less a reassuring answer. A heart attack itself or the acute occlusion of a coronary artery should not be triggered by an episode of DSVT. However, it is an elevated heart rate and patients who have coincident heart failure or coincident stenosis or partial closing of a coronary artery.

Patients who have chest pain or angina with exertion can get angina for chest pain with the rapid heartbeats associated with a tachycardia. So to summarize, it should not cause a heart attack, but it can exacerbate other underlying cardiac conditions. Right now, Doctor Stambler, if if you have a patient who's getting these fairly frequently and winding up in the ERA lot and getting the adenosine intravenously, are there any pills or medications they could take at home on a regular basis to try to prevent these episodes?

Sure. What we usually use is an oral calcium channel. Block already talked about that when they have an acute episode, they might have gotten in the emergency room again, such as diltiazem or verapamil or an oral beta blocker such as metoprolol that they might take every day to try to reduce the frequency of these episodes. Or a more powerful anti arrhythmic drug and one of which for example is flecainide, they may take daily to try to again prevent or reduce the frequency of these episodes. What I usually tell patients is that these drugs usually reduce the frequency of episodes, but maybe 5060%, but almost never entirely eliminate these episodes.

And the medicines do have some bothersome side effects. And then finally, you know, in patients who don't have that frequent of episodes, let's say it only occurs a couple times a year, it not sure it makes a lot of sense to take a medicine every day, maybe to reduce that two or three episodes to 1 episode a year, but it's up to the patient to decide. So those are the kind of medicines we might try on a daily basis to try to prevent these episodes. Right now, Doctor Barucha for for patients who have frequent episodes and let's say they're not responding to the medications that we just discussed, one of the things you mentioned was cardiac ablation procedures.

Can you explain what that is and and how it works for this condition? Sure. I'd be happy to speak about ablations, but if I may just add on a couple of comments to what Doctor Stambler just mentioned about the value or actually the poor effectiveness of taking an oral chronic medication. I agree fully with Doctor Stambler. The idea of taking a medication each and every day that has side effects for an episodic condition just doesn't make sense #1 #2 it's not even a a tremendously effective strategy.

In fact, what's interesting in the clinical data, the rapid study that I think we'll we'll talk about in a bit, 2/3 of patients coming into the trial with PSVT, including during their episodes of acute PSVT were on background therapy with an oral chronic medication such as beta blocker or calcium channel blocker. So Despite that treatment, patients still have very frequent episodes of PSVT #1 #2 when we start talking in a little more detail about a treadmill or cardiomyst. That's actually very reassuring that the drug was safe, seemed to be safe and effective even in that context.

But we can talk about that more when we talk about the drug. To answer your question about ablations, ablations are very effective for very many, a great number of patients. However, they're not great for each and every patient. An ablation is an invasive cardiac procedure in which patients are brought into a cardiac catheterization or cardiac electrophysiology lab. They're sedated lightly. Generally, catheters are inserted up through the legs, the leg veins, the leg arteries, and some veins and arteries located in other areas of the heart as well.

And these catheters, which are long flexible electrodes, are inserted to different locations within the heart. With those catheters in place, a tachycardia can be deliberately induced and then it can be mapped as to the exact location of let's say this electrical short circuiting or this extra electrical pathway. Once that additional pathway is located and it's been shown to be problematic, it can be targeted with what's called ablation energy. Most ablations in the United States take place by virtue of applying radio frequency current.

Radio frequency current causes a microscopic cauterization right over the targeted area. The issue is it takes a lot of skill and takes a lot of mapping of multiple sources of information in real time in order to be able to pinpoint that target. The other issue is sometimes even the best trained, most experienced electrophysiologist can be off just a little bit in that in those cases complications can ensue. These complications do not occur frequently, but when they occur they can be very, very serious for the patient.

Complications from even, let's say ablations done for the most frequent types of SVT. The doctor Stamler already mentioned ABNRT. If that ablation is a little bit off target, the patient can end up going into what's known as complete heart block and can require a permanent pacemaker implant for the rest of their lives. That's a tragedy for all patients, particularly for a young patient. It's an awful situation. So even though ablations are very effective procedures and even though the risk is very, very low, the risk and benefit and what's right for every single patient really needs to be taken into account through a very thorough conversation of all available options, how frequent and bothersome the episodes are for the patient, and just quite honestly what the patient's predisposition on is.

