Monthly Therapy for Hypertension Insights From the Phase II KARDINAL Trial

Podcast Transcript

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Steven Nissen, MD:

I'm Dr. Steve Nissen, and I'm here with my colleague, Dr. Luke Laffin. We're going to talk about the KARDINAL Trial. Now, the KARDINAL Trial addresses hypertension. Tell us a little bit more about how this study addresses hypertension, and particularly about angiotensinogen.

Luke Laffin, MD:

Well, KARDINAL was a Phase II trial amongst patients with uncontrolled hypertension. They were taking between two and five background drugs, pretty standard therapy. Then, they were treated with a drug called Tonlamarsen. Tonlamarsen is not your once-a-day pill like most blood pressure drugs. This is a once-a-month subcutaneous injection. What it does is, it's an antisense oligonucleotide, so an RNA-based therapeutic.

Steven Nissen, MD:

A DNA.

Luke Laffin, MD:

Excuse me. DNA-based therapeutic, a nucleic acid-based therapeutic, which then disrupts angiotensinogen production in the liver. As you know, angiotensinogen is the highest upstream component of the renin angiotensin aldosterone system, which we know is a major driver of hypertension.

Steven Nissen, MD:

And many other adverse outcomes. For sure, it’s used in, of course, kidney disease and protecting patients from a variety of cardiovascular diseases. Now, how does an antisense oligonucleotide affect angiotensinogen? What's its mechanism?

Luke Laffin, MD:

So, what it does is it's an injection that you get subcutaneously, and it goes and it comes into effect relatively quickly. It gets taken up by the liver and disrupts production of the angiotensinogen within the hepatocyte itself.

Steven Nissen, MD:

So, it blocks messenger RNA.

Luke Laffin, MD:

Exactly.

Steven Nissen, MD:

Or it blocks the protein production. Okay, tell us a little more about the study design.

Luke Laffin, MD:

So, the study was a US-based study performed at just under 40 sites within the United States. It ultimately randomized 198 participants, but it had three specific treatment periods. One was a placebo run-in. So, patients were on their background medicines, they received an injection, came back four weeks later. Then all participants received an active treatment. They received 90 milligrams of Tonlamarsen. And then four weeks after that injection, they were randomized to ongoing treatment every 4 weeks for a subsequent 16 weeks to either placebo or additional doses of Tonlamarsen.

The study's primary endpoint was really a co-primary endpoint of, number one, the difference between those treatment groups with respect to serum angiotensinogen levels, so circulating angiotensinogen levels after 20 weeks of total treatment. Then the other co-primary endpoint was change in office systolic blood pressure at week 20, in comparison of the two groups.

Steven Nissen, MD:

What did you find?

Luke Laffin, MD:

So interestingly, we found a few things. Okay. Number one, we found that the monthly Tonlamarsen suppressed angiotensinogen more than just the one-time treatment with Tonlamarsen.

Steven Nissen, MD:

How much?

Luke Laffin, MD:

It was about 67% in those that received every four weeks, compared with only 23% after 20 weeks after the first treatment with Tonlamarsen. This was a statistically significant difference. There clearly was a difference. But what I think was unanticipated to us was the fact that even 20 weeks after an initial Tonlamarsen dose-

Steven Nissen, MD:

One dose.

Luke Laffin, MD:

One dose, you still had 23% reduction in serum angiotensinogen, which based on the other early studies of it, you'd suggest it probably was all out of the body at that point. It may have had to do with some resetting of their renal angiotensin aldosterone system. So, that was number one. We saw that continuous administration of Tonlamarsen suppressed angiotensinogen more.

The other primary endpoint of office blood pressure lowering was pretty interesting. In those patients that received continuous Tonlamarsen, they had just under a seven millimeter of mercury decrease in systolic office blood pressure, which is pretty typical of most blood pressure medications. But this was no different than the group that received just the one-time dose of Tonlamarsen.

