Lorundrostat: Results from Advance-HTN Phase 2 Study

Luke Laffin, MD, shares the findings from a late breaker he presented at ACC 2025. Lorundrostat is an investigational drug found to significantly lower 24-hour blood pressure among patients with uncontrolled and resistant hypertension.

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Transcript

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Welcome to Cleveland Clinic Cardiac Consult, brought to you by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.

Luke Laffin, MD:

Hello. My name is Luke Laffin and I'm a preventive cardiologist and cardiovascular clinical trialist at the Cleveland Clinic. I'm going to discuss today the results of a trial called the Advance-HTN Trial, which I presented at the American College of Cardiology Scientific Sessions as a late-breaking clinical trial on March 29th, 2025. Advance-HTN was a pivotal study of a drug called Lorundrostat.

Lorundrostat is a new class of blood pressure lowering medicines. It's called an aldosterone synthase inhibitor. Aldosterone is a circulating hormone in our body, which we know is underappreciated in terms of its impact on blood pressure and sustained hypertension. This class of medicines works differently than what we typically think of as aldosterone modifying drugs, such as mineralocorticoid receptor antagonists like eplerenone or spironolactone.

The way it works differently is rather than blocking the mineralocorticoid receptor, what it does is it actually disrupts biosynthesis of aldosterone, so it's not made in the first place. There's some background to this lorundrostat. We helped do the trial, the phase 2a trial, which was published back in September 2023, which was a dose finding trial. Really what this trial did, was it did a few key things to really examine the efficacy of lorundrostat for the treatment of hypertension.

Number one, it looked at patients’ blood pressure over a 24-hour period. It used 24-hour ambulatory blood pressure monitoring rather than just office-based blood pressure. Additionally, what it did was, it put patients on a standardized antihypertensive regimen. Rather than, in usual care, which we know typically isn't that great for hypertension, we put patients on optimized background therapy and looked at their blood pressure lowering over a 12-week period.

Really, the flow of patients through the trial was as follows. There was a two-week screening period where patients on 2 to 5 blood pressure drugs with office blood pressure uncontrolled were then switched to a standardized background regimen. So, if they were on two blood pressure meds coming in, what they did was they were put on olmesartan, a potent ARB at 40mg and indapamide 2.5mg in most patients.

About 30-35% of patients got hydrochlorothiazide as their diuretic at a 25mg dose. Then, those participants that were on 3 to 5 blood pressure medicines coming in received an additional ten milligrams of amlodipine. So, you have patients on either two maximum drugs or three dose maximum drugs. Then, they underwent a three-week running period where they took the standardized regimen.

If blood pressure remained elevated after those three weeks, and that was based on 24-hour ambulatory blood pressure over 130mm of mercury, then patients were randomized to one of three groups. One group is naturally going to be placebo. One group was lorundrostat 50mg daily for 12 weeks. The third group was lorundrostat 50mg, with the potential to increase to 100mg, really a dose titration strategy, if the blood pressure was uncontrolled at the four-week time period. 

The primary endpoint was change in 24-hour average systolic blood pressure at week 12 in each of those lorundrostat groups. So, the lorundrostat 50 milligram group and the lorundrostat 50 to 100 milligram group, compared with placebo. What this trial then did was there was a washout period of about four weeks where serum biomarkers were checked, all of those things.

Importantly, within the trial, the trial enrolled about 40% women. Very importantly, it enrolled 53% participants of Black race. Now, this was done all at sites throughout the United States. It was 103 clinical trial sites in total. This is really important. A large burden of uncontrolled and treatment-resistant hypertension, particularly the morbidity and mortality associated with hypertension, rests in the African American community.

So, it was very vital that this community was studied. Probably one of the reasons why there was such a high percentage of Black patients enrolled was because of these strict enrollment criteria, that standardized regimen. And then, the needing to meet office and ambulatory blood pressure thresholds. 

Other factors within the trial, the average body mass index was about 31kg/m². Over a third of patients had diabetes. A third had lipid disorders as well. But those were balanced throughout the groups. 