Some patients are game to go ahead with it, even an aggressive procedure. Other patients would rather decline it or defer it until it's absolutely necessary. And it's up to the the physician, both the cardiologist and the performing the procedure, performing electrophysiologist to work out all those pros and cons and details of the procedure. Right. Sounds like ablation has some potential serious risks and you want to avoid that if if at all possible. Now, Doctor Sandler, can you tell us exactly what Cartomist is, which is this new drug and how's it different from every other PSVT treatment that's been available for the last 30 plus years?

And by the way, for people watching this, you can find out more about Cardamist at their website, which is CARD AM Y st.com, cardamist.com. But Doctor Stambler, can you tell us what Cardamist is and and how it's different than everything else we've discussed so far? Sure, sure. So a cardamist or Atripamil as it's also known is AL type calcium channel blocker. So I already talked about calcium channel blockers a bit. It's similar to this drug called Verapamil that I already mentioned once or twice that's been around 30 plus years it.

So Atripamil is an L type calcium channel blocker. But what's novel about Atripamil, importantly, is that the route of administration is intranasal via a nasal spray, rather than being taken as an oral pill or given as an intravenous medication. It can get into the body very rapidly and very quickly with peak concentrations of this drug in the blood within 7 minutes after a nasal spray. So it gets in very rapidly, which is important, and it gets out of the body very quickly. It's metabolized very quickly, so you get high concentrations quickly, and then it leaves the body.

So it's perfect for terminating this mechanism that we called AV nodal dependent SVT, because calcium channel blockers prolong what's known as the refractor electrical refractory period of the AV node block by blocking the influx of calcium ions into AV nodal cells prolongs the refractory period and thereby can terminate or short circuit these electrical circuits and stop tachycardia. So I've had the pleasure of working with milestone in the development of Atripinal for more than a decade now. And it was developed specifically to terminate symptomatic PSVT to sinus rhythm.

And recently in December, the FDA approved Cardamis for this indication. Right. And there's never been a nasal spray before that that can do this, right? Correct, correct. There's no no other nasal spray in cardiology. Obviously you know there are some other ways. For others in this. Phrase Norcan, Nephi, etcetera. Now that are out there, but this is brand new in the cardiology world giving medications via the nasal route rather than oral or intravenous which is or topical which we're used to for example.

This is a brand new route of administration with a mechanism of action that we've known about for 30 plus years to terminate PSVT. Right now, Doctor Brucha has the nasal spray delivery work. Do you have to spray it in, in both nostrils or just one? And how long does it take before it works? Can you just describe the steps the the patient goes through? And the question is, can this be prescribed for patients so they can keep it at home and and use it if they feel that they have a PSVT attack rather than having to go to the emergency room?

Yes. And that let me emphasize that last part of your question first, the basic foundation of this treatment is that it can be self administered by patients. It can be self administered outside of medical supervision. It can be administered in an at home setting or at work or whenever a patient has the sudden onset of a PSVT episode. The basic nasal spray, the device, it was designed to be portable and carried with patients wherever they might go. The drug is stable at room temperature. And again, the basic design behind this drug and this entire program has been to have patients be able to carry something and have it at the ready and therefore prevent having to go to an emergency room as often as they do currently for PSVT.

So back to more of the first part of your question.

A Trepmill is given to the patient after prescription in a in a small nasal spray bottle. I'm holding up my fingers this wide very deliberately. The nasal spray bottle actually is small enough they can fit into a man's shirt pocket. When a patient experiences the sudden onset of PSVT, they generally know it it's it's a customary set of symptoms. What they need to do is sit down because the the spray should be administered in a seating position with one spray bottle. They put one spray in one nostril, a second spray in the other nostril.

That's a total dose of 70 milligrams. If they still have symptoms after 10 minutes, the instructions are they take another spray bottle. These are delivered to the patient in a 2 pack. They take another spray bottle if their symptoms are still ongoing at 10 minutes. And again they put one spray into one nostril, one spray into another nostril. In our clinical studies and we studied this exact approach that was both safe and effective to terminate episodes of PSVT relative to placebo in 64% of cases.

