Hello, and welcome to Edgewise Therapeutics Investor Event. My name is Raphael, and I will be the operator for today's call. I would now like to pass the call over to Mike Carruthers. So please go ahead when you're ready.
Thank you, and good morning. This is Mike Carruthers, Chief Financial Officer of Edgewise Therapeutics. Welcome to our call to discuss our positive top-line data for EDG-7500 from the phase 2 CIRRUS-HCM trial in patients with obstructive hypertrophic cardiomyopathy and phase 1 trial in healthy subjects. We're using slides to accompany our remarks today, and they can be downloaded from our investor relations section of our website, and a replay of the conference call will also be available as a webcast on our website. I'd like to introduce Edgewise President and Chief Executive Officer, Dr. Kevin Koch; our Chief Development Officer, Dr. Marc Semigran; and our Vice President of Discovery and Translational Pharmacology, Marc Evanchik, who will present during our call today. As a special guest, we have joining us today, Dr.
Anjali Owens, the lead investigator on the CIRRUS-HCM trial and Medical Director at the Center for Inherited Cardiac Disease and Associate Professor of Medicine at the University of Pennsylvania. Dr. Alan Russell, our Chief Scientific Officer, Dr. Behrad Derakhshan, our Chief Business Officer, and I will be available to answer questions as needed. Before I turn the call over to Kevin, we want to remind everyone of the following safe harbor statement: The matters we're discussing today include projections or other forward-looking statements about the future results and research and development goals at Edgewise. These statements and estimates, based on management's current expectations, involve risks and uncertainties which could cause them to differ materially from actual results.
We refer you to risk factors discussed in our filings with the SEC, including our annual report filed on Form 10-K on February twenty-second of this year and other Edgewise filings with the SEC. These filings identify important risk factors that could cause actual results to differ materially from those in our projections or forward-looking statements. Edgewise specifically disclaims any obligation to update any forward-looking statements except as required by law. I'll now turn the call over to Edgewise CEO, Dr. Kevin Koch.
Thanks, Mike, and thanks for all of you joining us today. I think we've got some great news and really exciting data to provide to you. Edgewise Therapeutics is the leading muscle disease pharmaceutical company, developing novel therapeutics for the treatment of muscular dystrophies and serious cardiac conditions. The company's deep expertise in muscle physiology is driving a new generation of novel therapeutics. Sevasemten, our orally administered Type II skeletal myosin inhibitors in late-stage clinical trials in Becker and Duchenne muscular dystrophies. EDG-7500, the subject of today's disclosure, is a novel cardiac sarcomere modulator for the treatment of hypertrophic cardiomyopathy and other diseases of diastolic dysfunction, and is currently in phase 2 clinical development. The entire team at Edgewise is dedicated to our mission of changing lives of patients and families affected by serious muscle disease.
Let me tell you a little bit about how we discovered EDG-7500. The first program we chose to target at Edgewise was in the muscular dystrophy space, where we were going to selectively regulate the degradation of certain muscle fibers called fast skeletal muscle fibers. We ran a high-throughput screen using a functional myofibril assay with skeletal muscle as the assay constituent. This assay contains all the contractile elements of muscle, called the sarcomere. One can measure the contractile function of the sarcomere by quantitating the turnover of ATP to ADP as a surrogate for contraction. We then evaluated over a million molecules and found leads or starting points to develop drugs, which ultimately led to EDG-5506, our muscular dystrophy drug, now called sevasemten.
When we were first developing sevasemten, we ran a counter screen with cardiovascular tissue, so we wanted to identify selective skeletal muscle modulators. Interestingly, we found a group of lead molecules out of that high-throughput screen that were more potent on cardiac tissue. Some of them were exactly like the drugs now known as mavacamten and aficamten. They were direct Type I myosin ATPase inhibitors. However, at the time, we knew that one of the liabilities of direct cardiac myosin inhibitors, or CMIs, is that their mechanism of action required decreases in contractility of cardiac muscle fiber, as measured by the echocardiographic metric ejection fraction. Decreases in ejection fraction could lead to adverse effects like heart failure. So we decided to take a different path to invent something truly groundbreaking and novel.
We initiated lead optimization on a different chemical series that did not bind directly to the myosin ATPase, but still worked within the sarcomeric complex. While we didn't know the mechanism of these molecules, we noticed early on in preclinical models that they had a very wide therapeutic index and cardiac function, and that they were quite different than the cardiac myosin inhibitors. So we optimized the properties of these molecules, looking for a candidate that did not change ejection fraction, but was still highly effective. Ultimately, we identified EDG-7500 and moved the molecule into clinical studies about a year ago. What was truly exciting about EDG-7500 was that in preclinical models of obstructive and non-obstructive hypertrophic cardiomyopathy, we could decrease cardiac outflow gradients and improve diastolic relaxation, both measures of disease in these models, without affecting ejection fraction.