There are a few factors that might be at play. Number one, it may not be directly tied to the percentage of angiotensinogen reduction. That's what we'll just ultimately need to figure out.

Steven Nissen, MD:

Why develop a monthly blood pressure medication?

Luke Laffin, MD:

Well, we know that a major reason for uncontrolled hypertension is that patients don't like to take their pills. Okay? It's one thing if someone's taking a single pill once a day, they're okay at that. But we know every subsequent pill that they take, they're less likely to be adherent to their medication regimen. So, there's a lot of interest in this. Get your one injection and then don't have to think about it for another month.

Steven Nissen, MD:

Now, there have been some other studies done with nucleic acid-based therapeutics with this target. Your study was different. Can you tell us a little more about how your study was different?

Luke Laffin, MD:

Well, the major difference here was the active control component of it. Most of these other nucleic acid-based therapeutics, Zilebesiran being the most well-known at this point, they strictly compare with placebo. We know that they suppress angiotensinogen within the blood as well, and they lower blood pressure. So, this was a little bit different in that, in understanding that.

Number two, which was also important, was the fact that we did it in patients that were taking between two and five blood pressure-lowering medicines.

Steven Nissen, MD:

Including ACEs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers).

Luke Laffin, MD:

Exactly. The studies of other longer acting siRNAs that reduce angiotensinogen have been done initially in patients not taking any drugs, they were washed out of their drugs, but then just on a single drug, be it a calcium channel blocker, a thiazide diuretic, and/or an ACE or an ARB. We've seen in those studies, at least on a single drug, that the effect of blood pressure-lowering of these types of drugs was attenuated on ACE or ARB.

Steven Nissen, MD:

So, you really had a more rigorous study design, in the sense that you gave people a lot of drugs, you included ACEs and ARBs, and that's really the test that, in the clinical world, is going to be important to know the answer to that in order to know whether these drugs are going to be effective or not.

Luke Laffin, MD:

Exactly. I think that it's a more real-world design than anything else. We have to be realistic about where these drugs could potentially be used, in what patient populations, and it's not likely that they're going to be given to patients that are not taking any oral blood pressure medicines, which are tried and true and have been around for 40 plus years.

So, this is a real practical study looking at that. It provides almost more questions than it does answers at this point. We're excited to move to the next step of looking at it and studying it, but I think it's a really important study for the field.

Steven Nissen, MD:

Where do you go from here with this research?

Luke Laffin, MD:

Well, we know that in certain patient populations, blood pressure is probably driven by revving up or excess activation of the renin angiotensin aldosterone system, and really excessive levels of angiotensinogen. One such patient population are those individuals with what is called severe acute hypertension.

So historically, that's been referred to as hypertensive emergency or urgency, or malignant hypertension, but we think that that system being revved up could use essentially a resetting, shall we say. We're going to look at it in 100 participants in a Phase 2B study, patients that were in the hospital with severe acute hypertension, and shortly after the discharge, randomized them to placebo or active drug for three months. We'll see how they do.

Steven Nissen, MD:

Well, it's interesting because here we are, decades of antihypertensive therapy, we're still learning new things, and we've got a ways to go, don't we? Because what fraction of the population with hypertension is actually well controlled?

Luke Laffin, MD:

Yeah. It's a really embarrassingly low percentage of the population that has their blood pressure controlled. Depending on the threshold you look at, you could see less than 30% of individuals actually have their blood pressure controlled on medicines.

Steven Nissen, MD:

And I guess part of the reason why is it's difficult. Taking on a lot of pills every day, people are not very adherent, and they don't stay on therapy, but these kinds of longer-acting drugs really do have some promise.

Luke Laffin, MD:

Exactly. Most patients with even very high blood pressure, they don't feel it. They feel fine. Whereas drugs can have side effects associated with them, and people don't like to take medicines. We know that. If we can limit the number of times they actually have to administer or take a drug, that could be helpful.

Steven Nissen, MD:

Well, thank you very much, and thank all of you for listening to Cardiac Consult.

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