2026.09.24 | GP | Pharma | Heart Failure Clinical Landscape

Therapies, and Future Market Evolution

Associated:

KARD

CYTK

Imbria Pharmaceuticals, Inc.

TENX

TECX

MRK

LLY

BAYN:GR

Viewpoint:

KOL - Physician

Moderator: Himanshu Zade (HZ)

| Sep 23, 2026 | 43 Min Read

Ahmed Seliem (AS), Associate Director of Advanced Heart Failure - Cooper University Hospital

SUMMARY

Overview

The discussion centered around the current landscape of heart failure, focusing on the diagnosis, treatment, and management of different heart failure phenotypes, such as heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). The expert, a seasoned cardiologist, shared insights from their extensive clinical experience in managing heart failure patients and highlighted the challenges and considerations in treatment strategies.

Key Insights

The expert emphasized the importance of early diagnosis and intervention in heart failure management, noting that earlier treatment often leads to better patient outcomes. There is a significant delay in referrals from general cardiologists to specialized heart failure clinics, which can result in patients being seen at more advanced stages of the disease. The expert highlighted the need for phenotype-driven treatment strategies, particularly for HFpEF, and stressed the importance of managing comorbidities such as obesity and diabetes. The expert expressed skepticism about certain emerging therapies, suggesting that many do not show enough clinical benefit to warrant widespread use.

Competitive Landscape

Company/Product

Positive Aspects

Negative Aspects

SGLT2 Inhibitors

Foundational therapy for HFpEF, helps with diabetes management

Limited use in patients with CKD and hyperkalemia

GLP-1/GIP Therapies

Beneficial for weight loss and glucose control in obese HFpEF patients

Insurance coverage challenges, not universally applicable

IL-6 Inhibitors

Initially promising for inflammation-related heart failure

Trials terminated due to lack of efficacy

Omecamtiv Mecarbil

Potential for severe HFrEF patients

Limited market presence, overshadowed by existing therapies

Levosimendan

Explored for various heart failure indications

Consistently failed to show clinical benefit

Quantitative Insights

Metric

Value/Insight

Patient Adherence

65-70% adherence to therapy, varies by region and patient literacy

HFpEF Treatment

SGLT2 inhibitors, ARNIs, and MRAs are mainstays; combination therapy is phenotype-driven

Referral Delays

Patients often referred at advanced stages due to systemic issues in cardiology practice

Clinical Data

The expert discussed the use of various biomarkers and diagnostic tools in identifying and managing heart failure, such as echocardiograms, NT-proBNP levels, and right heart catheterization. The importance of phenotype-driven treatment strategies was emphasized, particularly in managing HFpEF with comorbidities like obesity and diabetes. The expert also critiqued the efficacy of emerging therapies and highlighted the need for treatments that demonstrate clear clinical benefits in reducing hospitalizations and improving patient outcomes.

HZ: Hello. Doctor, my name is Himanshu and I am from Guidepoint. I will be moderating today's discussion. Today we have Dr. Ahmed with us, and we will be talking about the landscape of heart failure. As a reminder, we will be discussing publicly available information today. Dr. Ahmed, thank you so much for taking your time and joining this discussion. To start with, can you quickly give your introduction on your clinical and professional experience?

AS: Sure. I'm a board-certified advanced heart failure transplant cardiologist as well as hold a board certification in interventional cardiology. I practice on the East Coast at a large academic medical center. I've been out of training for approximately 8 years. I was previously at another institution that was a large academic transplant institution on the West Coast. I transitioned over here about 2 years ago. I am the director of mechanical circulatory support. I'm the associate director of our heart failure program. I am the co-director of our cardiogenic shock program. I see a panel of about 1,200 patients a year in my combined heart failure interventional clinic. I'm a full-time interventional cardiologist, so I do coronary work, the lab work, et cetera. I'm the director of our CardioMEMS program, which is the second biggest in our region. I don't know what else to say. My interest in heart failure has always been cardiac shock and mechanical circulatory support.

HZ: Okay, great. Thank you for your introduction, doctor. Could you provide an overview of heart failure practice, like how you typically diagnose heart failure patient and how do you confirm different phenotypes of heart failure, whether it is HFrEF or HFpEF or any other phenotype?

AS: Yeah, sure. So very often patients are sent to us by our general cardiology colleagues for concern of heart failure or advanced heart failure. In general, the conversation revolves around patients who are already diagnosed and they're usually diagnosed by the general cardiologist with heart failure. And the question for us as advanced heart failure physicians is what we do with people that are more advanced or not tolerating standard goal-directed medical therapies.

HZ: Thank you for joining us today.

AS: If the patient is sent to us from our internal medicine colleagues and the diagnosis has to be made in a patient who's symptomatic and otherwise not carrying a diagnosis of heart failure. The initial workup is usually centered around an echocardiogram and then certain blood work including a metabolic profile, BNP or NT-proBNP, as well as

some other labs that can help us rule in or rule out heart failure. In general, the echocardiogram allows us to make a diagnosis of HFrEF or HFmrEF nowadays, you know, the mild to reduced EF. If the ejection fraction is normal, then there are other things that we need to do to make a diagnosis of HFpEF. The diagnosis of heart failure itself is a clinical diagnosis historically. The definition was changed about 2 years ago to not only include the signs and symptoms of heart failure, but also other attributable factors that are objective factors that we could document as supporting a diagnosis of heart failure.

HZ: Thank you.

