[00:00.0]
I'm Neha Pagidipati and I'm a preventive cardiologist at Duke University and the Duke Clinical Research Institute. And today I will be discussing the KARDIA-3 trial that I presented at ESC.

[00:12.7]
Uncontrolled hypertension is the single greatest contributor to cardiovascular morbidity and mortality worldwide. And we know that there are several, you know, effective available therapies, and yet most patients, at least many, are not reaching their target or maintaining their target blood pressure, and that's contributing to the global burden of cardiovascular disease.

[00:31.2]
But an effective long acting agent might help to obtain continuous control and help to combat that burden that we're seeing of uncontrolled hypertension and subsequent cardiovascular mortality and morbidity. And so we did the KARDIA- 3 trial to understand whether zilebesiran can help in that manner.

[00:49.3]
Now, zilebesiran is an investigational RNA interference therapeutic and it inhibits hepatic production of angiotensinogen - that's the most upstream precursor in the RAAS pathway. And it is administered subcutaneously once every 6 months, so it has the potential to provide continuous blood pressure control over that time period.

[01:07.9]
So the KARDIA-3 trial was the third phase 2 trial in the zilebesiran development programme so far. The first, KARDIA-1 trial, tested zilebesiran as monotherapy. The second, KARDIA-2 trial, tested zilebesiran on top of a single background antihypertensive agent, and it actually found significant blood pressure lowering on top of a diuretic in particular, but also on top of a calcium channel blocker and on top of ARB therapy.

[01:33.4]
And now KARDIA-3, which I presented here at ESC, tested zilebesiran in patients with uncontrolled hypertension despite 2 to 4 antihypertensive therapies at baseline and high cardiovascular risk. And the purpose of KARDIA-3 really was to understand the efficacy, safety and optimal dosing of zilebesiran in this high risk population in order to inform the design of a cardiovascular outcomes trial.

[01:55.5]
KARDIA-3 was a placebo controlled, multi-centre, randomised controlled trial across 5 countries and it included patients with elevated cardiovascular risk or known cardiovascular disease, uncontrolled hypertension, and who were already prescribed 2 to 4 antihypertensive therapies at baseline, one of which had to be a diuretic or a calcium channel blocker.

[02:15.0]
Now, there were 2 cohorts in KARDIA-3. I presented data on cohort A, which included patients with an eGFR of greater than or equal to 45. Cohort B, which will be presented at a later date, included patients with more advanced kidney disease. In cohort A, patients at baseline were randomised to a single dose of zilebesiran, 300 milligrams, 600 milligrams or placebo, and then they were followed for 6 months.

[02:38.0]
Randomisation was stratified by factors that we thought might impact the effectiveness of zilebesiran a priori, which included race, baseline systolic blood pressure and also baseline diuretic use. And then in the first 3 months, clinicians and patients were encouraged not to change their background antihypertensive therapy unless clinically indicated.

[02:55.6]
And the primary outcome was change from baseline to month 3, mean office systolic blood pressure. So we recruited 270 patients across the trial in the three arms, and these were patients at high cardiovascular risk. It was an appropriately diverse cohort, which was great.

[03:10.8]
I'm happy that we were able to recruit a diverse, you know, a good representation of patients. And at baseline, over 90% of patients were on ACE or ARB therapy, about two-thirds were on diuretic therapy, and just over half were on a calcium channel blocker.

[03:27.0]
About half the patients were on 2 therapies at baseline, about a third were on 3, and the minority were on 4 therapies at baseline. And what we found in terms of the primary outcome at 3 months, the placebo adjusted change in the zilebesiran 300 milligram group was minus 5 millimeters of mercury, and in the 600 milligram group it was minus 3.3 millimeters of mercury.

[03:46.7]
And after adjustment for multiplicity, those P values were not statistically significant. What we did find was a very encouraging safety profile, even on top of ACE and ARB therapy, there were few serious adverse events and they were generally comparable between arms.

[04:02.4]
The instances of hyperkalemia and worsening kidney function that we saw were generally not seen on subsequent measurement and none required dialysis or hospitalisation. And as I mentioned, one of the main purposes of KARDIA- 3 was to understand who was most likely to benefit from zilebesiran so that we could design the best possible cardiovascular outcomes trial.

[04:20.1]
And we knew from KARDIA-2 that zilebesiran appeared to be most effective in patients who are on baseline diuretic therapy, and that's why we built that into the design of KARDIA-3 by stratifying randomisation by baseline diuretic status. If we look at the pre- specified analysis in KARDIA- 3 of patients who were on diuretic therapy at baseline, you saw a placebo adjusted change in the 300 milligram group of minus 6.6, and in comparison, it was minus 5 in the overall population.

[04:46.9]
If you then look at patients who were on diuretic therapy, but who were truly hypertensive at baseline, so they had a systolic blood pressure of greater than or equal to 140, in this post- hoc analysis, we saw a placebo adjusted change of more than 9 millimetres of mercury. So that really helped us to inform the cardiovascular outcomes trial, which will be upcoming.

[05:05.6]
It's called the ZENITH Outcomes Trial, and it will include patients who have an elevated systolic blood pressure at baseline, elevated cardiovascular risk, and who are on diuretic therapy. In terms of the implications for clinical practice, we're still a little ways away. This is a phase 2 program, and so we still need to do the phase 3 outcomes trial, which I'm extremely excited about, and the hope and the expectation being that this therapy can provide cardiovascular benefit to patients.

[05:30.3]
If we do see that, I really see this therapy as being potentially paradigm shifting for patients. And I think that's true for a couple of reasons. This is not just another daily pill. This is a, you know, a subcutaneous injection that patients would get every 6 months. And it then provides continuous control of blood pressure.

[05:47.9]
That's day and night. And we know that nighttime blood pressure is probably the most specific prognostic marker for future cardiovascular disease, so that continuous control throughout day and night and decrease, likely decrease in blood pressure variation, is probably really important for cardiovascular risk reduction.

[06:03.5]
The other thing is that it saves patients from taking one more pill. And we know that adherence is a huge issue in hypertension about, you know, for any given antihypertensive agent, patients are taking it about half the time. And every additional pill you add, patients are that much less likely to take it.

[06:19.6]
So it actually is really important both for patient quality of life, but also for their likeliness of having kind of complete RAS inhibition on board to have a medication that they don't have to think about taking every single day. So for multiple reasons I think this could be a real paradigm shift both for individual patients and for population health.

[06:36.9]
And so we're very excited for the cardiovascular outcomes trial, and hopefully it will show cardiovascular benefit. We are going to be presenting cohort B data on the advanced, more advanced kidney disease population. So stay tuned for that. We're really excited about that. And then I really think we have to prove that this therapy not only can control blood pressure, but that it can actually improve MACE outcomes.

[06:59.1]
So the primary outcome is going to be cardiovascular death, non fatal MI, non fatal stroke and heart failure events. And so we're really excited to see what that shows.