2024-02-29 10:25:09
The high blood pressure lowering drug zilebesiran, which is based on RNA interference (RNAi), has the great advantage that it only needs to be injected every 3 or 6 months. In the phase 2 study KARDIA-1, it lowered blood pressure in mild to moderate hypertension to a clinically relevant extent, both during the day and at night, as the study authors in JAMA to report [1].
Dr. Lucas Lauder
“One of the main problems with drug therapy is poor adherence, especially in chronic diseases that do not cause symptoms,” explains Dr. Lucas Lauder from the Clinic for Internal Medicine III – Cardiology, Angiology and Internal Intensive Care Medicine at the Saarland University Hospital, Homburg/Saar. “About 10% of the new prescriptions we write for antihypertensive drugs are not filled. And following a year, only 50% of patients are still taking the medication as we prescribed. We need more therapeutic approaches that are independent of adherence, such as zilebesiran or renal denervation.”
Synthesis of certain proteins is specifically switched off
RNAi therapeutics specifically prevent the expression of certain genes and thus the synthesis of the corresponding proteins in the cell. “In the case of zilebesiran, it is the synthesis of angiotensinogen that is shut down. As a precursor protein of the renin-angiotensin-aldosterone system, it is significantly involved in blood pressure regulation,” explain the study authors led by Prof. Dr. George L. Bakris, director of the Comprehensive Hypertension Center at the University of Chicago Medicine.
The RNAi therapeutic is injected under the skin at intervals of several months. 394 patients with mild to moderate high blood pressure took part in the 6-month KARDIA-1 study. They were previously treated with various other antihypertensive medications and had an average systolic blood pressure (SBP) of 135 to 160 mmHg following a 2- to 4-week washout period.
The 4 RNAi therapeutic dosage regimens studied were
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Zilebesiran 150 mg alle 6 Sweet,
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Zilebesiran 300 mg every 3 or every 6 months and
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Zilebesiran 600 mg alle 6 Sweet.
The placebo group received an injection of the placebo every 3 months. The primary efficacy endpoint was the change in systolic blood pressure in the 24-hour ambulatory measurement, collected following 3 months.
Blood pressure reduction may be underestimated
Of the 394 randomized patients, 377 were ultimately analyzed: 302 in the zilebesiran groups and 75 in the placebo group. Blood pressure fell in all 4 zilebesiran groups over the 3 months, but increased in the placebo group. Specifically, the blood pressure reduction was:
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7.3 mmHg with zilebesiran 150 mg, every 6 months
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10.0 mmHg with zilebesiran 300 mg, every 6 months
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8.9 mmHg with zilebesiran 600 mg, every 6 months
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10.0 mmHg with zilebesiran 300 mg, every 3 months
In the placebo group, the ambulatory 24-hour systolic blood pressure increased by 6.8 mmHg. Compared to placebo, the RNAi therapeutic reduced blood pressure by 14.1 mmHg (zilebesiran 150 mg every 6 months), 16.7 mmHg (zilebesiran 300 mg every 3 months or every 6 months), and 15.7 mmHg (zilebesiran 600 mg every 6 months). All differences were statistically significant (p < 0.001).
“We know that a reduction in blood pressure of just 5 to 10 mmHg is clinically relevant,” says Lauder, member of the nucleus of the Arterial Hypertension Working Group of the German Society for Cardiology. “The comparison with the placebo group shows that the effect of zilebesiran on blood pressure may have been underestimated.” The fact that there was an increase in blood pressure in the placebo group might have been because the washout phase was too short. “Since this is a randomized-controlled study, this should also have been the case in the intervention groups,” adds the blood pressure specialist.
What is also significant, according to Lauder, is that zilebesiran lowered blood pressure over 24 hours, both during the day and at night. “This is not the case with many other antihypertensive drugs. And we know that nocturnal blood pressure is most strongly associated with cardiovascular events.”
Favorable safety profile
The safety of treatment with the RNA therapeutic was monitored throughout the 6 months of the study. Adverse reactions occurred in 60.9% of patients receiving zilebesiran. In the placebo group, the side effect rate was 50.7%. Serious adverse reactions were observed in 3.6% of patients with zilebesiran and in 6.7% of patients with placebo.
Study drug-related adverse reactions occurring in at least 5% of patients included injection site skin reactions and hyperkalemia.
“Based on the data available so far, it is a very safe drug,” says Lauder. Hyperkalemia also occurs with other antihypertensive medications such as ACE inhibitors, angiotensin receptor blockers and aldosterone antagonists, especially in patients with severely impaired kidney function. “This is something that needs to be taken into account in future combination therapies with zilebesiran.”
Some questions are still open
Most patients with hypertension receive combination therapy with various antihypertensive drugs. “Even in the KARDIA-1 study, 20% still had additional medication due to escape criteria.” In the KARDIA-2 Study Zilebesiran is currently being investigated as an add-on to olmesartan, amlodipine or indapamide.
According to Lauder, other open questions include whether the blood pressure-lowering effect and safety also persist over longer periods of time and how the RNAi therapeutic performs in other patient groups, such as those with poorer kidney function or more comorbidities.
A remedy for the ever-present adherence problem
This also agrees with Dr. Ernesto L. Schiffrin from the Sir Mortimer B. Davis-Jewish General Hospital of McGill University in Montreal, Canada: In an accompanying editorial, he points out that the follow-up was limited to 6 months [2]. “It is not clear whether the effects of zilebesiran persist following repeated administration beyond 6 months or whether the safety profile still changes.”
However, the results of the phase 2 study speak for further research into zilebesiran as a therapeutic agent for patients with high blood pressure. “If a sustained reduction in blood pressure is confirmed with few side effects, use every 6 months might represent a significant advance in the treatment of high blood pressure. Lack of adherence is responsible for 25% to 50% of alleged cases of treatment resistance.”
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