AS: Biomarkers such as elevated troponin or elevated NT-proBNP that can also rule in heart failure, as well as the symptoms of heart failure from a clinical perspective, which as we all know is fatigue, shortness of breath, decreased exercise capacity, PND, orthopnea, lower extremity edema, etc. So those things altogether make us come to the diagnosis of heart failure. The echocardiogram allows us to make a diagnosis of HFrEF or HFmrEF with anything below 50% or 52% sex-based diagnosis. The question then about HFpEF is a very touchy subject. Different people have sort of different criteria you know in general in a patient who has classic symptoms of heart failure with a normal ejection fraction an elevated NT-proBNP that cannot be excluded by other things such as renal failure or other disease processes that could explain why the NT-proBNP is elevated sort of fits the bill for HFpEF. I'm sort of a purist, I like to see in those patients a right heart catheterization that provides evidence of elevated intracardiac filling pressures in the patient who's not on diuretics to sort of support the diagnosis of HFpEF versus somebody who has, you know, pulmonary hypertension, for example, and isolated RV failure explaining why they're fatigued, etc. So that's sort of the workup process. Once you've made the diagnosis for heart failure, there's a whole slew of workup as to, you know, the HZ: Thank you so much for joining us today. Thank you for watching.

AS: The underlying cause for the heart failure, whether it's ischemic, non-ischemic, you go through that workup of left heart catheterization versus stress test. If the patient has non-ischemic cardiomyopathy, then the question comes down to the sort of the history and physical, whether you think that there's high-risk features for amyloid, for example, or sarcoid or a PYP scan, for example, on some amyloid labs versus. If you think there's an autoimmune component or infectious component like HIV or some other labs like autoimmune labs, HIV, thyroid functions, if you think that the disease is driven by tachycardia with tachycardia induced, so if it's AFib, Aflutter, et cetera, or arrhythmogenic in nature. And then obviously coming on in the last couple of years is cardiac MRI to better elucidate if there's any other non-ischemic or infiltrated disease that could be causing the actual underlying cardiomyopathy as well as the genetic testing that can also help us delineate more genetic cardiomyopathy. So that's sort of the whole workup process from beginning to end.

HZ: Okay, got it. And doctor, approximately what proportion of heart failure patient have these phenotypes, whether it is HFrEF, HFpEF or any other phenotype? And in your clinical practice, which phenotype is growing faster and what is the underlying cause that is driving that growth?

AS: Every practice is completely different, right? It's just the way that the practice is built and how big the practice is and what they're looking for. So I'll give you a very quick example. Where I was at before was a very large heart failure department. We were 8 physicians and 15 NPs and we had a very large transplant program. We only saw the sickest of the sick patients. My panel up until 2 years ago was 90% HFrEF, and they were only advanced therapy patients who were needing either advanced MCS, LVADs, transplant, etc. We didn't see sort of general heart failure patients in our advanced heart failure clinic. Where I am now, we are 2 physicians and 2 nurse practitioners and we are building a program and so we see all heart failure patients. My panel now is about 60% HFrEF, 35% HFpEF, 5% improved EF, etc. And so the panel, the breakdown is very much dependent on the program you're talking to, where the program is in development, if it's a community program or an academic program. So there isn't necessarily a generalized figure that could be generalized to the whole population of physicians.

HZ: Okay, got it. And doctor, generally, what stage of this is progression, generally, patients visit to you, especially patients with the HFpEF phenotype, and where do the main diagnostic or referral delays occur?

AS: Again, there's a different answer based on where you're at in your career and what kind of facility you're at. In my current situation, the majority of our patients that come to see us are, I would say, class 2 or class 3 patients. The majority of them are class 3 New York Heart Association patients, so symptomatic. The majority of them are further along in their disease process or they've had heart failure for some time being managed by general cardiology. I'm sorry, I missed the second part of your question.

HZ: So as you mentioned, generally at level 2 or at level 3, generally patients refer to you. So why this delay occurs? Is it due to the diagnostic delay or patients are lately referred to you?

AS: No, the delay is purely because patients are delayed in referral to us from the general cardiologist. And this is a big problem we've seen across the country, not just at our institution. Like I said, I was on the West Coast, I'm on the East Coast, so I have a good flavor of multiple different institutions. And it's a systematic problem I've seen or a systemic problem I've seen all over the place. So you have to remember, in general, general cardiologists feel like, you know, they are also cardiologists, they can take care of them. Quote-unquote heart failure. I would say that's not necessarily true and so patients end up being managed by their general cardiologist for a very long time and sort of maintain on the same goal-directed therapies and they only come see us when they're either failing therapies, the general cardiologist is feeling like they're weaning therapies that they otherwise couldn't wean and so you know, that's sort of the perspective of where we're at. The patients sit around forever in the general pool before they see us, and they come to see us when they're extremely symptomatic or sort of end-stage part of their disease process sometimes. So it's very frustrating, but sometimes patients come to see us and they're, you know, very, very ill and they're beyond any sort of help that we can give them, which is unfortunate because we could have otherwise helped them earlier in their disease process. So, you know, it is what it is, but like I said, it's a problem that we've seen around the country.

HZ: Okay, right. Got it. And what treatment sequence do you typically prefer for your newly diagnosed patient with HFrEF versus HFpEF? And in your experience, which phenotypes remain responsive to your current therapy?

