Lorundrostat LAUNCH-HTN Trial

Dr Thomas Nero discusses the new aldosterone synthase inhibitor Lorundrostat with Dr Liffert Vogt and the outcomes from the Launch HTN trial. 

Transcript

Launch HTN and ASIs with Dr Vogt

Dr Nero: Hi, I'm Dr. Thomas Nero, and welcome to Future Pulse. Today, I have the pleasure of talking with, , Professor Liffert Vogt , he's a professor of nephrology at the University of Amsterdam and the Amsterdam UMC in the Netherlands. He was also the, main speaker at the European Society of Hypertension, where he presented data on a novel , aldosterone synthase inhibitor.

Thank you, Dr. Vogt, for joining us today

Dr Vogt: Yeah, thank you for inviting me. I, it's an honor to me

Dr Nero: So, , first off, , I'm really excited about these new class of medications, you know, aldosterone synthase inhibitors. I think they're going to be a very important, , piece to the puzzle. Can you talk about , where the idea for aldosterone synthase inhibitors came from and why these - are going to become important?

Dr Vogt: Yeah, I think it's a very relevant question. I think it really readdresses the role of aldosterone in cardiovascular and renal medicine or what we now call the cardio-kidney metabolic syndrome. , But it's also a little bit an old story. I mean, aldosterone has been invented in 1953, and then, Conn this-- had his own primary hy-hy-hyperaldosteronism, , syndrome.

And since then , we acknowledged the adrenals being very important, in cardiovascular physiology and it's all focused on the so-sodium handling, and that's perhaps explaining the blood pressure phenotype and also why in cardiovascular patients where sodium retention and a cumulative sodium balance is relating to all kinds of, , symptoms, but also - it's important , from a prognostic, aspect.

, We know this already very long time. And spironolactone is there as a steroidal, , medication. It's already , out there for , many years and we know it's blood pressure lowering, it's helpful in heart failure, but there were no official trials at that time. And now, uh, with new compounds, we now really building on a very solid evidence, I think, that aldosterone is key player , in many cardiovascular and renal, , patients.

That also holds true for not only hypertension, heart failure, but also for, I think, atherosclerotic patients, CKD patients, and diabetes patients

Dr Nero: I agree with you that MRAs they're a bit underutilized, especially in the United States. , A lot of people don't tolerate them because of hyperkalemia and because of the excess cortisol effects of them, and probably because of the increased aldosterone in the system , that aldosterone antagonists create.

, So there's a need for something that's easier to use and as effective and maybe even more effective, than the current agents. . So tell us a little bit about the agent that you studied, and what the, , goals of the trial were.

Dr Vogt: Yeah. So aldosterone synthase inhibitors, -- these are the new aldosterone intervening, , medication. And I think we are very lucky that we now have synthase inhibitors that have highly selective, because if you block, , the aldosterone synthase, , in an unselective way, you will always have , the risk.

And that was also the, the biggest fear in the past few years, that you would in-introduce an Addison's crisis so that you will have very severe, adrenal, insufficiency. But, but these se-selective blockers, you really block aldosterone synthase itself with-- without this blocking effect on the cortisol, generation.

And in that sense, , you'll benefit from, the effect of aldosterone besides their effects on the receptor. And that's very different from spironolactone. And that's also very, different from the m-more selective, mineralocorticoid receptor antagonists like finerenone, which is also now in vogue, if you look at the latest trials in mainly, nephropathy patients, but that's also true with heart failure patients.

And also these trials, they support again, that aldosterone is perhaps an overlooked key factor in cardiovascular and renal medicine. So if you , block aldosterone, and you al-also acknowledge the effects, , independent, of the receptor, . well, you can of course hypothesize that it has a more efficacious way, in addressing all the negative effects of aldosterone

Dr Nero: So the big piece of these trials was trying to prove that you, can really effectuate im- impressive blood pressure lowering while at the same time not having significant side effects from hyperkalemia or intolerability. So tell us a little bit more about LAUNCH HTN

Dr Vogt: Yes. So LAUNCH-HTM is actually the follow-up study. It was also already a, a phase two study with lorundistat in this case, the aldosterone synthase inhibitor, , there are also other ones, Baxdrostat and Vicadrostat, but this one was really dedicated to uncontrolled blood pressure. So a patient that, had uncontrolled blood pressure, meaning an office systolic blood pressure above hundred thirty-five, , over eighty, and using already two to five antihypertensive agents were studied, to see whether if you add aldosterone synthase inhibitors to this re- regimen, whether they would improve, , control of blood pressure in , these patients.

