A Shot in the Arm for Uncontrolled Hypertension

This transcript has been edited for clarity.

Michelle L. O'Donoghue, MD, MPH: Hi. This is Dr Michelle O'Donoghue, reporting for Medscape. Joining me today is Dr Akshay Desai. He's the director of the heart failure program at Brigham and Women's Hospital.

One of the interesting studies that's being presented here at American College of Cardiology (ACC) 2024 is the KARDIA-2 study. KARDIA-2 is looking at an RNA interference medication called zilebesiran that is being developed to target patients with refractory hypertension. It's a tough one to pronounce, perhaps, but let's talk a little bit about what zilebesiran is, what it targets, and how well it works.

What Is Zilebesiran?

Akshay S. Desai, MD, MPH: Michelle, zilebesiran is an RNA interference therapeutic that's targeting hepatic angiotensinogen, which is the most upstream precursor in the renin-angiotensin system and is the sole precursor for all of the angiotensin peptides.

The concept is that, by targeting hepatic production of angiotensinogen, we can suppress about 90% of plasma levels of angiotensinogen, and if angiotensinogen is depleted, then all the downstream metabolites, such as renin, angiotensin I, and angiotensin II, in theory, should also be suppressed.

This is another approach to complete suppression of the renin-angiotensin system that is analogous to some of the existing oral drugs we have in practice, such as angiotensin receptor blockers, angiotensin-converting enzyme (ACE) inhibitors, and renin inhibitors in terms of the mechanism. Because it acts more upstream, it offers the potential for more complete suppression of the system, and because it is an RNA interference therapeutic, the potential for a subcutaneous therapy with infrequent dosing and prolonged duration of action.

O'Donoghue: To that point, it's a small interfering RNA (siRNA), which allows it to have a more prolonged duration of action. How frequent is the dosing for this?

Desai: The dosing, which was worked out in phase 1, is that when you give a single dose of subcutaneous zilebesiran, plasma angiotensinogen agent levels fall to a peak level of about 95% or 98% by week 2. Then they are sustained and suppressed all the way out to 6 months with a single dose before the levels start to recover.

With the 600-mg dose, which was the dose that was chosen for the KARDIA-2 trial that we'll be discussing, the suppression of angiotensinogen is more than 95% for 6 months. Right now, this is positioned as a twice-annual medication.

O'Donoghue: It definitely has appeal for patients who may not be very compliant with a daily medication regimen. To be fair, some of these medication regimens can be very complicated if they have refractory hypertension and are on four or five different antihypertensives.

Desai: Michelle, I think this is one of the great things. We haven't seen much innovation until recently in the hypertension space. I think one of the great challenges we have is despite the availability of many drugs to treat high blood pressure, some of which are generic and low cost, we don't do a great job of treating blood pressure, especially to the more aggressive targets that have recently been set by our guidelines. In fact, if we look in practice, about 40% of patients with diagnosed hypertension are not treated to guideline-recommended targets. That leaves a large amount of residual risk on the table.

I think some of that is probably driven by many factors, such as access to care, social determinants of health, and maybe the cost of medications, but some of it is that patients, even when prescribed medicines, don't take their medications. I think the other component is that physicians seeing patients in routine practice are prone to keep things as they are, maybe kick the can down the road a little bit with regard to blood pressure, and see whether it persists in elevation before they act.

One of the great opportunities for a long-acting therapeutic, like an RNA interference therapeutic, is the opportunity to overcome some of those adherence challenges and some of the inertia that happens on the physician side.

O'Donoghue: What did the top-line results of KARDIA show? What are we learning?

Desai: KARDIA-2 is a follow-on trial to the first KARDIA trial, which was reported and published in JAMA earlier this year, in which patients with hypertension were washed out of their medicines and then randomized to treatment with zilebesiran or placebo.

In this trial that we're reporting at the ACC, the KARDIA-2, patients who either had untreated hypertension or those with treated hypertension on one or two medications that were still uncontrolled, were then transitioned to background therapy in random fashion with either amlodipine, indapamide, or olmesartan. They were then followed open-label on those therapies for 4 weeks to ensure background blood pressure control. Those patients who had persistent elevation in blood pressure and were adherent to their medicines were then randomized to treatment with zilebesiran or placebo.

This trial, KARDIA-2, is investigating the effect of zilebesiran as add-on therapy to some commonly used medication classes that we see in clinical practice dosed at levels that would be expected to provide background reduction in blood pressure.

The primary findings of the trial are that regardless of the background therapy (a thiazide diuretic, indapamide 2.5 mg; a calcium channel blocker, amlodipine 5 mg; or a potent angiotensin receptor blocker, olmesartan 40 mg), the addition of zilebesiran compared with placebo was associated with important reductions in 24-hour ambulatory systolic blood pressure at 3 months. The reductions were as much as 12 mm Hg in the indapamide arm, as much as 10 mm Hg in the amlodipine arm, and as much as 4 mm Hg in the olmesartan arm compared with placebo.

What we were able to show is that the addition of zilebesiran does appear to have incremental effects in lowering blood pressure over standard commonly used medicines in practice in a hypertensive population that was uncontrolled. Those effects, if we look at the 6-month data, do appear to endure to 6 months, at least in the indapamide and amlodipine arms particularly, even though after 3 months, investigators were allowed to add on additional antihypertensive therapy. At least there is some evidence that there is incremental efficacy over standard available therapies and complementary effects in blood pressure–lowering.

Changes in Renal Function

The other important result is that there is additional evidence in this trial, complementing what we had from phase 1 and from KARDIA-1, of additional safety. There were no major concerns identified with regard to hyperkalemia, worsening renal function, or serious hypotension, although there were more episodes of mild hyperkalemia and some transient declines in renal function that were seen during the study and more reported cases of low blood pressure.