AS: I think all the phenotypes are responsive to the therapy. I just think it's where in the disease process that you catch the patient, right? I think that earlier in the disease process, if you catch patients where even if they're class 4 symptomatically, but it's a new diagnosis, you can make a lot more headway and a lot more difference in their underlying clinical disease process and their prognosis than in patients who have longstanding cardiomyopathy. You know, even if you have a patient with an EF of 35% to 40%, but they've had heart failure for 30 years, that metric was burnt out. It's been sort of very sick for a very long time as opposed to somebody who's newly diagnosed and you have 35%; you have a much better chance of remodeling and affecting their overall prognosis. So I think overall, it's not necessarily about the disease process, but the chronicity of the disease itself. If you're talking about purely the disease process and sort of all comers, if they're newly diagnosed, in general, we do a better job with non-ischemic disease. So newly diagnosed non-ischemic cardiomyopathy, I feel like, responds better to goal-directed medical therapy. Severe underlying ischemic disease, you know, even when we diagnose it early and we revascularize it in patients who have very severe underlying ischemic disease, usually their disease process, if it's causing a very low EF, is not necessarily something that is always amenable to full revascularization, and thus, in my mind at least, my experience portends a worse prognosis overall. The ischemic disease is obviously very homogeneous as opposed to the non-ischemic disease; they're very heterogeneous. So there's a lot of different things we can talk about. You know, if it's amyloid, if it's sarcoid, versus if it's idiopathic non-ischemic disease or genetic cardiomyopathy, those all portend a completely different prognosis. So it's hard to put them all into one bucket.

HZ: Okay. But still, in most of your practice, if let's say newly diagnosed HFpEF patient comes to you and it has either

diabetes or obesity, do you have certain treatment sequence like you put such patient on a SGLT2 inhibitor or GLP inhibitor or GIP therapies? Is there any sort of...

AS: Yeah, if you're talking about HFpEF versus HFrEF, it's different than ischemic versus non-ischemic. We're talking about HFrEF versus HFpEF. So for HFpEF patients specifically, those patients, I follow the guidelines. The guideline recommended therapies for somebody with HFpEF are SGLT2 inhibitors and an ARNI, so most likely the only one on the market now is Entresto. There's been more doubt recently with the steroidal MRAs, so spironolactone and eplerenone based on the SPEAR-HF trial. There's more doubt whether or not we should be using those upfront in non-hypertensive patients. And the third medication we go to is really finerenone based on the FINEARTS-HF trial. So those 3 medications are sort of the mainstay of HFpEF therapy as well as in controlling other comorbidities, which what you had just mentioned a little bit, their diabetic status, their hypertensive status. So anti-hypertensive, anti- diabetics, you also want to take care of underlying obesity, diabetes, etc. So we try to attack all those things to try to stabilize the underlying comorbidities that can make the HFpEF worse. But the mainstay of HFpEF therapy is really the SGLT2 inhibitors, the ARNIs, and the MRAs, based on the guidelines.

HZ: Right. Got it. Doctor, I would like to discuss more on heart failure patient with the HFpEF phenotype with the obesity or diabetes comorbidities. How do you sequence SGLT2 inhibitor, GLP, or GIP therapies in HFpEF patients with obesity or diabetes? Do you use them as a monotherapy or do you use them in a combination? Combination of SGLT2 and GIP or combination of SGLT2 plus GLP-1 therapies. So do you put such patient of HFpEF with obesity or diabetes comorbidity on an SGLT2 inhibitor monotherapy or you also add another therapy in combination, either GLP-1 or GIP?

AS: I will say that in general, when you're talking about HFpEF diagnosis, the guidelines recommend that we should use foundational therapies, the things that have been proven in trials to be specific for HFpEF. Those therapies are SGLT2 inhibitors as well as non-steroidal MRAs like we had discussed and ARNIs. Those are the therapies that we know are the foundational therapies for our patients. If you're talking about like phenotype-guided stratification for patients, if you have a patient with a BMI above 30 and they're diabetic, then yes, you're going to use other therapies such as GIP, GLP-1s, Ozempic, et cetera. And then for non-obese patients, you're targeting more, you know, the other stuff we talked about, antihypertensives, et cetera. So I don't use GLP-1s or GIPs in combination therapy just for HFpEF. It's very much phenotype guided. And so if the patient is obese, so BMI above 30 and a diabetic, then I'll use a GLP-1 or GIP up front with an SGLT2 inhibitor. The SGLT2 inhibitor is for the HFpEF, helps a little bit with diabetes, and the GLP-1 GIP is for glucose control as well as for the weight loss to help with the overall underlying milieu and the comorbidity management. So that's the only time where I'll use them up front together, but I don't use combo therapy in all HFpEF patients. There has to be a foundational reason to use the GLP-1 GIP, not just because the patient has HFpEF and diabetes.

HZ: Okay, so you don't use combination therapy. Okay, got it. And doctor, talking about guideline directed therapy. So what are the unmet needs in HFpEF or HFrEF patients despite guideline directed therapy and which outcome have the greatest influence on your treatment decision?