Today, we will discuss the first human data, looking to validate our original hypothesis of the value of this novel mechanism for the treatment of cardiovascular disease. I'll now turn the discussion over to our Chief Development Officer, Mark Semigran.
Thank you, Kevin. HCM is the most common genetic cardiovascular disease. While the diagnosis can be made at any age, HCM is most commonly identified when a patient is in their late teens or twenties, or when they are in their forties. Thus, it affects adults when they are in the primes of their lives. HCM is an important cause of sudden death, atrial fibrillation, stroke, and heart failure in adults at any age. Even before these major events occur, HCM dramatically impairs physical, emotional, and financial quality of life. While observational studies suggest that HCM impacts one in 500 adults, the prevalence of the genetic variants associated with the disease suggest its presence in one in 200, with as many as 85% of HCM patients undiagnosed. This slide shows the cardiac structural abnormalities associated with HCM. The normal heart is shown on the left.
The middle illustration diagrams a heart with obstructive HCM. It has asymmetric thickening of the left ventricular wall, greatest in the interventricular septum. This septal thickening, in combination with the apposition of the anterior mitral valve leaflet, leads to a narrowing of the left ventricular outflow tract, we call the LVOT, impeding the heart's ability to do its job, to pump blood to the rest of the body. On the right, we see the major structural abnormality present in non-obstructive HCM patients, a symmetrically thickened LV wall. There is no obstruction to the outflow of blood. Heart function is impaired by diastolic dysfunction or impaired relaxation, and the lack of compliance of the heart, limiting its ability to fill with blood to pump. In the large majority of patients, abnormalities of the cardiac sarcomere, the force-generating component of the heart muscle cell, cause both excessive contraction and diastolic dysfunction.
Both LVOT obstruction and diastolic dysfunction contribute to the development of heart failure in HCM patients. In obstructive HCM, both blood flow obstruction and diastolic dysfunction are present. In non-obstructive HCM, it is diastolic dysfunction that leads to the failure of the heart to adequately pump blood. As a senior HCM cardiologist recently said, "I've been studying cardiac function for 45 years, hoping for a drug that could improve diastolic function. The development of such an agent would be an incredible achievement that would address the unmet needs of many patients." Current treatments for HCM, including surgical and pharmacologic approaches, have key limitations that leave substantial gaps in the treatment of HCM patients. These include the limited efficacy of drug therapies, including beta blockers, calcium channel blockers, and the cardiac myosin inhibitors, or CMIs.
CMI efficacy may be limited by its mechanism of action, which is associated with reductions in LV ejection fraction, requiring monitoring and dosage reductions or interruptions. CMIs are not recommended for use in patients with an LVEF of less than 55%. Septal reduction therapy is invasive and associated with significant morbidity and some mortality. There are no approved therapies for non-obstructive HCM. Off-label therapies, which do not target the underlying disease pathophysiology of diastolic dysfunction, are of limited efficacy. Cardiac transplantation may be necessary for non-obstructive HCM patients with persistent symptoms. The presence of a black box warning on the mavacamten label cautions that it, quote, "reduces left ventricular ejection fraction and can cause heart failure due to systolic function." This limits clinicians' ability to easily and safely prescribe mavacamten.
Concerns about the risk of development of heart failure in patients treated with mavacamten have led to a risk evaluation and mitigation strategy as a part of the label. This REMS mandates frequent echocardiographic monitoring of patients on mavacamten, both during initial dose titration and during the indefinite maintenance phase of treatment. This frequent monitoring is very burdensome on patients and clinicians. I'd like to now introduce Marc Evanchik, Vice President of Discovery at Edgewise, who will describe the characteristics of EDG-7500, a novel cardiac sarcomere modulator that we are developing to address the significant unmet needs of HCM patients.
Thank you, Mark. It is now well established that HCM is a disease of the sarcomere with a large number of identified pathogenic mutations in the contractile proteins. While most of the known mutations are either in myosin heavy chain or myosin-binding protein C, we know that control of contraction and relaxation is a complex and elegantly coordinated effort involving many proteins. In the healthy heart, there are approximately 10% of the myosin motor heads pulling on actin at any one time. In the HCM heart, there are more active myosin cross-bridge interactions, resulting in a hyperdynamic state that contracts at a faster rate and has impaired relaxation. We designed EDG-7500 to target disease at the source: excessive actin-myosin cross-bridge interactions. We took a new approach by engineering EDG-7500 to be more potent during diastole and early systole....