Though they were only selected on being uncontrolled in terms of blood pressure regulation, not necessarily on the comorbidities. I think that's also the - beauty of this trial. And I said it's a phase three trial. It's an international study, , conducted in 30 countries, not only in the US, but also in other countries.

It was placebo-controlled, of course. There was also an uptitration arm. But if you only look at the fifty milligrams dose, , we appreciated a more or less ten millimeters mercury decrease in blood pressure on top of the other medication already used.

Dr Nero: Which is, which is, yeah, very impressive. You really knocked it out of the park. And for this study, they recommended that every patient be on an ACE inhibitor or an ARB as the primary medication, and then the secondary medication was

Either a thiazide diuretic or a calcium channel blocker.

Dr Vogt: So there's a, so there was a solid background therapy there before you introduced this drug in a placebo-controlled fashion

Dr Nero: and they were not on, an MRA because of the potentials with hyperkalemia, et cetera, so you had a 10 millimeter mercury, uh, decrease. You only had, if I remember correctly , a 2%, dropout because of hyperkalemia.

Is that correct?

Dr Vogt: Yeah, that's right. Yeah

Dr Nero: which, which is again, very impressive in comparison to some of the other trials, and really does compare well with the finerenone trials. , 

Dr Vogt: With the note that the blood pressure improvement was more convincing as compared to finerenone

Dr Nero: Absolutely. Yeah, I think that, not to throw shade on finerenone,, I think that they were a step forward, but they were not quite as impressive., Although the, improvement in, decreasing hyperkalemia was important in those drugs.

, But you had, - limitation of hyperkalemia and also you did, some sub-studies looking , at the renal function and the, , and improvement in urine albumin,

Dr Vogt: yeah. , That study also the G- eGFR effects were studied. Uh, but yeah, you're right. We also wanted to see in - this group that was only selected based on uncontrolled hypertension, what share having some features of kidney damage, so either being albuminuric or having decreased eGFR below sixty, how these patients would respond if the aldosterone synthase inhibitor , was introduced.

In general for the launch, again, it was the beauty. If you select patient just being on uncontrolled, blood pressure, you'll have a very balanced, background pop- population that's included. So very balanced representation of both sexes, also with the other race and ethnicity backgrounds, , and not all diabetic.

And if you, for instance, do these kind of studies in, let's say, high-risk patients in terms of cardiovascular renal risk, then you end up with more males, older people, , less representing the clinical practice. And I think also this is a very strong point of this study. And if we then look at the share of the people with having CKD, which was about twenty-five percent or a quarter of the people appear to have CKD.

And if we then look at the blood pressure re- reducing efficacy, this is very similar to the non-CKD population

Dr Nero: Precisely., And the one population I was really impressed with the, blood pressure lowering was in obese patients. They seem to be do- they seem to do even better, which brings up some theoretical things we'll talk about a little bit later on the effect on adipocytes and inflammatory reactions with these medications.

, The obese patients seem to do better than the non-obese patients , who also did extremely well. I think on the obesity population, it was almost a 15 millimeter lowering , of blood pressure.

The one piece I was interested in was that you had a relatively low use of GLP-1s and SGLT2 inhibitors. It was only about 5% in each of those groups, and obviously this trial has been undergoing for a while, so the uptake of these medications has been dramatic.

What do you think is going to be the effect of adding in these medications? Do you think that it will be a greater benefit, less benefit?

Dr Vogt: So the reason that this, when you select only on hypertension, you also don't have so many diabetics in your population. So that was also true for this study. So the number of diabetic patients was lower.

From a - mecha- mechanismal point of view, I think SGLT2 inhibitors, well, yeah, some people will disagree with me, but for me, they are very powerful diuretics. So you expect an increase of renin because of the diuretic effect. You, you'll turn up in a negative sodium balance, so renin goes up, and automatically aldosterone will go up, too.

If you then combine this with an aldosterone synthase inhibitor, I think this... Well, I would expect a synergistic effect, maybe additive or... But syne-

Dr Nero: Perhaps greater than that

Dr Vogt: here might be also true. So that's-- And then, of course, is it synergistic in the terms that it will even lower blood pressure even more, or are we now looking at independent or blood pressure-independent effects that now are more tackled in a synergistic way?

That can be, I think, a very reasonable, hypothesis. For the GLP-1s, it's a bit different because we don't know how these work and why they are kidney protective and why they are cardiac protected. I think these are-- this is independent of fluid state, independent of blood pressure. This is really some...

You are targeting the vasculature itself. That, that's my idea here.