AS: The unmet needs are very much in those patients. I want to go back a second. I wouldn't say that I don't use combo therapy. I do use combo therapy for the correct subset of patients. I don't use combo therapy for all HFpEF patients. And I think that the idea of using combo therapy for all HFpEF patients is actually wrong and it's not really supported by science. So even the 2026 ACC consensus statement by heart failure, it's very much documented that this should be very much phenotype-driven subset patients. It shouldn't be for all HFpEF patients. If we're going just based on our guidelines, we should not be using combination therapies for all HFpEF patients. At that point, it doesn't mean I don't use the therapy. I do use it for a very defined population. If we're talking about pain points and unmet needs in the world of heart failure with preserved EF, the real big thing is therapies that help reduce hospitalizations as well as reduce symptoms in patients and decrease mortality, but also are able to be used in patients with high-risk

features from the sense of CKD, hyperkalemia, and hypotension. It's very hard to treat that patient population that has any one of those 3... hypotension, hyperkalemia, or CKD... with drugs like SGLT2 inhibitors that are very hard to be indicated in patients with GFR less than 20 and very much discontinued on a regular basis. And then the other 2 therapies we talked about, Entresto and Spirulactone, are very hard to maintain in patients with significant CKD or histories of hyperkalemia.

HZ: Okay, got it. And doctor, thank you for clearing that combination therapy part. I just have a follow-up question on that. So for the patient for which you are using the combination therapy of SGLT2 or GLPs, do you face any reimbursement challenges when you combine those drugs? Do you face any reimbursement issue or any reimbursement challenges?

AS: Yeah, it's not reimbursement challenges. It's more about access for our patients and payer support, right? So I could tell you that I ordered a GLP-1 and a GIP in the last 2 weeks on 3 different patients that were denied by their insurance companies because there's no indication. Patients are non-diabetic, they're obese and they have heart failure and they refuse to pay or cover the drug because there's no, quote, unquote, medical comorbidity that supports the diagnosis and that obesity itself wasn't the reason behind it. And another patient, they said that there was no indication for underlying heart failure and that that wasn't something correlated. So again, it's very hard to get these drugs covered by their insurance companies even though you have a diagnosis of heart failure in somebody who's also obese. They want to meet very specific criteria and it's almost impossible to get covered in a non-diabetic. And so we're still bumping into these barriers trying to get medications covered for our patient population that otherwise would do very well on those things.

HZ: Right. And I want to discuss patient adherence. So approximately what proportion of your heart failure patients remain adherent to prescribed therapy and what are the real-world challenges or barriers do you face or the patient faces to remain adherent to the therapy?

AS: I would say overall adherence is very much dependent on the geographical area and population you're treating. I think here where I am, I would say my overall adherence is probably around 65 to 70% on goal-directed medical therapy. Where it was before, it was a little bit more of a rural environment, and I think that patient population are closer to 80%. It just depends on the patient population you're taking care of, their medical literacy, et cetera, and financial status. I think those all play a big role. Obviously, the biggest thing that affects compliance is, I feel like medical literacy is the number one, as well as access to health care, right? Those two things are the biggest reasons why we'd have noncompliance. Either patients not understanding their disease process, not having the support to continue their medical management or the financial ability to continue to monitor and manage their heart disease. I also feel like, and this may be a controversial statement, but I'm going to say it anyways, in general when you look at underserved communities and inner city communities, those patients in general, unless they are hooked up with a good academic medical system in one of those larger city areas, if they're relying on routine free health care by free healthcare programs, the quality of care is extremely poor especially if they're not able to see specialists and are maintained by family medicine physicians or internal medicine physicians. So better than nothing, but I think that those patients are still very much underserved and overall do poorly.

HZ: Okay, right. And doctor, HFpEF in itself is a dynamic phenotype. So which HFpEF phenotype is most likely to yield reproducible treatment effect in your opinion, and what clinical, hemodynamic, imaging, or biomarker criteria best identify the population of this HFpEF phenotype?

AS: So HFpEF is not a diagnosis that's made by biomarkers, right? HFpEF, the definition is extremely, extremely narrow. And it's those patients who have clinical signs and symptoms of heart failure, who have evidence of elevated filling pressures, either by elevated NT-proBNPs, evidence of elevated pressure on echocardiogram, or right heart catheterization that shows elevated intracardiac filling pressures, all without another reason. So it can't be a patient

who's on dialysis who's not getting dialyzed appropriately. So it's a patient that otherwise has no reason for the increased intracardiac filling pressures and has symptoms. You would have to show me either an elevated NT- proBNP, an echo with evidence of elevated intracardiac filling pressures, or a right heart catheterization with proof of intracardiac filling pressures. So one of those 3 things. There are no other biomarkers or any other lab tests that could prove HFpEF.

HZ: Right, okay, got it. And, doctor, in your opinion, what minimum background standard of care use should next- generation HFpEF trial require to maintain clinically relevant without making trial enrollment impractical?

AS: Yeah, I think that all patients that are enrolled in a HFpEF trial should be on tolerated current standard of care. And so those patients are going to be on, if they qualify, obviously from medical reasons, from a CKD, hyperkalemia perspective, an SGLT2 inhibitor, an ARNI, and a possible non-steroidal MRA. I think that the finerenone is plus minus, but I feel like for it to be a standard of care sort of trial that is relevant to our day-to-day, you need to be on at least an SGLT2 inhibitor and an ARNI if possible; anything else really wouldn't be necessarily guideline recommended. And so I would say that the subset of patients that are obese and have diabetes should also have a high background therapy of GLP-1s or GIPs.

HZ: Okay. Although we already talked about it, what clinical measurement are the most useful for selecting HFpEF patient and identifying the treatment response in the clinical trial?