This resulting mechanism both slows the rate of actin-myosin cross-bridge formation and speeds disengagement without inactivating myosin heads. As a reminder, we have gathered a compelling preclinical package that supported the investigational new drug application and clinical studies of EDG-7500 as a novel therapy for both obstructive and non-obstructive HCM. Preclinical studies support the mechanism of action that was described on the previous slide. Animal models of obstructive HCM demonstrated potent gradient reduction uncoupled from reduction in left ventricular ejection fraction. Genetic models of non-obstructive HCM demonstrated improvements in diastolic function and restoration of cardiac reserve, a direct correlate of improved peak VO2, the approvable endpoint in HCM. And lastly, measures of systolic and diastolic performance in the dog showed that even with reduced left ventricular ejection fraction consistent with heart failure, EDG-7500 improved diastolic compliance without significant changes to left ventricular ejection fraction.
We believe EDG-7500 is positioned to address unmet needs in HCM. The targeted mechanism of action addresses both the hyperdynamic nature of HCM and the impaired relaxation associated with both obstructive and non-obstructive HCM. Preclinical efficacy is dissociated from changes in left ventricular ejection fraction, which may allow for a deeper therapeutic response, and lastly, potential ease of use by avoiding complex titration schemes needed to reach therapeutic doses and exposures. Now I will turn attention to the results from our placebo-controlled phase 1 trial in healthy adult subjects. We conducted a single ascending dose trial over the dose ranges of five to three hundred milligrams, and the multiple ascending dose phase studied once-daily administration of drug for fourteen days at twenty-five, fifty, or one hundred milligrams.
The subjects in the SAD and the MAD portions of the study received a mix and drink liquid formulation, which allowed for flexibility in the dose strengths evaluated. We also conducted a crossover study to evaluate a solid tablet that will be used in the outpatient portion of CIRRUS-HCM. The main goals of the study were to assess safety, tolerability, PK, and pharmacodynamics measured by echocardiography. Across the SAD and MAD, a total of 72 subjects were enrolled, with each cohort consisting of two active and two placebo. The drug was well-tolerated across all doses in both the SAD and MAD cohorts. There were no reported serious adverse events. The incidence rate of treatment-emergent adverse events was low at 25% in both the placebo and EDG-7500 groups. All AEs were mild, with the exception of one reported moderate AE of ECG tab site irritation.
In the MAD, the treatment-emergent adverse event frequency was also low, at 33%, and identical between placebo and EDG-7500 groups. All TEAEs in the MAD were mild. In addition, across both the SAD and the MAD cohorts, there were no significant changes in vital signs. EDG-7500 was well-tolerated, with no clinically significant changes or trends in clinical chemistry, hematology, or ECGs. The incidence of treatment-emergent AEs was similar between the two groups, and left ventricular ejection fraction remained within the normal range for all subjects at all time points. Importantly, none of the subjects experienced a decrease in left ventricular ejection fraction below 50%. In terms of pharmacokinetics, EDG-7500 behavior was favorable, with a measured half-life of approximately 30 hours across all dose groups. Exposure was largely linear and dose proportional, except at the highest group tested, 300 milligrams, which was less than dose proportional.
In the MAD cohorts, exposures were consistent with the results from the SAD cohorts, linear and dose proportional increases across the three dose levels investigated. As anticipated, with a measured half-life of thirty hours, the accumulation ratio at steady state was twofold. After day fourteen, EDG-7500 washout was similar to the SAD, with a terminal half-life ranging between twenty-three and thirty-four hours. Trough levels of EDG-7500 demonstrated the rapid attainment of steady state, which occurred approximately four days after the start of dosing. As a reminder, it has been reported that pharmacologically active doses of CMIs decrease left ventricular ejection fraction in a concentration-dependent manner. Several examples from the literature, including an FDA-approved agent and those in development, are shown to illustrate the exposure-dependent nature of the left ventricular ejection fraction reduction.
It's worth noting that while the trend is linear in these examples, there are reductions in LVEF outside of the confidence intervals. In addition, dose-related reductions in left ventricular ejection fraction to less than 50% have been reported for each of these CMIs. As Kevin mentioned earlier, we decided to take a different approach with the EDG-7500 and optimized a compound that prioritized slowing of the contractile apparatus and preserving systolic performance. In our phase one study of healthy subjects, the baseline left ventricular ejection fraction was 61% in both the SAD and the MAD cohorts, and was balanced to the placebo arms. The pooled SAD/MAD cohort showed no change in systolic performance versus placebo, and no change to baseline with increasing exposures of EDG-7500, up to a concentration of 874 nanograms per mL.
