Milestone Pharmaceuticals Inc.

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

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

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