AS: That is a good question. I think there are 2, 3 things that we should be looking for. One is going to be a biomarker, so there be BNP, NT-proBNP, so you'd want to see a reduction in the NT-proBNP. Number 2, you'd want to see a reduction in other imaging/other markers such as right heart catheterization numbers or filling pressures based on echocardiograms. So you want to see that there's some objective evidence of change in the intracardiac filling pressures, et cetera, based on either imaging or invasive monitoring like a right heart catheterization or CardioMEMS. The third thing I would say is important is a semi-objective measure of functional status. So whether it's a 6-minute walk test or a KCCQ questionnaire, a change in the patient's overall daily clinical status or functional status. So you would want to see those 3 things happen in somebody who you're looking for a... clinical response to the heart failure management you're giving them and HZ: Okay.

AS: then finally a reduction in hospitalizations. So if you can any therapy that can show you a reduction in heart failure hospitalizations or mortality, obviously it would be huge. Yeah.

HZ: Okay. So basically like symptom parameter, hospitalization parameter, and physical parameter, right? If I understood correctly.

AS: Yep.

HZ: Okay. Now, doctor, I would like to discuss on, you know, Ziltevacimab. What do the mixed results across IL-6 targeted HFpEF programs imply? Do you think IL-6 targeted mechanism been adequately tested or could inflammatory phenotype or earlier intervention or different endpoint still make IL-6 targeted pathway relevant in heart failure space?

AS: So, I think that in general, 1 second, sorry. I think that in general, the IL-6 targeting was something interesting. I think that, you know, it worked on earlier, especially in patients who had elevated markers for inflammation, especially elevated hs-CRP. There's been a multitude of trials, whether it was like the Zeus trial, the Hermes-Athena trials that came out looking at different populations of patients. I think that, you know, obviously those trials are different whether it came to I think Hermes and Athena were more for us heart failure doctors and looking at the heart failure

population. Zeus was looking at more of, you know, ASCVD and CKD patients. And there was a third trial, I can't remember, that their trial was based on just CKD and elevated inflammatory markers. And so, you know, they've looked at... The population, I don't necessarily think that there is enough data at this point for IL-6 markers to be used as sort of standard of care.

HZ: Right, doctor. So you rightly pointed out like Hermes and Athena trials. So they are terminated and I guess you are talking about the Zeus trial. It failed to produce like a primary outcome. But the Ziltevacimab is still active in acute myocardial infarction settings. So just curious to know whether IL-6 inhibition pathway is still relevant in heart failure space.

AS: I don't think so. And if you're talking about the continued study of the drug under the AMI indication, then it's fine. But again, in Zeus, Hermes and Athena were stopped due to futility and they weren't able to enroll enough patients and what we took away from that trial is that IL-6 inhibitors are probably not going to be a valid target for long-term therapy, especially in just heart failure patients. The Zeus trial was a bigger trial, looked at patients that just had ASCVD, CKD, and elevated markers, and still that trial showed nothing, no change in base at all, and it was a neutral endpoint. For me, that was the death of the drug. Using in AMI is a completely different population, in the sense that when you look at chronic heart failure patients... if you're not checking their HSCRP, a lot of those patients don't have elevated CRPs. They're just chronic HFrEF patients. So using an inflammatory drug or anti-inflammatory drug to treat the disease process may not be relevant or have any place in the disease process we're talking about. And that may be alluded to by the results of the Zeus trial and those set of patients that are ASCVD, CKD, otherwise stable; the marker, this drug doesn't change the milieu at all to a point where it changes the MACE. If you're talking about AMI patients coming in with an acute MI, which is a high-risk setting, very high-risk inflammatory setting of the inflamed myocardium, you just had an infarction, a lot of myocardial edema, etc. This drug may play a role in those patients and in that patient subset, but that's not going to be something that's generalizable to the entire heart failure community.

HZ: Right. And doctor, what are your views on Nenafloxetate in heart failure? So, given the initial OPAL-HF result with Nenafloxetate, what would a convincing placebo-controlled trial need to demonstrate to validate impaired cardiac energetics as a treatable health path mechanism?

AS: Nothing. I think it's garbage. That's just a nice way of saying it. I think that you either have to do a trial that shows a mortality benefit and a clinical benefit for the patient. So the trial needs to show me 1, either a reduction in MACE, 2, a change in overall heart failure hospitalizations, or 3, heart failure mortality. And then the weakest kind of trial is a trial that would show us a difference in functional status. So improving patients' KCCQ or 6-minute walk test. If you can't show me any of those things, the drug is garbage and will never be approved for a good indication for heart failure. All these other trials are showing changes in kinetics and energetics and all that kind of stuff, it means nothing if it does not translate into a clinically relevant endpoint, then the drug is useless. And it's very simple, man. If I build the best engine on the planet and I put it in your car and your car explodes as soon as I turn it on. Who cares what the energetics showed in the shop, right? If it doesn't work when you put it into the car, then it's useless. So let the trial control a clinically relevant endpoint and nothing else matters.

HZ: Right, doctor. No, no, I definitely understand your perspective, but like they are stating the result such as it has showed an effect on myocardial energetics with modest signal in exercise capacity and symptoms. So do you still think it is not relevant in heart failure space?

AS: Yep, completely relevant.

HZ: Okay.

AS: Yeah, I mean, the moderate signal means nothing unless it's a statistically significant change in multiple markers,

right? So it can't just be there's a signal for KCCQ change or a signal for a 6-minute increase. That doesn't mean anything, right? Anything can show a signal if it's not statistically significant, especially if you're only showing me 1 marker, right? So if they're showing 1 marker, for example, there's a 5 to 7 point change in KCCQ... that's relevant, I think about 5 points... but if it's like 2, 3 points and it's only a signal, it's only 1 marker, then it's most likely not relevant at all.