Now, the primary efficacy endpoint was the change in 24-hour systolic blood pressure at week 12. What was seen was, comparing placebo to the lorundrostat 50mg daily group, there was a placebo subtracted difference of just under eight millimeters of mercury of systolic blood pressure, 7.95 to be exact. 

Then, when you compared placebo to the titration strategy group, the 50 to 100 milligram group, the blood pressure lowering was similar. It was about 6.5mm of mercury of placebo subtracted blood pressure. Now, to put that in context as well, the placebo group got about a seven millimeter mercury decrease, whereas the lorundrostat groups got between about a 15.5 and 14mm of mercury reduction in blood pressure. Thus, leading to those placebo subtracted numbers. 

Important to note, there were multiple key secondary endpoints that were controlled for multiplicity. Probably the most pertinent to our listeners here today is going to be blood pressure control at the four-week period. So, in this endpoint, what was done was the placebo participants that achieved a systolic blood pressure on their four-week ambulatory blood pressure monitor of less than 125 were compared with all the lorundrostat participants at week four. Everyone had received 50mg up to that point. So, all the participants at week four that had a systolic blood pressure less than 125. It was 18% in the placebo group, versus 41% in the lorundrostat treated group, an odds ratio of 3.3. It’s clearly effective in terms of lowering blood pressure, in getting patients more to goal in terms of where they want to be. 

Important to note, in any study that you're going to do with a drug like this, there's some expected effects on the renin angiotensin aldosterone system. There was more hypotension, of course, in the lorundrostat treated groups. Well, that's what the drug's supposed to do. Right? But then, there were small increases in potassium, small decreases in serum sodium, although a lot of that was driven by the potent thiazide type diuretic use. Small decreases in EGFR as well. It's important to note about the EGFR is that, oftentimes a decrease in EGFR in the short term actually signifies a therapeutic benefit because you're lowering those intraglomerular pressures. It’s something that's important to note here. 

To give you some specifics about the potassium levels, because it's something that we always worry about, 5 of the 94 patients in the lorundrostat 50 milligram group had potassium values over 6.0 millimoles per liter. But importantly, three of those five, on repeat within 72 hours, still taking the same dose of the drug, had normal values, suggesting that hyperkalemia is not a major issue with this drug. You should watch potassium with anything that's going to impact aldosterone, but it's something to keep an eye on. 

What's next lorundrostat?  Well, there's a phase three study, looking at not 24 hour ambulatory blood pressure monitoring, but just office blood pressure and not on patients on a standardized regimen, but just those on usual care. That study has been completed. Those data are expected at some point in the middle of the year, sometime. Then beyond that, this drug, depending on approval by regulatory agencies, may be available for patients to get their hands on within the next year or so. 

So, I think there's some very important lessons to take home from this trial. Number one, was lorundrostat effectively lowers blood pressure, particularly at the 50mg dose. Going from 50 to 100mg didn't decrease your blood pressure any further and led to numerically more adverse events. So, probably not worthwhile increasing to 100mg. 

But even more importantly, we're failing as a physician group at treating hypertension effectively. When you look at the data every year, 30% of patients with hypertension have their blood pressure controlled. Of course, that's an unacceptable number for the number one modifiable risk factor for strokes, heart attacks, heart failure. We have to do better. One of the ways we can do better is putting patients on optimized therapy, but then also using new therapies and availing ourselves of new therapies that could have benefit. 

I think also a real important point from this trial is we need to study these therapies in the patients that really need it. We don't need another blood pressure medicine for someone on no drugs or on one drug. We need it for patients who are on more than two drugs and blood pressure is uncontrolled. That's really important to study it in the patients that really need it.

This trial, importantly, was performed with the C5 research group here at Cleveland Clinic. We've been working with the sponsor on this trial for more than three years to ensure its planning, site selection and, ultimately, execution of the trial was done with the highest academic rigor.

 C5 is a great resource that we love to use here at Cleveland Clinic. We're lucky to have it. It's the best academic research organization in the world.

For more information or to refer a patient, you can call our referring physician hotline at (855) 751-2469. That's (855) 751-2469. Thank you for listening to Cardiac Consult.

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