Twice-yearly injectable antihypertensive drug lowers BP at 6 months: KARDIA-2
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Key takeaways:
- Injectable zilebesiran reduced systolic blood pressure at 6 months on top of other antihypertensive medications.
- The twice-yearly drug shows promise as part of combination therapy.
ATLANTA — A single subcutaneous dose of zilebesiran, an investigational RNA interference agent, significantly reduced 24-hour mean ambulatory and office systolic BP at 6 months vs. placebo when added to other antihypertensive therapy.
Data from the phase 2 KARDIA-2 study also showed that zilebesiran, which targets hepatic synthesis of angiotensinogen, was generally safe and well tolerated, offering a potential option for combination antihypertensive therapy with a more tolerable dosing regimen for patients.
“Poor adherence to complex, multi-drug oral treatment regimens may be one factor contributing to inadequate BP control,” Akshay S. Desai, MD, MPH, FACC, FHFSA, cardiovascular medicine specialist and director of the cardiomyopathy and heart failure program at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School, said during a late-breaking clinical trial presentation at the American College of Cardiology Scientific Session. “Even among those who are treated, residual BP variability and lack of nighttime dipping may further increase CV risk.”
Zilebesiran as add-on therapy
As Healio previously reported, zilebesiran lowered systolic BP for 3 months with a sustained reduction seen at 6 months in the phase 2 KADRIA-1 trial, and rates of major adverse events were low.
For KARDIA-2researchers analyzed data from 672 adults with untreated hypertension or hypertension treated with one or two antihypertensive medications and a seated office systolic BP of 145 to 180 mm Hg. The mean age of participants was 59 years; 43% were women and 28% were Black; and approximately 25% also had type 2 diabetes. Mean baseline systolic BP was 143 mm Hg.
After discontinuing any antihypertensive medications, researchers randomly assigned participants to one of three once-daily medications: indapamide (n = 127), amlodipine (n = 238) or olmesartan (n = 301). Those who consistently took those medications as prescribed and still had a 24-hour systolic BP of 130 to 160 mm Hg at 4 weeks were then randomly assigned to receive a single injection of zilebesiran 600 mg or placebo.
Researchers followed participants for 6 months and permitted the addition of other antihypertensive drugs at 3 months to achieve guideline-recommended BP targets.
The primary endpoint was change from baseline in 24-hour mean ambulatory systolic BP at 3 months. Secondary endpoints included change in serum AGT, change from baseline at month 3 in office systolic BP, and time-adjusted changes from baseline at month 6 in 24-hour mean ambulatory and office systolic BP.
At 3 months, the least squares mean difference in 24-hour mean ambulatory systolic BP compared with placebo was –12.1 mm Hg for the indapamide group (95% CI, –16.5 to –7.6; P < .001), –9.7 mm Hg for the amlodipine group (95% CI, –12.9 to –6.6;P < .001), and –4 mm Hg for the olmesartan group (95% CI, –7.6 to –0.3; P = .036).
Despite allowance for add-on therapy, time-adjusted reductions in office systolic BP between zilebesiran and placebo remained significant through month 6 for all groups, Desai said.
Desai said the phase 2 KARDIA-3 study will evaluate patients with hypertension not controlled with at least two standard-of-care antihypertensive therapies who are at high CV risk or have advanced chronic kidney disease.
Acceptance of injectable therapy
During a discussion of the results, Nanette K. Wenger, MD, MACC, MACP, FAHA, FASPC, emeritus professor of medicine (cardiology) at Emory University School of Medicine, consultant at Emory Heart and Vascular Center and founding consultant at Emory Women’s Heart Center and a Healio | Cardiology Today Editorial Board Member, said acceptance of an injectable antihypertensive therapy vs. oral tablets could be a potential barrier going forward. Desai said uptake of injectable therapies overall has increased, particularly with the approval of the latest obesity medications.
Wenger said she was excited by the KARDIA-2 data.
“Only about one-fourth of the patients in our country have control of their BP,” Wenger said. “A great deal is that asymptomatic patients get bored with medication taking and do not continue on a regular basis. This is a very different approach, where patients could achieve better control, and a therapy taken just once every 6 months may be a way to conquer some of the problems we see.”
Perspective
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Kim A. Williams Sr., MD, MACC, FAHA
This was a fascinating trial. What is striking is if a person takes [zilebesiran] and then an angiotensin II receptor blocker, you do get a response, but you do not see as much of a response as you do when taking a calcium channel blocker or a diuretic. I hope there will be further analysis of not just zilebesiran vs. placebo, but analyses of the intergroup differences. It looks like the indapamide group did substantially better than the olmesartan group. Part of that has to do with the half-life of drugs and efficacy, but part of it might be due to the physiology of hypertension.
When it comes to hypertension, the motivation to initiate therapy is often disease. People are much more dedicated to a therapy if they have kidney disease or have a relative or someone they know dealing with the effects of hypertension. The African American community makes up 12% of the population and 35% of the dialysis patients. The major leading cause of dialysis is hypertension. If you have a patient whose father is on dialysis, they are going to show up looking for a therapy that is quick, easy and inexpensive. Cost with this therapy is a concern. These are new, fancy drugs we are talking about — things that increase health care disparities. The people who could benefit from drugs like these the most often cannot afford them.
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Desai A, et al. Late-breaking clinical trials II. Presented at: American College of Cardiology Scientific Session; April 6-8, 2024; Atlanta.
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