The points largely center around zero. There were no reductions of more than 10%, all within the observed placebo range. There were no reductions of left ventricular ejection fraction to less than 50%. And lastly, this exposure range exceeds those observed to have beneficial effects in preclinical models of both obstructive and non-obstructive HCM. To summarize, EDG-7500 was well-tolerated in the phase 1 study of healthy subjects. 7500 showed optimal PK properties supporting once-daily fixed-dose administration, reaching steady state in four days. None of the subjects experienced left ventricular ejection fraction reductions to less than 50%, and no correlation between plasma exposures and LVEF up to 874 nanograms per mL above our predicted therapeutic exposure was noted. All this together supports a differentiated mechanism of action that preserves systolic performance. And now I'd like to hand it back to Dr. Semigran, who will introduce CIRRUS-HCM.
Thank you, Mark. The CIRRUS-HCM study design was informed in part by the results of a study of the administration of a single dose of mavacamten to two obstructive HCM patients. At baseline, both patients had modest LVOT gradients between thirty and forty millimeters of mercury, as you can see in the lower graph on the left. It was observed that after mavacamten administration, reduction of the gradient occurred, along with a reduction in LV ejection fraction below normal. This led to the conclusion at that time that quote, "Reduction in contractility leads to reducing outflow tract gradients," close quote. CIRRUS-HCM is a multi-part study primarily designed to assess the safety and tolerability of single and multi-day EDG-7500 administration to adult HCM patients.
Exploratory endpoints include pharmacokinetics and pharmacodynamic effects of EDG-7500 on the cardiac manifestations of HCM, including LVOT gradient in obstructed patients, LV ejection fraction, and circulating cardiac biomarkers. Part A has been completed, and Parts B and C have begun enrolling patients with obstructive and non-obstructive HCM, respectively, for twenty-eight days of study drug administration. The Part B study population does include patients that have completed Part A. We will focus for the next few moments on Part A, where eleven patients with obstructive HCM were studied before and after the administration of a single dose of EDG-7500. Key entry criteria at screening were notable for the presence of a resting LV gradient greater than or equal to thirty millimeters of mercury and a provoked Valsalva gradient of greater than or equal to fifty millimeters of mercury. We included patients with New York Heart Association functional Class I through III.
Assessment of safety and tolerability was our primary objective, with assessments of rest and provokable gradients, circulating cardiac biomarkers, and EDG-7500 pharmacokinetics also conducted. Assessments were made prior to drug administration, during an eight-hour observation period in the clinic, and when the patients returned to clinic on day two and day eight. Our exploratory hypothesis is that the novel mechanism of EDG-7500 will uncouple gradient relief from reduction in LVEF. Due to the intrinsic variability of several of the measurements we are making,
we pre-specified an efficacy analysis plan that defined both a safety population consisting of all patients that were administered EDG-7500, and an efficacy-evaluable population who met entry criteria at both screening and baseline. Eleven patients constituted the safety population, and seven qualified for efficacy evaluation. Four patients who were eligible at screening did not have a large enough LVOT gradient at baseline to meet efficacy-evaluable eligibility. Dr. Anjali Owens, Associate Professor at the University of Pennsylvania Cardiology Division and the CIRRUS-HCM investigator, will now report the results of the key outcome measures of CIRRUS-HCM part A. Anjali?
Good morning, Mark, and thank you for the introduction. It's my absolute pleasure to be here today to discuss with you these exciting new results. So let's start with the baseline characteristics of our cohort. And to remind you, this is the full 11-patient cohort with a mean age of 59. We had a majority of female participants, which is notable for an HCM trial. We did include, as Mark mentioned, asymptomatic Class I patients, 27% in this cohort. The remainder of patients were Class II and III NYHA. With regard to severity of HCM. We had a mean maximal end-diastolic wall thickness of two centimeters, which is pretty typical of an obstructive HCM population, and they had severe obstruction. As you can see, resting gradient mean of 60, Valsalva gradients in the 80s.
The LVEF in this cohort, mean of 68%, again, in the normal to hyperdynamic range. And as pretty typical, 64% of patients were on background therapy with a beta blocker. And I should note, the LVEF and gradients were read by a core laboratory for this cohort. Next slide. Let's start with tolerability. What we saw in this cohort of patients was EDG-7500 was well tolerated by all participants across the doses studied. We saw no treatment emergent abnormalities in blood work, and no patients experienced a decrease in LVEF to less than 50%. In the table, I have summarized the four AEs, starting with a patient who had a paroxysm of asymptomatic atrial fibrillation at the 200 mg dose. This was deemed to be mild and not related to study drug.
This occurred in a patient who had a known history of paroxysmal AFib, which occurs in 20%-30% of patients with obstructive HCM. This patient was already treated with a beta blocker and an oral anticoagulation and continued on therapy. The second AE was one of hypotension occurring in the 100 milligram dose cohort. This was deemed to be mild and unrelated to study drug, and upon further review, this patient was receiving oral vasodilating medications for treatment of systemic hypertension and had a history of lightheadedness after receiving those vasodilator medications. The final two AEs occurred in the 50 milligram cohort. One was nightmares in a patient with a history of PTSD, anxiety, and depression, and the second was isolated hypokalemia. Next slide. Let's look next at the efficacy, and we'll start by looking at resting LVOT gradients across the dosing cohorts.