Dr Nero: , I agree with you. I think that there's a prodromic question here that, um, that you're going to start addressing, and that the decrease in aldosterone itself That you're targeting is going to have a very good add-on effect. But as, one of my friends once said, "You know, you don't have to, uh, understand fire to use fire," right? I will be very interested to see what's happening with these drugs as there's a number of phase two and phase three trials for ASIs in heart failure with preserved ejection fraction, and also in patients with high risk for heart failure, with mild renal insufficiency.

So, those trials are ongoing now with, uh, mostly with Baxdrostat I think.

Dr Vogt: . They use outcome trials, long-run outcome trials. And again, this supports really the idea, and I think it's an important teaching point here, that dysregulated aldosterone is now really the key of cardiac kidney metabolic patients. So you will have heart failure, you will have impaired kidney function, you will have metabolic syndrome because you're obese and, you are hypertensive.

We know that these patients have dysregulated aldosterone. And that's, I think, the beauty of this new era, right? We have different angles to attack that

Dr Nero: It's gonna be very exciting. , One of the keys with these medications appear to be, decreased myocardial fibrosis, that has a l- number of downstreams effects potentially about decreasing the risk of atrial fibrillation. People are talking about GLP-1s in atrial fibrillation and on the SGLT2s in decreasing, the frequency of atrial fibrillation in those, especially in patients with heart failure with preserved ejection fraction.

, There's issues with improved endothelial function, with the decrease in the aldosterone, , so that it's beyond just necessarily going beyond, , the cardiac function. And then, I'm really interested in what's happening with- in the adipocytes and how the adipocytes are going to be affected by these drugs.

There does seem to be a decreased inflammatory effect of ASIs on the adipocytes by decreasing TNF alpha, and if that's true, then you can really start scratching your head and saying, "Okay, well, what are we gonna be seeing with these drugs by decreasing atherosclerosis and heart failure?"

- We're looking at GLP-1s and their effect on the adipocytes. I know that there's a lot of work going in, , anti-inflammatory pathways, those things are going to be very, very interesting to see what happens over the next, , year or two years.

Dr Vogt: Yeah, and I think, I think the g-good example from the diabetic field comes from the GLP-1s for instance, that they really looked in, intervention studies where they biobanked, they did imaging studies, they did hemodynamic profiling. They really want to grasp why the blood pressure goes down.- So I think we, of course, we will go for the solid, solid data for registration purposes to control blood pressure.

The other, important thing is well, myocardial fibrosis,, uh, inflammatory processes, they're also happening in the kidney. And, so we already showed that I presented that dur-during the European Society of Hypertension, that despite the blood pressure reduction, there is also a very significant albuminuria-reducing effect.

So albuminuria goes down, and that's now also acce-accepted cardiovascular risk factor together with eGFR. So it's important to understand that CKD is not only driven by cardiovascular disease, but also vice versa. CKD, , can lead to a, negative cardiovascular risk profile. So in, in, in that sense, it's very interesting to see what is driving this albuminuria effect, because I think it's also a reflection of anti-inflammatory effects in the kidney itself and the vasculature, but also anti-fibrotic effect in the kidney itself.

Or is it just all blood pressure driven? So can we understand why blood pressure goes down and why albuminuria goes down? And are these the similar mechanisms? And for th-this, these kinds of things, you need to really need to do intervention studies in your cardiac CKM patients, uh, preserved kidney function, impaired kidney function, obese, non-obese, and see how all these factors change.

And you can do it very easily. Not only measure blood pressure, but also isolate, monocy-monocytes, see how their profiles are, , do good profiling of, the microcirc-circulation, uh, do a good ultrasound of the heart, do MRI studies to see if there is sodium accumulation in tissues.

, Per-perhaps PET scanning to see where the inflammatory cells are? With even with, with all these kind of isotopes, you can even image the, the vascular arch, the aortic arch, for instance, to see if there is a signal there. And we know this is signal. If there is FD-FDG in the aortic arch, that's glucose uptake by macrophages.

So what does aldosterone synthase inhibitors do? What do they do there? So if you have all these factors measured, you really get the grasp of how these, aldosterone synthase inhibitors will, have their action besides the old sodium-related reuptake in the kidney itself.

That's the starting point. We always focus on the epithelial sodium channel in the tubules of the kidney. Sorry, I'm a nephrologist, as you, as you know. and we always think, oh, blood pressure goes down because it affects the tubules via this transport.

But this sodium chan-channel is present in the endothelium. It's present in a lot of other cells, but what is doing there, the sodium channel? Why, what's the purpose of this? Not, not regulating the sodium balance, of course. No, it has all kind of other effects on transcription , of other proliferative genes, very relevant to the fibrosis in the myocardium, but also in the kidney and in the vasculature itself

Dr Nero: All of these mechanisms I think are, are super important. As a cardiologist, you know, I realized a few years ago, um, that I made a mistake of not really diving into the cardio-cardiorenal effects quite as well as I ought to have.

