Edgewise Therapeutics, Inc. Common Stock Study update

Please go ahead, Michael. Thank you and good morning.

Welcome to the Edgewise Therapeutics conference call to discuss the differentiated mechanism of action of our cardiac sarcomere modulator, EDG-7500. This morning, we issued a press release announcing these findings. Along with the presentation slides for this call, it's available in the investors and news section of our website at www.edgewisetx.com. A replay of the event will also be available as a webcast on our website. Joining me today are Dr. Kevin Koch, Chief Executive Officer, Dr. Alan Russell, Chief Scientific Officer, and Dr. Michael Ayers, a cardiologist and Executive Director of Clinical Development and EDG-7500 program lead. Before we begin, I would like to remind you that some of the statements made today during the call are forward-looking statements that are subject to a number of risks and uncertainties.

These may cause our actual results to differ materially, including those described in our reports filed with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, and Edgewise disclaims any obligation to update these statements. I will now turn the call over to Kevin.

Hi, Michael. Thank you. I wanted to provide some historical perspective on the company and where we're going as a company and our new focus on the cardiovascular pipeline. We'll spend most of the day discussing the mechanism of action of 7500 and how that fits in the therapeutic portfolio for the treatment of cardiovascular disease. I'll end up with some near-term milestones for the company. As you all know, we started back 2017 as a muscle platform company, looking to invent and develop drugs for the treatment of orphan and rare muscle disorders with a high unmet medical need. We started our program working on identifying a drug for the treatment of muscular dystrophies.

That target of interest there was a type 2 skeletal muscle myosin inhibitor that was really a novel concept at the time. We ran a high-throughput screen, identified some leads, produced thousands of molecules, and ultimately selected sevasemten as the clinical candidate and filed the IND in 2020. Very rapidly, we were able to mechanistically validate the hypothesis that we would prevent muscle damage in muscular dystrophies and move that forward into phase III. That phase III will be reading out by the end of the year. Along the way, though, Servier found our data really compelling and made us an offer that really changed the nature of the company. Actually acquired sevasemten for $2.65 billion last July, with the deal closing last July.

$1.5 billion upfront and $1.1 billion in milestones. It was a great milestone for the company and provided us significant cash to be able to propel and fund our cardiovascular programs. Great work by that team. I want to turn back to the cardiovascular portfolio because really the initiation of the cardiovascular portfolio came out of a counter screen for the skeletal muscle program. When you run a high-throughput screen, you will get a number of hits. We ran through about 2 million molecules. We found dozens of lead series, and then we ran a counter screen to make sure that we had selective skeletal muscle inhibitors. During that time, we found a set of leads that were actually more potent on cardiac tissue than skeletal muscle tissue.

We found molecules that were quite similar to what were found previously, which were type 1 cardiac myosin inhibitors, very similar to the drugs aficamten and mavacamten. But we chose not to just follow that path and make a third-generation type 1 myosin inhibitor. We found another lead series that was quite unique. What was unique about them, they were pharmacologically active, partial inhibitors, and when tested in vivo, they did not lower fractional shortening or ejection fraction in the rat. They had a unique profile, and then after we had completed the IND of sevasemten, we started to really focus in on the cardiovascular program and that particular lead series. We made several thousand molecules in this space and ultimately chose EDG-7500 for development in 2023, where we filed the IND.

Just in the past couple of months, in June, we reported on the 12-week Part D data and showed really in a lot of ways, validation of much of what we have seen pre-clinically with the drug. We will be talking extensively about that in the coming 45 minutes. Turning to the next slide, EDG-7500 is poised to go into phase III by the end of the year. We found a second-generation molecule that has a somewhat different metabolic profile optimized for HFpEF. You probably saw on clinicaltrials.gov, enrollment is open for the HFpEF study. We will not say too much about EDG-003, but we do feel like we have a lead series and are in the candidate selection mode.

We are very excited about the portfolio in cardiovascular disease, and look forward to talking to you about how we discover the drug and some of the key biologic nuances of this value proposition. Next slide. I just wanted to give you a quick executive summary of what you are going to hear today. EDG-7500 regulates the cardiac cycle. Essentially, we are controlling the rate in which the cardiac cycle moves throughout different parts of the cardiac cycle through control of the lever arm, which is the drug binding to the regulatory light chain. This targeting of the regulatory light chain can produce really diverse phenotypes and pharmacologic profiles. There are RLCs that look virtually identical to CMIs, and there are regulatory light chain modulators that have very strong diastolic effects and are completely sparing of systolic effects, which is exemplified by EDG-7500.

Preclinically, EDG-7500 slows early systolic pressure, speeds up mid to late systole, enhances early diastolic relaxation, which is the key pathology in HCM and HFpEF. Clinical findings have been consistent with these preclinical observations, whereas EDG-7500 has reduced gradients, preserved net systolic function, and improved diastolic relaxation. We will be showing some of that data today. More interesting, we will show you a bit of data on the biophysical arrangement of the heads associated with the lever arm, and that by maintaining availability of the heads to reengage the actin filament during exercise, we believe that we will be having a strong effect on endpoints like pVO2 and KCCQ when a patient exercises or exerts themself. We will show you data to support that position. With that, I am going to hand it off to Michael Ayers and allow him to discuss some of the details of the story.

Thank you, Kevin. When I went from running a full-time HCM practice to part-time, I did so because I find this narrative and story so compelling for our HCM patients, and I am just over the moon excited to talk to you today about this mechanism. When we go around and we talk to investors, cardiologists, knowledge leaders, or just anyone about this drug, four questions come up with some constancy. One, how exactly does this thing alleviate gradients? Two, how does it do so, how does it modify contractility without ultimately suppressing ejection fraction, previously thought of as the holy grail for obstructive HCM treatment? How does it improve diastolic dysfunction, and is it doing so in a unique way relative to other agents?

Lastly, is there something in this secret sauce that allows for meaningful symptom and functional improvements relative to other things in the class? I am really excited to go through those four questions with you today. Let us start on the next slide with a little bit of a disease state background to make sure we are all on the same page. HCM is the most common inherited heart condition, affecting around 1 in 500 people. It is dramatically underdiagnosed, misdiagnosed, and there are delays in diagnoses that impact care. It is defined as having a heart muscle thicker than 1.5 centimeters in absence of some cause, and broadly speaking, we like to classify it into two buckets or phenotypes. While both of these patients have thickened heart muscles, they have slightly different pathologies or problems. The first is your obstructed group.

This group has a thickened heart muscle right at the outflow tract, which results in a divorcing of the pressure inside the ventricles relative to the aorta. There is a pressure difference, so now to generate your 120 millimeters of mercury systolic blood pressure, you might have to do 170 millimeters of mercury of work. The second subtype is the non-obstructed subtype, which also has thickened heart muscle, but doesn't have that misplaced thickened heart muscle right at the outflow tract. Though I'll point out, both the obstructed and non-obstructed groups suffer from diastolic dysfunction or abnormal relaxation. When it comes to current therapies in this area, to be honest, there are some effective agents at relieving outflow tract obstruction, but they do so directly via negative inotropy. They decrease how hard the heart is squeezing, and they keep that highway out of the heart open.