You can see on the left, the resting LVOT gradient across the time points. In the three dosing cohorts, we have the 50 milligram, 100 milligram, and 200 milligram cohorts. The group mean values showed a substantial and rapid improvement in LVOT resting gradients, with three out of five patients receiving the higher doses, with a resting gradient of less than 30 millimeters of mercury after a single dose at the two-hour time point. Those gradient values returned toward baseline at the 24-hour mark. This represented a 67% change from baseline in resting LVOT gradient in the higher dose cohorts. Next slide. We'll turn our attention to the Valsalva gradient on this slide, a similar setup in terms of the graphs.
On the left, LVOT Valsalva gradients, which you can see are in the severe range at baseline, come down substantially at the two-hour time point, with three out of five patients, again, in the 100- and 200-milligram cohorts, with the Valsalva gradient less than 50 millimeters of mercury. That is our threshold for defining severe obstruction after a single dose of EDG-7500, and this represented a 55% change from baseline at the two-hour mark. Next slide. Perhaps most notable was there was no correlation between EDG-7500 plasma concentration and LVEF change across the time points. The first patient we dosed here at the University of Pennsylvania was a young woman of mine who I followed for over a decade. She had had two failed septal myectomies, which are open heart surgery.
She was class three, one of the sickest hearts I've seen in terms of obstruction. And when I went to check on her after the two-hour dose, she said to me, "Dr. Owens, I felt my heart touch the inside of my rib cage with each heartbeat since I was a teenager, and for the first time in my life, I don't feel that." And I immediately went to listen to her heart and noted that her gradient and her murmur was much improved, and her echo substantiated those findings. So a truly remarkable result after a single dose and no change in EF. The slight changes you see here with a positive of 2.4% to a negative of 3.2% is well within the noise of what we see in measuring LVEF by echo.
As a reminder, the safety threshold we have is an LVEF of 50%, and no patient declined to less than 50%. Next slide. The final data I will show in this cohort is with regard to cardiac biomarkers and specifically NT-proBNP, which we know is a marker of stretch within the myocardium diastolic function, and we know that this marker, when it is elevated, correlates with adverse events in patients with cardiomyopathy and heart failure, and what we observed after a single dose of EDG-7500 was a dose-dependent reduction in NT-proBNP that occurred quite quickly after dosing. You can see an eight-hour and twenty-four-hour reduction, with the highest dose cohort achieving a decline, a relative change from baseline, of greater than 60% in NT-proBNP.
In addition to being a marker of diastolic function, we also know that reductions in NT-proBNP have been associated with an increase in peak VO2 or functional capacity, which has been the primary endpoint in several obstructive HCM trials. Next slide. In summary, what we found from this Part A cohort of EDG-7500, single-dose administration was well-tolerated across all doses. We saw that EDG-7500 led to a substantial reduction of resting and Valsalva gradients, ranging from 67%-50% for the higher dose cohorts, with multiple individuals achieving gradients less than the threshold for defining obstruction.
This gradient relief was achieved without an observable reduction in systolic performance, as measured by left ventricular ejection fraction. The NT-proBNP decreased in a dose-dependent manner. Taken in whole, these are very encouraging observations from a single-dose study, and they highlight this molecule's potential as a novel mechanism of action and therapy for patients with HCM. I will turn it back over to Dr. Semigran.
Thank you very much, Anjali. The positive data from Part A has supported the initiation of CIRRUS-HCM Parts B and C. The development of a solid dosage form has enabled outpatient administration of EDG-7500 and enrollment of both obstructive and non-obstructive HCM patients in Parts B and C, respectively. In both parts, we continue to evaluate the safety and efficacy of EDG-7500 administration to patients. In Part B, we will also evaluate for potential deepening of the efficacy response with twenty-eight days of EDG-7500 administration.
In Part C, we will further explore the effect of twenty-eight days of EDG-7500 administration on cardiac diastolic function in non-obstructive HCM patients. Upon completion of Part B or Part C, patients may be eligible for enrollment in a long-term extension study, where evaluation of EDG-7500's tolerability and effects on patient feel and function will be assessed. I would now like to pass the microphone back to Kevin Koch, our CEO, for closing remarks.
Thanks, all. That was a great presentation. I really I'd like to summarize our optimal and differentiated target profile for the treatment of hypertrophic cardiomyopathy. Based on the observations to date, we have identified a molecule that does not require the reduction of ejection fraction to ought to define disease amelioration, as measured by gradient reduction in biomarkers such as NT-proBNP. None of our healthy subjects or HCM patients fell below the threshold for heart failure, as measured by ejection fraction less than 50. And in fact, we saw no meaningful relationship between concentration of drug relative to ejection fraction changes. This safety profile might allow us to minimize monitoring requirements similar to standard of care agents in HCM and cardiovascular disease.