HZ: Right. Got it. And doctor, in obese patient with HFpEF who is already on SGLT2 inhibitor, would you add tirzepatide or finerenone first? Which factor would drive that choice?

AS: I don't know that I necessarily have any 1 GLP-1 or GIP that, you know, I find that with Mounjaro, sorry, with Zepbound, patients have maybe a little bit more weight loss than with Wegovy or Ozempic. And so most times I reach for Zepbound for better weight loss. I do find that they still have more GI upset symptoms maybe with Zepbound over some of the others, or Ozempic or Wegovy, for example. But you know, again, it's more about the weight loss for me. So in general, I feel like patients have a little bit more weight loss with Zepbound from my clinical practice. And so if I'm using it just for weight loss, I'll use Zepbound. And then they're usually on SGLT2 inhibitors at that point. It helps them get their A1C under control.

HZ: Right, got it. And when it comes to semaglutide, how do you interpret semaglutide's STEP-HFpEF trial symptom and function benefit versus tirzepatide's SUMMIT trial symptom and worsening HF results? Is there enough evidence to infer a meaningful clinical distinction between these 2 therapies in heart failure?

AS: No, I don't think so. I think it's very hard with any of these trials to infer anything except for they both have good data and you can use either one and that should give your patient a benefit from a heart failure perspective. Once we start talking about, well, should I use A or B, unless A and B are trialed against each other, then it's very hard to say which one is better. We really HZ: Okay.

AS: shouldn't comment on which one's better unless there's a head-to-head trial.

HZ: Okay. Now talking about tirzepatide, you know, following FDA asked Lilly to conduct one confirmatory trial and not to simply rely on SUMMIT. So in that response, Lilly withdrew its HFpEF application for the US FDA approval. So do you think SUMMIT... You know, real-world data and subsequent data with the CKD is sufficient enough to use tirzepatide routinely in obese HFpEF patients, although it does not have approved FDA label for heart failure.

AS: Next question. All right, how do I say this the right way? The data regarding decompensation and improvement in functional status in patients is very good when it comes to tirzepatide. And I agree. I think that the SUMMIT trial results were very good. The primary outcome was CV death and worsening heart failure exacerbations, and they met that baseline as well. With the longer follow-up data and the real data, I think that the FDA will probably give them an indication coverage for maybe a 2B indication for heart failure. I think in general when we're talking about indications and the guidelines, they want multiple trials and that's what the FDA wants to see. So that's not new. Most of the time there isn't a drug or a device that gets an indication by the FDA or coverage based on one trial done by the company. They want to see multiple trials and most times they want to see those trials very much powered for the primary endpoint, not secondary endpoints. So I'm not surprised that that's what happened. I think the real world data will help. I think that Lilly is very much betting on the real world data being just enough to get them covered. The problem with this is that you're asking me, would I be comfortable using it? 100%. I already use it. The problem is that, as I told you before, insurance companies don't cover it for heart failure. So if you have an obese heart failure patient, they're going to tell you you have to go through weight loss programs, through other drugs, through fen-phen, metformin, everything else under the sun before they will approve just this drug for weight loss in a heart failure patient. There's a lot of hoops to jump through just to get the patient coverage for this, right? So it's not just about the FDA and trials

and that kind of stuff. Who's going to pay for the drug? So I already believe in it. I think that it makes a big difference in our patients' overall prognosis and livelihood. I just think that getting it covered by a payer, that's a different story altogether.

HZ: Right. Got it. Now, Doctor, talking about comparison between tirzepatide and finerenone, given the substantial differences in trial population, endpoint and background therapy, how should tirzepatide profile in obesity-related HFpEF be weighed against finerenone's broader HFmrEF or HFpEF evidence?

AS: I don't know that it's a fair comparison.

HZ: Okay.

AS: Yeah, I don't think that's a fair comparison in the sense that one is an obesity-diabetes drug and you are taking a population of patients that is morbidly obese with very bad diabetes complications, etc., comorbidities, and treating them with a diabetic drug that so much so happened to show that there was a good outcome for those patients from a cardiac perspective which would make sense. In any diabetic, we've always talked about how the underlying diabetes can play a big role in vascular injury, inflammation, myocardial edema, etc., and so controlling that disease process makes sense, that there should be a MACE sort of protection at some point, and so, and then which is what we see in the trials. And the finerenone is a completely different mechanism of action. And so, comparing those two drugs... that's like saying, "Well, should tirzepatide be more important than an ARNI or an SGLT2 inhibitor?" And the answer is no. We have countless trials and much more supportive data for those therapies than tirzepatide. It doesn't mean that we should compare the two unless we do a head-to-head trial. So I don't think that the comparison is very fair, and that they're two completely different mechanisms of action. And putting that into context, I mean, even in the world of HFrEF, when we talk about like the four pillars of heart failure therapy: the beta-blocker, HZ: Right.

AS: The MRAs, we don't have an algorithm that shows us which one is the right one to start. Should you be on a 3- drug regimen at low dose versus a 4-drug regimen? We don't know, right? There's no sort of science that ever showed us that, for example, a patient at max dose Coreg and Entresto is going to do better than a patient that's on the smallest dose of all 4 drugs, right? So there isn't really any answers for that stuff, so I don't know.