If you look at, urine albumin, you have a profound cardiovascular risk.

And we do not look at that enough. We just don't. ,

Dr Vogt: Yeah. And it, be-being a, , new and upcoming risk factor, uh, so monitoring the effect on albuminuria and showing that it's, that the albuminuria levels half after treatment with aldosterone synthase inhibitors, which is a massive effect. If we can link this reducing effect to cardiovascular outcomes, and we, we can do it based on other, um, uh, mainly trials done with ACE inhibitors and ARBs.

But if we can reproduce that, if you want to have a kind of clinical idea about this, the health of your vascular system, just sample urine and measure albumin. That tells you where you are, and it tells you also the effi-efficacy of your regimen you started.

, And if you still are microalbuminuric or you have too high, albuminuria then you know you're not doing well enough. You need to try to get it down because that's a reflection of how your endothelial system works. Not necessarily only the kidneys, but it's, it's mainly a cardiovascular outcome prognostic factor.

Dr Nero: Yeah, , and it's interesting in some of the trials that we're involved in, we're using urine albumin as one of the risk enhancers for getting into these trials. And that I think that we'll also be able to look at those, outcomes as being, correlated at least.

, This trial was wonderful in the fact that it dropped blood pressure so, , dramatically and so safely. But it's also wonderful in the fact that we got a lot more data out of this trial than just what the top line results were. And I think that that really,, is to your credit and to your team's credit.

, So from this trial, what do you think the next steps are going to be for ASIs, and how do you foresee them being used in our armamentarium?

We have a lot of drugs - to choose from. , How would you put this into our , regimens?

Dr Vogt: Yeah, I think it's a great question because from the clinical perspective, we know that patients hate to take pills, right? And now we have a, a very efficacious blood pressure-lowering drug. But , we only, , study this as a third, maybe fourth, fifth-line therapy, uh, because if you look at the Launch-HTN, uh, data, the patient inclusion crite-criteria were using two to five different antihypertensive agents.

If you now control blood pressure, and we did so in over forty percent of the people, they were on target when you introduced this drug. Perhaps people had such a low drug blood pressure that you already can reduce the other compounds. So you can decide whether it is to stop, uh, the thiazide diure-diuretic or a beta blocker, an alpha blocker, I'm not sure, or the calcium channel blocker, and just see if you can maintain the blood pressure regulation with a lower number of different pills.

And I think this is also very important from the patient's perspective, a very important outcome,, and if we then still can obtain the same, , level of cardiorenal protection,

but we need to register the data and to see, to see whether this... we can reduce the number of pills, we can reduce the pill burden

Dr Nero: So looking at the, your data The majority of patients were on an ACE inhibitor ARB. You could in theory say, yes, this drug, especially with that com- with a combination with an ACE inhibitor ARB, , seems to be effective. , Do you think that, , you'll be able to, see from, , secondary analyses whether or not the, there was more benefit or less benefit with IZI diuretics or , or calcium channel blockers?

Or do you, or would you say that at least initially that you might even consider doing ACE ARB , and an ASI with the knowledge that potentially that creates more risk for hyperkalemia?

Dr Vogt: Yeah, that's a very difficult question I cannot answer, of course. But the good thing is the, the LAUNCH-ADN data, trial has some open-label extensions., I think these data , can tell us, -- more about these kind of signals, safety signals, efficacy signals, and what regimen, uh, was used to keep the blood pressure well-regulated.

Because in the open-label extension, all the-- the placebo users, of course, were getting lorundustat

Dr Nero: There'll be certainly be a lot you'll be able to see in that crossover group , even though it is open label at that point. In the end, when we take care of our patients, we take care of our patients in an open label fashion,

... Is there any, , projected timeframe on, assessment for these, drugs for the US and for Europe?

Dr Vogt: I cannot answer that question by sure, but, we know FDA accept blood pressure reduction as an outcome to re-- for registration. And also that's, I think, also a very important element. Also, albuminuria reduction now is recognized by the FDA as an outcome. So you can design trials on these outcomes for registration.

So in that sense, -- these agents presumably gets available more easier to our-- for our clinics-- clinicians., And that also means that we can also then see how the implementation affects all the regimens we are using now

Dr Nero: Well, thank you very much, Dr. Vogt. Really can't, thank you enough for, , spending the time today and, I look forward to more publications and more information. Thank you.

Dr Vogt: , Thank you very much. It's a great pleasure to, to join, uh, this podcast