Data on zilebesiran from the KARDIA-2 trial, in combination with other hypertension medicines, are expected in 2024.
A single injection of the investigational RNA interference therapy
Data on zilebesiran, from the phase 2 KARDIA-1 trial (NCT04936035), were presented at
“Uncontrolled high blood pressure is a leading cause of death and disease, so there is a need for new treatments that provide sustained blood pressure control over longer periods of time. This will improve outcomes for people with hypertension,” Bakris said in a press briefing.2 “Uncontrolled hypertension also increases the risk of heart disease.”
Zilebesiran targets angiotensinogen (AGT), a hormone produced predominantly in the liver that contributes to blood pressure regulation. KARDIA-1 randomized 394 participants with mild-to-moderate hypertension. Participants had an average systolic blood pressure of 141.8/81.8 mm Hg and received subcutaneous doses of zilebesiran (150, 300 or 600 mg once every 6 months or 300 mg once every 3 months) or placebo. Of these patients, 377 were ultimately included in the analysis, with 302 randomized to a treatment arm and 75 to the placebo group. The participants’ average age was 57 years old and about 25% of participants were Black adults and 56% were men. Participants were from Canada, Ukraine, the United Kingdom and the United States, data from participants in Ukraine were excluded.1
As of June 2023, investigators found that treated participants had a mean of more than 10 mm Hg reductions in 24-hour systolic blood pressure and greater than 90% reductions in serum levels of AGT. At 3-month follow-up, participants that received the 300 mg and 600 mg doses had 24-hour average systolic blood pressure lowered by 15 mm Hg or more on average. After 6 months, people receiving zilebesiran were significantly more likely to experience 24-hour average systolic blood pressure reductions of 20 mm Hg or more on average without the need for additional high blood pressure medications. Altogether, people receiving zilebesiran were more likely to achieve 24-hour average systolic blood pressure measurements of 130 mm Hg or less at 6 months.1
“Our study demonstrates that either quarterly or biannual doses of zilebesiran can effectively and safely lower blood pressure in patients with uncontrolled hypertension,” Bakris said.2 “It is well known that reductions in systolic blood pressure of greater than or equal to 5 mm Hg are linked to a reduction in cardiovascular risk. These results reinforce the potential of zilebesiran to provide sustained blood pressure control, improve adherence to medication via infrequent dosing, and in turn, improve outcomes for people with high blood pressure.”
In terms of safety, there was a low incidence of zilebesiran-related adverse events (AEs). Four related AEs led to study discontinuation, although not categorized as serious. These were 2 cases of orthostatic hypotension, 1 case of blood pressure elevation, and 1 case of injection site reaction. The placebo group experienced no AEs. Mild injection site reaction was the most common AE. Investigators observed no clinically relevant changes in kidney or liver function.1
Alnylam plans to evaluate zilebesiran’s long-term safety and efficacy outcomes in future research, as the current findings are limited to the 6-month placebo-controlled period and only in people with mild-to-moderate hypertension.
“We are thrilled that the KARDIA-1 Phase 2 results show zilebesiran’s ability to achieve sustained blood pressure reductions of greater than 15 mmHg, as well as long-term efficacy out to 6 months with infrequent dosing. We believe these results further validate the differentiated profile we observed in Phase 1. Moreover, they reinforce the potential for zilebesiran to be a transformative therapy to reduce cardiovascular risk in patients with hypertension and to offer new possibilities in a field of medicine that has seen limited innovation in nearly 20 years,” Simon Fox, PhD, Vice President, Zilebesiran Program Lead, Alnylam, said in a statement.3