HZ: Okay, fair enough. Doctor, in the CADENCE trial, reduced PVR, Sotatercept was able to reduce PVR with both doses, but is the 0.3 mg per kg dose able to show improvement in 6-minute walking distance with the Apex trial of TX45 due in early 2027? What must TX45 demonstrate or show to challenge Sotatercept in the heart failure space?

AS: Sotatercept? Yeah, Sotatercept is really talking about PH therapies at this point, not talking about heart failure therapies anymore.

HZ: So, basically, TX45 enrolled 191 patients in the Apex trial and results are due in early 2027. Does CADENCE establish Sotatercept as a current leader, and what hemodynamic, functional, or safety profile must TX45 show to compete with Sotatercept?

AS: I would say that it would have to show the same outcomes. There has to be a change in a patient's functional status. I would say they have to really overcome the key vulnerabilities that were exposed in CADENCE. I think that overall, you would have to show a PVR reduction like they saw. You'd want to see a bigger decrease in the left side of filling pressures than we saw in CADENCE. I think that as long as you can show the same sort of efficacy from a 6- minute walk test perspective, then you're okay. The problem with the Sotatercept was a very narrow therapeutic window. So if you could show some superior safety data, that would be helpful as well.

HZ: Thank you for joining us. Okay, got it. Now, doctor, talking about the phase 3 Levosimendan trial. So although phase 3 trial results were negative overall, should Levosimendan be retested in PH-HFpEF patients with poor baseline exercise capacity? And how its role differs from sotatercept and TX45?

AS: Listen, the Levosimendan story has really been a story of failure, so I can tell you that the first trials that were done with Levosimendan were done when I was a resident, 15 to 20 years ago, and they've been trying Levosimendan with every underlying way of breaking down trials and different populations and it's never proven to have any sort of positive impact on primary endpoints. And so I would just say, Levosimendan, no, stop, period and end of story. I don't think that's there. We're never going to show that there is a big enough clinical effect on any subset of heart failure that would warrant Levosimendan being something that we use on a regular basis. Thank you.

HZ: Okay. Got it. Now, Doctor, the CADENCE trial requires PVR of greater than or equal to 4 Wood units while APEX focuses on PVR of greater than 3 Wood units and the Levosimendan trial was neutral. So, do you think, as these trials are majorly focusing on PVR, should future PH-HFpEF trials require PVR enrichment? And if so, at what threshold?

AS: You can't do a PH trial without involving the PVR as part of the inclusion criteria. The definition of PH is a PVR, depending on if you're trying to use it for Group 2 versus non-Group 2. The PVR definition is a 3 cutoff. So, I think it's appropriate to use a PVR cutoff of 3 in that patient population. Now, whether or not you're trying to show an effect in post-capillary versus pre-capillary patients depends on what you're trying to do. But the PVR definition of 3 is appropriate. I don't think that anybody would respect a PH trial that doesn't use PVR as either a cutoff. I don't think you need to use it as an endpoint. I don't think it necessarily matters whether you show a sustained reduction in PVR, as long as you can show a sustained reduction in RV afterload with a mortality benefit. So, if you're not going to use PVR, you have to use something, whether it's a reduction in the mean PA pressure, a reduction in the transpulmonary gradient, et cetera. You need to show a reduction somehow in the RV afterload, which is why they use PVR. It's sort of the easiest one to calculate on a regular basis, and it's the basis of most PH trials, historical PH trials. And so, getting away from using historical data numbers doesn't really make sense either. So, I think that anybody that's going to respect a good PH trial is going to respect a trial that uses the classic definition of PH, which ends up being a PVR of 3.

HZ: Okay. Now doctor talking about omecamtiv. Omecamtiv is testing myosin inhibitor in AMBITION trial, having patient with LVEF greater than or equal to 60% while on the other hand, Nenafloxetate targets myocardial energetics. So out of this, both mechanism, which mechanism is stronger and how should responders be identified?

AS: Again, it's these questions are interesting, but they're not fair, right? You're talking about theoretical, a CMI versus a relaxin versus something else, and we can't tell, right? I mean, these are all new therapies, their trial data is all Phase II randomized, very small trials, which honestly, at the end of the day, don't mean anything, right? So, another CMI, I can tell you that CMIs are probably going to be completely useless in the next 3 to 5 years. So some of the newer drug therapies, I think the one that's coming out is Edgewise 7500, EDG-7500, it is a sarcomere modulator, and that whole class of drugs, if you look at their Phase II trial data, looks much better and safer for patients than CMIs and short of HCM. So that one class of medication could come and sort of really make CMIs completely no longer important in the field of HCM. And so, comparing drugs in different therapy classes for indications doesn't really make sense. So, omecamtiv is fine, it's another CMI; we have very good basis for CMI in the first place, it'll be the third or fourth drug on the market. I don't think there's going to be any market for it because you have 2 huge ones between Camzyos and Myocardia, now having, you know, dual indication for non-HCM and obstructive HCM, why would you take on a third drug? You know what I mean?

HZ: Right. No, totally understood. Now, Doctor, talking more about EMBER HFpEF trial. Since EMBER HFpEF is principally a dose-finding and safety study, what magnitude and consistency of supportive changes in filling pressure, exercise capacity and NTPRO-BNP or KCCQ would justify advancing omecamtiv despite LVEF monitoring requirements?

AS: Nothing, honestly. I don't think that there's any reason, you know, to monitor and look at another CMI at this point. I don't necessarily think that there's a place on the market for a third or fourth CMI. So I'm not sure why Cytokinetics is going out of their way to design another one, but I can't speak to why they're doing that, but I can tell you that there's not really necessarily an indication at this point. means that before they offer the clinical benefits.