It was also demonstrated to terminate episodes of PSVT very quickly. The median time to conversion was only 17 minutes in patients administered randomized blinded a treadmill as opposed to weigh out more than threefold longer 54 minutes for patients self administering placebo. So the data show that this is safe and effective. And to your first point, it's quite feasible. The way we studied this drug was with patients self administering the drug as an outpatient and without direct medical supervision with packs they carried with them or kept in their purse or their desk drawer.

And patients in the vast majority of cases, in fact all cases that we're aware of knew how to deploy the spray and knew how to self administer it very effectively. And without too much trouble or or practice. All right, that's that sounds great, very effective. Now, Doctor Stamler, is it for people who are getting these episodes frequently? Is it safe to administer Cardamis frequently? What if you get it every few days for a while? Then it can stop for months. Yeah, that, that's, that's a very good question.

In fact, one of my patients in the clinical trial that led to the development of this drug and the approval used it 11 times for termination of PSVT. Each time it reliably terminated PSVT and they were limited to 11 times because that was the trial design. They couldn't do it more than 11 times. But but I'm aware of another patient that has now used it up to 18 times reliably. So yes, you can use it repeatedly and conversion is reproducible. That is, as David said, 64% conversion within 30 minutes is reproducible on subsequent episodes.

So yes, that's an important finding that we saw and observed that it was effective for repeat episodes on a chronic basis. That's very important. Now Doctor Bruce, you, you mentioned the the clinical trials that were done and that 64% of of patients converted to a normal sinus rhythm. Was there any evidence from the trials that using this might prevent the frequency or severity of episodes? Or or there's no data like that? There are no data like that, and quite honestly, there's no reason to predict that an acute treatment, even one that quickly terminates an episode, will have an impact on the frequency of future episodes.

I see so each episode is is separate but the the drug works now. Doctor Stamler. One of the biggest complaints from PSVT patients is the fear and anxiety of never knowing when the next episode will occur and worrying about winding up in the ER. Were there any studies done to show that patients feel better knowing they have something that they can use and it reduces the anxiety and the fear and. Yeah, yeah, yeah. Patients in the in our clinical trials milestones sponsored these trials, filled out questionnaires asking quality of life questions, asking symptom questions.

And yes, the quality of life in patients who were randomized to received and treated themselves with a trip amil improved over time. Their level of anxiety was reduced, their symptoms were reduced, and their overall well-being was improved. They thought this was a very convenient, effective treatment. They rated it very highly on those scores. And in all these areas it was better than those who were randomized in a double-blind fashion to receive placebo. So Atripomil improved quality of life better than placebo in all these patients evaluated by questionnaires.

That's great because. And my own just to say in my own experience and talking to patients who used it and you know, substantiate this, that patients really like this. They like the fact they can quickly terminate an episode and they like the fact that they got some control over this condition. This sense of loss of control, the unpredictability of this, having some self-directed therapy give them some sense of empowerment that patients often told me that and were eager to use this drug, kept asking me when it would be approved.

Right. And keeping them out of the ER, let's say there's a storm or a Blizzard or whatever, they can't get to the ER or comic jam. So that's that's very important. Now, Doctor Barucha does cardamis from the trials that were done. Do we have data on whether it works well for both male and female patients or different age groups? Was that studied? In our clinical trials that was looked at very carefully and there's no substantial difference in either effectiveness or in safety between genders, between the young and the old, between patients who were on pre-existing oral therapy with a calcium channel blocker, a beta blocker and those who are not.

And no differences in another series of demographic or clinical features that patients might have. So essentially the drug is labeled very accurately in its FDA approval. It's indicated for the conversion of acute symptomatic PSVT to normal sinus rhythm in adults with a history of PSVT without really qualifications based on, excuse me, based on age or gender thereof. Right. What's the youngest age it's approved for by the FDA? It's approved for adults, meaning anyone at or over the age of 1818. OK, Yeah.

Just to follow up on the emergency department question, we've talked about the need to avoid emergency department visits as much as possible, right? They're long, they're onerous, they can be uncomfortable, they're time consuming, they're costly. Our trial data, both in the rapid trial and across our trials showed a reduction in emergency department use and a reduction in patients needing to seek external rescue medications with statistical significance in one pre specified pooled study, a relative risk reduction of 40% between patients who were administered or self administered A treadmill relative to those who self administered placebo.