O'Donoghue: In terms of those changes in renal function, are they akin to what you might see after initiation of an ACE inhibitor, for instance? Is there reason to believe that there could be long-term benefit from this type of therapy for renal function? Could they be renal-protective?

Desai: That remains to be demonstrated, but absolutely. I think the effects are exactly as you've stated them. There's an early decline in estimated glomerular filtration rate that's seen in some patients, as much as 30%. But on repeat testing, most of those changes in renal function appear to be attenuated in the zilebesiran-treated patients.

I think much like ACE inhibitors and angiotensin receptor blockers, other drugs active in this axis, we do seem to see some early effect on renal function. Whether, like those agents, there is long-term protection from this approach with regard to renal function, I think we need to explore further in the trials. There's reason to believe that suppression of this axis has value, particularly in high-risk renal populations like those with diabetes or proteinuria.

O'Donoghue: In terms of other risks that one might consider, things like angioedema from that pathway in particular, is there any reason to believe that this drug could pose problems for people who have a history of edema with renin-angiotensin drugs?

Desai: We haven't seen a signal of concern with regard to angioedema in the experience so far. I think one of the reassuring features is that this drug has a targeted action to suppress only hepatic angiotensinogen in the liver. We think that much of the angioedema-related effects of ACE inhibitors, for example, or neprilysin inhibitors, has to do with their effects on bradykinin metabolism. Because there is a very targeted effect here on the angiotensinogen gene and the RNA, we don't think that there should be a signal of angioedema, and we haven't seen one so far.

Long-Acting With No Reversal Agent

O'Donoghue: In terms of the prolonged duration of action, I think one of the questions that people have raised, too, is what about a patient who then runs into problems with hypotension? Of course, it's a relatively small study that has looked at this so far, but if this was to become more available on a widespread basis, there's no option really for reversing the therapy, I suppose.

Desai: A few notes there. One is that, as you say, we hope it's reassuring that in the experience that has accumulated so far there hasn't been a serious signal of severe hypotension. As you know, the trial was a relatively short duration, they're fairly small, and have not involved many very high-risk patients. I think we need more long-term safety data before we can be sure.

The few reassuring things that have been noted so far is in the early phase 1 experience, there was a component of looking at the effect of high-sodium diets on blood pressure in patients treated with zilebesiran, and it does appear that, with salt loading, there is a rescue of the blood pressure-lowering effect of zilebesiran.

There are also some data from the preclinical experience in animal models that the animals treated with zilebesiran still do respond to conventional pressor agents, including norepinephrine, angiotensin II, and volume loading. The final piece is that there has been work to develop a targeted reversal agent for zilebesiran in the event that more serious hypotension is observed.

O'Donoghue: The blood pressure–lowering effects are quite impressive. It's great to see, too, some incremental blood pressure lowering on a background of an angiotensin receptor blocker as well. I think that certainly speaks for there being a potential role here for this type of therapy, and especially for perhaps a noncompliant patient, perhaps even more benefit in that particular patient population.

More Consistent Blood Pressure–Lowering Effect

Desai: I think the other potential advantage, although we haven't seen whether this will translate into any meaningful benefit with regard to cardiovascular outcomes, is the consistency of the blood pressure–reduction effect. We know that when a patient takes an oral medication, as the medication half-life is exceeded, the blood pressure tends to rebound.

There's a large amount of volatility in blood pressure that we see in patients taking oral medicines in practice, particularly if they miss medicines from time to time, and that blood pressure variability in large datasets does seem to correlate with some risk for worsening outcomes. The more volatility one sees, the more risk there is.

One opportunity with RNA interference therapeutics like zilebesiran is that there is such a consistent effect that we have reductions in blood pressures that endure over the full 24-hour interval. Nocturnal blood pressure is lowered as much as daytime blood pressure. Between visits, there isn't much variability in the amount of blood pressure–lowering seen. Whether that translates into a meaningful benefit in practice or at any advantage over the other available therapies is something we'll have to learn in future trials.

Role of Renal Denervation

O'Donoghue: That's very interesting. The last thing I'd like to get your thoughts on is renal denervation. I think that people have been perhaps confused by the conflicting evidence that has emerged through the years and may not really be sure how that fits in right now for management of patients with hypertension that seems to be refractory to several antihypertensive medications.

Desai: I think that much of the confusion arose really because of the results of SYMPLICITY HTN-3, where an early approach to renal denervation with radiofrequency ablation, in its early iteration, was associated with no statistically significant benefit in that trial. However, subsequent trials of both radiofrequency ablation and newer ultrasound methods for doing renal denervation have shown convincing evidence of efficacy with regard to blood pressure lowering, on the order of 5-7 mm Hg on average, in patients with fairly resistant hypertension on multiple medications.

The FDA has recognized this recently and provided regulatory approval for use of renal denervation to treat selected patients with resistant hypertension. I think we now have it available as a therapeutic option. It's still a little unclear to me as a clinician exactly which patients are likely to benefit. I think right now, we'll follow the lead of the trials and refer those patients, presumably, who have the most treatment-resistant hypertension.

Whether there's a role for earlier utilization of that therapy in the populations that we've been discussing with nonadherence or who just prefer not to take as many medications as earlier-line therapy, I think that still remains to be seen.

O'Donoghue: Thanks for walking us through that. I think, as you say, very nicely. For a long time, there really hadn't been much to reach for that was new in this space. I think now, between renal denervation and some of these newer therapeutics that are in development, it is a very exciting time.

Desai: Exciting times in prevention, in general, I think. It's good to see innovation on this end of the spectrum.

O'Donoghue: Thanks for joining me today to discuss it.

Desai: Thank you.

O'Donoghue: Signing off for Medscape, this is Dr Michelle O'Donoghue.

Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.

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