Add-on injectable agent may alter hypertension treatment landscape

Patients with inadequately controlled hypertension (HTN) may benefit from a single subcutaneous (SC) injection of the investigational RNAi therapeutic zilebesiran, on top of standard antihypertensives, findings from the phase II KARDIA-2 trial suggest.

“Compared with placebo, a single injection of zilebesiran resulted in clinically meaningful blood pressure (BP) reductions at 3 months when added to commonly used antihypertensives,” said Dr Akshay Desai from Brigham and Women’s Hospital, Boston, Massachusetts, US, at ACC.24.

In the open-label run-in phase, 1,500 patients with untreated* or treated** HTN were randomized 4:7:10 to indapamide 2.5 mg, amlodipine 5 mg, or olmesartan 40 mg QD for ≥4 weeks. Following which, 672 individuals (mean age 59 years, 57 percent men; 130 on indapamide as background antihypertensive, 241 on amlodipine, 301 on olmesartan) were further randomized to zilebesiran 600 mg or placebo on top of their daily antihypertensive regimen. [ACC.24, LBCT II]

At 3 months, zilebesiran led to significant drops in 24-hr mean ambulatory systolic BP (SBP) vs placebo in the indapamide (least squares mean difference [LSMD], –12.1 mm Hg; p<0.001), amlodipine (LSMD, –9.7 mm Hg; p<0.001), and olmesartan arms (LSMD, –4 mm Hg; p=0.036).

In terms of office SBP at month 3, the patterns of changes with zilebesiran were mirrored and amplified across subgroups (LSMD, –18.5 mm Hg [indapamide], –10.2 mm Hg [amlodipine], and –7 mm Hg [olmesartan]; p<0.001 for all).

There were also rapid median reductions in serum angiotensinogen >95 percent as early as week 2 and sustained through month 6 with zilebesiran vs placebo irrespective of background antihypertensives.

Secondary endpoints that improved with zilebesiran at month 6 were time-adjusted 24-hr mean ambulatory SBP (p<0.001 for indapamide and amlodipine) and office SBP (p<0.001 for all).

There were also more zilebesiran recipients who achieved SBP response without rescue medication, be it in the indapamide (64 percent vs 14 percent; odds ratio [OR], 12.4; p<0.001), amlodipine (40 percent vs 14 percent; OR, 5.1; p<0.001), or olmesartan arms (26 percent vs 17 percent; OR, 1.8; p=0.077).

While more zilebesiran recipients experienced hypotension than those on placebo, most events were transient and resolved without intervention. No deaths were reported nor were there any adverse events leading to study discontinuation. “Most laboratory abnormalities of interest were mild, occurred in the first 3 months, and resolved upon repeat measurement within 1–2 weeks without intervention,” said Desai.

Biannual dosing may be favourable

Despite various effective therapies, many HTN patients do not meet guideline-recommended BP targets, leaving them with unattended risk for cardiovascular (CV) events, Desai noted.

Moreover, poor adherence to multidrug oral regimens may influence BP control. “Even amongst those who are treated, residual BP variability and lack of nighttime dipping may further augment CV risk,” he added. Zilebesiran may offer an alternate treatment strategy for HTN that overcomes some of these barriers.

“[KARDIA-2 shows that] treatment with a single SC dose of zilebesiran 600 mg was associated with clinically significant reductions in 24-hr mean ambulatory and office SBP compared with placebo at month 3 when added to a diuretic, calcium channel blocker, or maximum-dose angiotensin receptor blocker,” Desai said.

“A safe and effective BP treatment that could be dosed as infrequently as twice a year might improve consistency in BP control, reduce overall burden of pills needed to treat [HTN], and significantly reduce CV risk,” he noted in a press release.

“Importantly … the addition of zilebesiran to indapamide, amlodipine, and olmesartan was associated with no new serious safety concerns with regard to potassium elevations, kidney injury, and low BP,” he continued.

Although the study was not sufficiently powered to guarantee long-term safety, the findings support the potential of combining biannual zilebesiran with standard antihypertensives to achieve additive BP reductions.

KARDIA-3 will explore the potential of zilebesiran in individuals with uncontrolled HTN despite being on 2–4 antihypertensives who have high CV risk or advanced chronic kidney disease.

“More studies are certainly needed, but if we can truly demonstrate safe and consistent BP reductions with two injections a year, this approach might dramatically alter the approach to managing HTN in clinical practice,” said Desai.