HZ: Okay, got it. And COMET-HF trials, CVR-HF enrichment identifier, clinically useful role of omecamtiv mecarbil or contemporary therapies and which baseline feature would make most confident in this benefit.

AS: I don't know. Honestly, I read COMET-HF a while back. I wasn't really too much impressed with COMET-HF sort of results. I don't necessarily think that's something that's going to, you know, have sort of take off or be used in our overall guideline therapies in the future.

HZ: So just a quick follow-up question on that. In the COMET-HF trial of omecamtiv mecarbil, they basically enrolled severe HFrEF patients and they think that this HFrEF enrichment if molecule able to show improvement in HFrEF patient, this HFrEF enrichment would give them an edge over contemporary therapies. So do you think that is the case?

AS: I don't think so. And I think that the mechanism is very important. So again, this trial was run on patients with severely reduced EF. I think the target population that had the best benefit was that under 25%. You're talking about end stage heart failure patients. You're talking about a drug therapy that is basically an oral inotrope and basically that's what it is, right? So instead of coming home on IV milrinone or coming home on this drug instead, we know from all the data from the past that these drugs improve functional status for most of our patients. But overall, it will reduce BNP, will make the rest of the numbers look better and decrease the heart failure hospitalization. That's the whole idea, is to palliate the patient and make them feel better. I think that the, I don't necessarily think that we know what the overall mortality data looks like. We do know that on inotropes, patients feel better, the numbers look better, they clear their lactate, all their biomarkers look better, but then patient survival decreases. So their overall length of life at 2 or 3 years is much lower than if you didn't do inotropes. So it's always that trade-off about how well you feel versus how long you live with inotropes and I think it's going to end up showing the same story. So I wouldn't use it unless it was a palliative medication or as a bridge to advanced therapies but not as a direct medical therapy for heart failure in place of, you know, goal-directed medical therapies that we have nowadays, or like GDMT.

HZ: Okay, got it. And in phase 2B kinship DCM trial of danicamtiv, they have also enrolled genetic selection cohort, specifically MYH7 or TTN-associated dilated cardiomyopathy cohort. So does danicamtiv's genetically defined DCM strategy sufficiently differentiate it from the omecamtiv-mecarbil, or this 2 comparison is irrelevant in your experience?

AS: I think that it's irrelevant. We don't do enough genetic testing on most patients to be able to subset those patients on a regular basis.

HZ: Okay. And Doctor, like what is the most important evidence gap that must be addressed before an emerging heart failure therapy can change the clinical practice?

AS: I just think it's a therapy that has to show that in its own right, on top of the reasonable goal-directed medical therapies that we have available to us today, still show either a mortality benefit or benefit in hospitalization. So you take a patient population that is, for example, HFrEF, you put them on the recommended goal-directed medical therapy at a good dose, and on top of that, these medications still show a mortality benefit or a heart failure hospitalization benefit or benefit in functional status. If you can show that, then you're a reasonable trial. If you're talking about kinetics and energetics and other stuff like that, then what you're telling me is that you're not able to show a MACE, mortality, heart failure hospitalization benefit, and that you're a useless drug.

HZ: Right. And Doctor, like among the emerging HFpEF and cardiorenal therapies, which mechanism is most likely to add meaningful benefit beyond current standard of care in your opinion?

AS: Nothing that I've seen recently. I think that maybe relaxin, maybe I don't think that they've shown very much strong clinical data to support it yet. I think that the sarcomere modulators in specific disease processes like HCM, I think that, you know, TTR depleters in disease processes like amyloid have all shown that they're going to have some sort of change in the field and how we treat those specific disease processes. Thank you. Thank you. Thank you.

HZ: Hello? Hi doctor, I lost you for a couple of seconds. Yeah. Now your voice is clear. So moving to the next topic, the next question.

AS: Well, sorry, it's 3 o'clock. I mean, I know it's been an hour. I just don't have much more time at this point. So if we need to spend more time, is there a way we can reschedule for another meeting? I just have to go back to some clinical duties.

HZ: Just last question from me, looking 5 years ahead, what single successfully emerging therapy, primarily replace an existing drug, or it would be added to a current therapy, or it will bring, you know, previously untreated phenotype into care.

AS: I think that anything that's going to come on the market in the next few years is going to be an added therapy. I don't think that, you know, all the drugs that we have on the market now from a heart failure or GDMT perspective have shown in their own right and their own trials that they decrease mortality and improve patients' quality of life. So I think that if you're talking about therapy in a specific population like amyloid or HCM, there may be new therapies that come on the market that take the place of older therapies like beta blockers and calcium channel blockers. But I think that you're talking about generalized heart failure, you know, those therapies that come online would have to be add-on therapies, not necessarily take the place of older therapies.

HZ: Okay, sure. So doctor, just a last follow-up question. Out of these all-emerging therapies, according to you, which mechanism or which effect has having potential?

AS: To start, I have nothing. Like I said, I don't see anything, and I have not seen anything in the last 2, 3 years that's going to upend the world of heart failure. Like I said, there's a couple of new targeted therapies I think would be beneficial in specific processes, but generalized heart failure therapy, I don't see anything that's going to come in that's going to totally change everything. But with that, I really do have to go.

HZ: Sure, sure. Thank you so much, doctor. Thank you so much for taking your time and sharing all your insights. Have a rest of the day. Yeah, take care.

AS: Thank you.

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