The acute reductions observed with NT-proBNP, a biomarker of diastolic dysfunction and exercise capacity like peak VO2, bodes well for the utilization of our drug across heart failure, especially non-obstructive HCM, disease of limited treatment options. Finally, EDG-7500 could be utilized in a fixed-dose regimen without the need of a complicated titration scheme to obtain suitable efficacy. From the company's standpoint, we are poised to deliver on our promised milestones for the year. We have already reported positive data from ARCH and DUNE for the treatment of Becker muscular dystrophy. Today, we reported the first human results on EDG-7500 and have initiated a twenty-eight-day dosing. We are nearing the completion of our placebo-controlled CANYON study in Becker muscular dystrophy, with top-line data to be released by the end of 2024.
We'll also provide dose-ranging data with sevasemten for the treatment of Duchenne muscular dystrophy by the end of the year. As for 2025, we will provide an update on our 28-day data with EDG-7500 by the end of the first quarter, and additionally, by the end of the first quarter, to the complete enrollment of GRAND CANYON, our pivotal study in Becker muscular dystrophy. Importantly, we are well-financed, with $512 million in the bank, zero debt, and cash runway through 2027. In conclusion, I'd like to personally thank everyone who has chosen to support our mission, particularly our talented and dedicated employees and their families.
Most importantly, I'd also like to thank our patient community, trial participants, and clinical investigators, especially Dr. Owens, and to our shareholders for the continued confidence and enthusiasm. It's been an exciting time here at Edgewise, and I truly believe we are on the cusp of demonstrating the potential of our therapeutic agents that could help improve the lives of patients in need of more effective treatments. Thank you all for joining the call. I'll be happy to take any questions.
Thank you. If you would like to ask a question, please click the Raise Hand icon at the bottom of your Zoom window. If you are joining via mobile phone, please use star six to unmute your line. We ask that each person only asks one question. Our first question today comes from the line of Joe Schwartz from SVB Securities. Please go ahead. Your line is now open.
Hi, Joe, might be on mute. Joe?
Yeah, he's unmuted. Joe is unmuted. You are welcome to ask your question, Joe.
Maybe let's jump to the next person, and then we can come back to Joe.
No problem. The next person in line is Yaz Rahimi from Piper Sandler. Yaz, I'm afraid maybe Yaz is not-- is there. I'm allowing Yaz to open-
Yeah.
His microphone now.
Hey, Yaz.
Yes. Hey, good morning. Can you hear me?
Yes, go ahead.
Yes.
Okay, perfect. All right, team, congrats on the strong data. I guess the question that comes up for everybody is: could you comment on which doses you're moving forward in your MAD portion of your study?
Yeah, um-
Which could give us also some color, whether we could drive up the LVOT further. Would appreciate if you could provide some color around that, because I think, and I'll jump back in the queue in respect to wishes of one question per group.
Yeah, no, I think, you know, we've said that, this is all. I mean, what's amazing about this data, this is a single-dose data. If you look at the history of any of the sarcomere modulators, the depth of the response increases over time with these drugs. Because essentially, you're remodeling and normalizing the heart function. And what we were quite surprised is how rapid the stress response, like BNP changed, so we would anticipate that you could go to even lower doses with this drug, and observe and see really profound benefit, and that the efficacy would deepen over time, so we're starting our 28-day study at 50 milligrams. We think that level will provide efficacy, even though it was around the border of providing efficacy in the single dose, and we will move up, or perhaps down from the results.
Great. Thank you so much. I'll jump back in the queue.
Thank you. The next question today comes from the line of Laura Chico from Wedbush. You are welcome to unmute your line now.
Good morning, and thank you for taking the question. With respect to the 28-day data, I'm wondering if you can expand a little bit more on what's going to be most important to learn there, beyond increased or deepening response on the gradient reduction. I guess I'm trying to understand, how does the bar for success change at 28 days versus the initial SAD data? Thank you.
We would like to see all these gradient changes occur at trough, which is important. Of course, like to continue to see the elimination of a concentrational relationship with left ventricular or left ejection fraction. We would like to see a deepening of the response of BNP if we can get everyone into a normal range, which would be exciting. We'd also like to look for a diastolic function in the non-obstructive HCM patients, where we think is the most likely place we will be able to measure that quantitatively.
So all of those things, I think this is what we're showing today is kind of the minimal effect you might see with this drug, and I think it looks very exciting. We're also be measuring, at the twenty-eight-day time point, things like KCCQ and New York Heart Association changes. Ultimately, in the open label extension, we will actually move to looking at things like peak VO2, but that's kind of the next step after the twenty-eight day.