So there's a significant reduction in the need to go to ERS with obvious benefits along those lines. And some of those benefits are right along the lines that you asked Doctor Stambler about. It gives patients a sense of empowerment. It gives them a sense, hey, I can go on vacation, I can go on a day hike without fear of what if I need to be urgently transported to an emergency department. That's critically important. Now, Doctor Sandler, every medication we use and prescribe has side effects. What what are the important side effects of of cardamis?

Are there any severe side effects from the clinical trials? Are there any patients who should definitely not use this or any serious drug interactions that should be avoided? Sure. So this is an important take home message when especially talking about the cardiology space and cardiology medications. And this is very important to be aware of in my mind is that overall the drug is safe to give during PSVT and that was a very important finding in my mind. There's no important cardiovascular adverse events associated with this medication.

There's no what we call advanced off block or major pauses after conversion to sinus rhythm. There are some side effects of the medication primarily related to the root of nasal administration and the volume of liquid that has to be squirted up the nose. So patients did complain of runny nose, nasal congestion, some irritation of the nose. Some of the patients if they weren't seated and possibly swallowed the medicine got some coughing related to the volume of liquid they may have swallowed. So there are some of the side effects.

It was related as mild to moderate and otherwise well tolerated. But again, I would emphasize this important because as a cardiologist, this is very important to me. This is safe. There are no cardiovascular events noted of importance or significance associated in the clinical trials. Right. So it didn't cause, for example, severe low blood pressure or extremely low pulse that results in fainting or other complications or anything like that. Well, let me just add a little bit on that. So you know these patients self administered these outside the hospital.

So we didn't know what their blood pressure was necessarily during an episode. However, in one of the pivotal trials, they had to get get a test dose of a trip mill in normal sinus rhythm in the clinic in front of us where they had their blood pressure repeatedly measured with a trip. And we called this the test dose and it's. A great idea, yeah. Yeah, we all patients had to pass the test dose before they could take this medicine home with them to use by themselves during PSVT. We measured their blood pressure.

We did EKG's repeatedly after the medication. And 1st off, it's important to know him. Over 1000 patients got it in sinus rhythm and only 2% of patients failed the test dose, so to speak. But for no really cardiovascular reasons, there are no cases of law major low blood pressure. There were no heart rate issues in sinus risen. And in fact because the data was so robust on the safety, the FDA approved this medicine without the need for the test dose in the office. Patients could get the prescription and just take it home with them and use it on an as needed basis for symptomatic PSVT.

So no test dose is part of this, although we studied that no longer needed. Wow, that's. I think Doctor Bruccio probably wants to say something about this as well, because we know that's an important finding. Yeah. No, it was a critically important finding. And in fact, FDA was fine with us in the development program not using a test dose even in the middle of development. So some of our clinical trial data patients had a preceding test dose, but a good portion of our trial data patients did not have a test dose.

So what we call some of our quote, UN quote real world trial where patients were given a pack of Atripomil to use as I described before they the first time they used it was without a test dose. And the rate of tolerance, the the rate of good safety signals that we saw was equivalent to those trials in which we didn't use the test dose. One other point just about some of the nasal administration site related symptoms that Doctor Stambler already mentioned. What's very interesting is in our clinical trials in which patients were allowed to administer Atripamil over separate consecutive episodes of PSVT, the rates of reporting these side effects dropped not so much even because they patients acclimated to it, but after the first time they knew what the drug felt like in their nose, there is some nasal discomfort, they got used to it.

So it was no longer a complaint that they even reported as frequently, right? Yeah, I can concur that that was my experience that patients who use it on repeated episodes, there was some uncertainty the first time, but with subsequent episodes, they were knew what to expect, so to speak. Right. Yeah, They get used to it. That's good. Now, Doctor Barucha does. If a patient has this PSVT, do they need to see a cardiologist to get Cardamis prescribed? Or if they have a primary care physician who's familiar with this and has known about their treatment, it can be prescribed by any primary care physician.

The drug in the United States, Cardamis, can be prescribed by any licensed healthcare practitioner. You does not need to be a cardiologist. Now, when you look across the medical community in the United States, it's cardiologists and cardiac electrophysiologists who are becoming more and more aware of this treatment option. But the prescription of the drug is not restricted to cardiologists or cardiac electrophysiologists. What's interesting is some of the concepts that Doctor Stambler and I have described to you are complex cardiovascular or cardiac electrophysiology concepts.