Thanks very much.
Thank you so much. The next question will go to Joe Schwartz from SVB Securities, who I think can now unmute his phone via the star six.
Hi, thanks for coming back to me, and congratulations on the data. I was wondering if you can talk about what you see in terms of the width of the therapeutic index, and what exposures do you think you need for efficacy, versus what exposures do you think might be associated with any EF reductions of import? I know you didn't see anything over 10%. I was just wondering how are you feeling about the potential to have flat dosing with EDG-7500? Thanks.
Yeah, I mean, what we've seen preclinically is concentration levels between 100 and 200, providing benefit both acutely and for up to five months in the porcine model of non-obstructive HCM. Here, we still need to do additional work to understand the depth of response with the continued dosing. I think I still believe that there's probably an overlap between the preclinical models and healthy humans, so that I would expect the dose range between 100 and 300 as far as concentration. But obviously, we will explore the entire range. We had a concentration of up to 850 nanograms per milliliter and showed really nothing outside of the normal range in the left ventricular ejection fraction.
So we have a wide range to increase dose. And so I think what we're really shooting for here on the fixed-dose aspect of the drug is to provide benefit to the patients as measured by gradient or proBNP in 80% of the patients with a fixed dose. Now, of course, whenever you're trying to optimize efficacy, there will be some outliers, but you know, if you can pick a dose where 80% of the patients benefit, I think for all intents and purposes, you've defined a fixed-dose regimen.
Very helpful. Thank you.
Thank you. The next questions today comes from the line of Tessa Romero from J.P. Morgan.
Congratulations on the result here, Kevin and team. Can you hear me?
Yes, Tess. Thanks.
Great. So my question is for Dr. Owens. Thank you so much for sharing your insights today with us. Are you able to opine a little bit on the natural intra-patient variability in LVEF, and how you interpret the PK/PD relationships that we're seeing in the healthy volunteers here and also in the patients? Where did these results fall relative to your expectations heading into these results? And big picture, where do you have key questions, if you do, about the mechanism and its downstream impact in the heart as we move ahead here? Thanks so much.
Hi, Anjali. Feel free to opine.
Great. We see a lot of intra-patient sort of variability. It's rarely a one-size-fits-all approach for patient management in terms of how you select the drug that's right for them, and then ultimately, what you decide to do in terms of dose titration of a medication. So in general, patients with hypertrophic cardiomyopathy of the obstructive variety have preserved or hyperdynamic contractile function. And in that group of patients, you know, you are able to modulate contractility or force of contraction with agents that provide benefit to outflow tract obstruction and gradient reduction. Where I think the variability is highest or we see the most heterogeneity is really within the non-obstructive HCM population. And there, you really see a continuum of the disease, from hyperdynamic function to normal function to hypodynamic function.
We see patients with advanced stages of non-obstructive HCM, where they have a predominant feature of diastolic dysfunction, high filling pressures, and in some cases, even almost restrictive filling, where you do not want to impair systolic performance. It's already been impaired, and that's through years of disease and fibrosis that can accumulate. It's really important to think about the mechanism of action of any drug that you're using, and really, this goes for any patient with cardiomyopathy and heart failure, and try to normalize that physiology. Different patients need different targets in terms of what needs to be normalized. That's where it becomes, you know, more of an art than a science when you really look at the hemodynamics of the patient in front of you, what their heart looks like, what their filling pressures are, what their cardiac biomarkers are.
Essentially, what we're trying to do is take someone from a pathophysiologic state, pathologic, to more normalization. The more tools we have that address different targets, the better it is because that expands our armamentarium. I would not be surprised if we find that it's a combination of therapies, similar to what we've developed in disease states like heart failure with reduced ejection fraction, where we have several pillars that target different mechanisms in that model.
We're in our early stages of understanding that in HCM, and we may find that modulating different pathways, sometimes in concert, might even be the most beneficial. Again, I think we're in the early stages of understanding that, but critical to that is gonna be sarcomere modulation, which, as Marc Evanchik said, you know, this disease is many times one of the sarcomere. And also, I think, you know, other mechanisms such as energetics, other pathways in the genetics, will also be important.
Thank you. The next questions today comes from the line of Leonid Timashev from RBC Capital Markets. Leonid, your line is now open. You're welcome to unmute.
Hi, guys. Yeah, thanks for taking my question, and congrats on the data. I had a question on the 200-milligram dose. You know, I'm curious how you're thinking about what it showed there on gradient reductions. And you know, if there's any reason to think that, you know, similar to how there might be a self-limiting mechanism on how low LVEF can go. You know, is there a threshold or sort of a cap to the efficacy that this mechanism can drive, given that two hundred didn't seem to necessarily show a lot more gradient reduction than one hundred milligrams? And maybe how you reconcile that with the proBNP data, which looked to be significantly better for two hundred milligrams than for one hundred. Thanks.
Yeah, I think, you know, if we're at this point with low numbers, it's hard to really interpret, you know, the depth of the response. There obviously were patients who were greater than 80% reduction in this group. But, depending on where you start from your gradient, and we also have noticed that there's significant variability. As you saw, four of the patients came in at screening with one gradient, and you looked at baseline numbers, and they didn't attain the same level of gradient.
So, I think it's hard to look at this and say there's any limit to the efficacy that we can see. I don't really see that from the data, and in fact, from the data we have, I think that you can continue to drive efficacy. And again, this is only a single dose. We're doing what other agents, like the CMI, are doing with twelve weeks and twenty-four weeks of dosing. It's hard to compare.
Thank you. The next questions today comes from the line of Kripa Devarakonda from Truist Securities. Kripa, your line is now open. You are welcome to unmute. Kripa, if you are calling from a mobile phone
Yes. Can you hear me?
Yeah.
Yeah.
Okay. Thank you. Congrats, guys, on the data today. So, going back to one comment that Dr. Owens made, I was just wondering if was there any evidence of diastolic benefit in the echo data generated? Any comments that you can make on, you know, changes to the E to A ratio?
Anjali, why don't you provide your thoughts on BNP and how that relates to diastolic function? And just to answer your question directly, we're still crunching data in and around the other measures of echo parameters. We have multiple echo parameters we're looking at, so this is, in some respects, just-in-time data, but maybe, Anjali, speak to the BNP in relationship to diastolic function.
Sure, absolutely. So, you know, it's really a marker of stretch. You can think of. That's released from the myocardium, in response to strain or stretch. So when we see an acute drop, in NT-proBNP, that, you know, almost certainly to me means that the left atrial pressure, is dropping and compliance is improving in the ventricle. And again, it's a pretty marked change when you see it occur, so quickly after administration of a single dose. So to me, that suggests that we will see an improvement in diastolic function long term. Again, with chronic dosing, we have to see and get that data, but I think it is promising in terms of, what we might see.
I just
Just to follow up on that. Sorry, go ahead.
I was just gonna point out that if you go back to our preclinical data, remember that we had significant but you know smaller responses after a single dose in a big model of non-obstructive HCM, and then we took that out at five months, and you saw a profound normalization of the heart across diastolic function after prolonged dosing. So, I think everything that we've seen preclinically has now translated from the preclinical models to the clinical human experience.
Just to clarify, regarding the echo assessment schedule, what were the time points when you had the echoes? Was it only at two hours and twenty-four hours?
Mark? Marc, S?
Sure. Well, we also had an echocardiogram performed at hour six, and when the patients returned on day eight, one week after administration of drug.
Great. Thank you so much, guys. I'll jump back in the queue.
Thank you. The next question today comes from the line of Paul Choi from Goldman Sachs. Your line is now open, Paul, and you are welcome to unmute. If you are calling from a mobile phone, please press the star six.
Hi. Thank you. Good morning, and thanks for taking our question. My question is for Dr. Owens. In your presentation, on slide 32, it looks like the 200 mg dose and 100 mg dose curves are more or less superimposed. Can you maybe comment on your thoughts on the dose-response there, relationship between 100 and 200? I recognize it's relatively small patient numbers.
And for the patient example that you shared, thank you for sharing that, heartwarming example. Can you comment on whether that incident was seen with the 50, 100, or 200 mg dose? Thank you very much.
Yes, the first patient we dosed
Go
Oh, go ahead, Kevin.
Go ahead, Anjali.
The first patient we dosed received a hundred-milligram dose, and as Kevin alluded to, you know, when you look at the dose response, a lot depends on where the patient is starting, and there was a slight difference in the starting gradient between the one hundred and two hundred milligram, and we do see variability. This is a very dynamic number, and so once you get below that somewhat arbitrary threshold of thirty, we consider it pretty normal, and so you know, how much below thirty do you need to go?
You can sort of argue, and I would say the most important thing is that when we see chronic dosing, we want our patients to feel better and function better, so although we use the biomarker of gradient to assess response, and it is meaningful, the disease goes beyond that. And we look at the other biomarkers, we look at remodeling over time, and most importantly, we look at markers of feel and function to really assess how the patient's responding. So I wouldn't read too much into it. This is a small number of patients. When we get more patients with chronic dosing, we may be able to better assess that dose-response relationship.
Thank you. There are no further questions at this time, so I would like to pass the call back to Kevin Koch for closing remarks. Please go ahead.
Thank you all for joining. It was really great to be able to present this data, and look forward to speaking to you in the future, and update you with future data releases. We're excited about the potential of this program in the treatment of our patients. Thank you.
That concludes today's webinar. Thank you all for your participation.