The administration of the drug and how the drug works is actually relatively simple. We talked before about this being a calcium channel blocker. This is very similar to a calcium channel blocker, as was mentioned, verapamil. Verapamil has been around for decades. Physicians, patients, regulators at the FDA are very familiar with verapamil and misuse. That ended up being very reassuring not only to FDA reviewers, but it's been very reassuring to physicians that we've we've spoken with. So just to summarize, even though we've talked about a lot of cardiovascular and electrophysiologic detail that the administration, the self administration and the way this drug targets one specific area of the heart is relatively simple.

That's great. Now Doctor Stambler, would you know if if Cardamis because it's it's newly approved, is it covered by insurance and how can patients access it? I think I'm going to defer to Doctor Barucha who's the Chief Medical Officer for Milestone on that exact question because this is it was just FDA approved in December and this is rapidly changing as we speak. So he can probably provide you with the updated information about this. All right. What's the latest on that? Yeah, the drug is available in retail pharmacies across the United States.

In terms of coverage that is always a challenge for any drugs soon after its approval. In fact, when you look at the rates of prescription coverage, it always accelerates after many after several months of it being available to physicians across the US. In terms of coverage, actual coverage, Milestone has worked with multiple payers and payer organizations to ensure the following if patient has commercial insurance, it should be covered and not covered at a tremendous out of pocket co-pay. If a patient has Medicare, it is approved for Medicare patients, but it has not yet been approved for Medicare payment, although there is an exception process that patients have and doctors have been successful at thus far.

Third, we have what's called APAP or a patient assistance program, and that is for a patient of certain means, as long as their annual income is below 3 times the upper limit of the federal poverty level, the drug can be provided to patients at no or little cost to them. So what we've done even in these very early stages while we're waiting for full quote, UN quote payer coverage is we've made sure that wide swaths of patients can get this drug and can get it with little, little hindrance or little out of pocket payment.

Is that information available on the cardamis.com website for for patients? Some of that information is available. There's also 1800 numbers that any patient or prescribing physician who's running into these types of questions can call, including patients who are having a difficult time, I hate to say it, with just red tape of getting a exception approved. We have people at the ready to assist with that process. Great. That's that's good news. Now Doctor Rucha is is cardamis being studied for other conditions, cardiac or or others?

Sounds like it's a unique drug with unique mode of of treatment. It is. What's already been mentioned is another cardiac arrhythmia called atrial fibrillation. Patients with atrial fibrillation have very rapid heartbeats, very symptomatically rapid heartbeats. It can be a real problem. We've already studied the drug, although it's not indicated for atrial fibrillation yet. We've studied the drug in patients with atrial fibrillation and actually published and presented some very compelling phase two data several years ago at the American Heart Association meetings.

These data are strong and promising enough both from a safety perspective and from an efficacy perspective that we are shortly in short order initiating a phase three study of atripomil in atrial fibrillation. We've spoken to FDA. We have what we believe is an efficient regulatory path towards approval should this upcoming phase three study be successful. And we have every reason based on pharmacologic theory and based on these very promising Phase 2 results that we're very optimistic that this phase three trial will run very successfully.

Well, that would be great because atrial fibrillation is much more dangerous type of arrhythmia with lots of potential complications. So that would be great if if it's proven to be effective for that, right?

Yes, it's very exciting to be able to potentially in the future give this to patients with a fib. They're very symptomatic when the heart rate is racing off and there are limited options just like PSVT when their heart is racing off very irregular, very fast. They also like PSVT patients end up in the emergency room frequently for intravenous medication. So this is an exciting new potential other application of this new drug, right? Hopefully those clinical trials will show that. So that's great.

Yes. So that is really exciting news that we have a new way to treat this annoying, difficult problem that over 1,000,000 people in the USA have. And really grateful that you took your time to share your knowledge and information about Cartomist and a new way to treat this condition. So I really appreciate that and I'm sure the audience will as well. So thank you very much for appearing on the your podcast show to tell us about it. Thank you for your invitation and the interest. Yeah, I appreciate it.

Doctor Sicher, thank you very much. And this is a very exciting time for all of us in the cardiovascular community. As we discussed, the data show Cardamis is safe for self administration in an at home setting. It's effective and quickly stopping symptomatic PSVT. And so we're really looking forward to the near future here. Sounds great. Thank you.

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