The results of a phase II study with the RNAi therapeutic zilebesiran have appeared in the specialist journal “JAMA”. Accordingly, injections of the drug every three or every six months lower blood pressure sustainably.

Zilebesiran is a substance that exerts its pharmacological effect via RNA interference (RNAi) . The active ingredient is a short RNA section that, as small interfering RNA (siRNA), leads to the breakdown of complementary messenger RNA (mRNA) in the cell. This prevents the production of the protein that the mRNA codes for . In this case, this is angiotensinogen, which, as a precursor protein of the renin-angiotensin-aldosterone system, plays a key role in blood pressure regulation.

In a phase I study, the manufacturer Alnylam was able to show that a single subcutaneous injection of zilebesiran dose-dependently lowers both the angiotensinogen serum level and blood pressure over 24 weeks. The results of the phase II study KARDIA-1, which have now been published in the journal “JAMA” , confirm this and narrow down the dose range, which will now be further investigated in follow-up studies. In the KARDIA-1 study, four dose regimens were compared with each other and with placebo in 377 evaluable participants: 150, 300 or 600 mg zilebesiran subcutaneously every six months and 300 mg zilebesiran every three months.

Although the study ran for six months, the primary efficacy endpoint, the change in systolic blood pressure in the 24-hour ambulatory measurement, was recorded after just three months. The safety of the therapy was monitored over six months. During this period, 60.9 percent of patients treated with zilebesiran and 50.7 percent of patients in the placebo group  experienced side effects . Serious side effects were more common in the placebo group with 6.7 percent of patients affected than in the verum groups with 3.6 percent.

The study protocol stipulated that all antihypertensive medications were initially discontinued in the participating patients. After an appropriate washout period, systolic blood pressure should then be 135 to 160 mmHg, which corresponds to mild to moderate hypertension. Blood pressure fell three months after the injection in the zilebesiran groups , but increased in the placebo group . Specifically, blood pressure fell on average by 7.3 mmHg in the 150 mg group, by 10 mmHg in the 300 mg group, and by 8.9 mmHg in the 600 mg group; in the placebo group it increased by 6.8 mmHg.

Alnylam will most likely continue to investigate the 300 mg dose in the subsequent phase III studies. In further studies, it will primarily be necessary to clarify whether injections every three months are necessary for a permanent reduction in blood pressure or whether six-monthly administration is sufficient. Both would simplify therapy for many patients with high blood pressure. In principle, it would not be ruled out to add one or more classic antihypertensives in addition to a basic blood pressure reduction with zilebesiran if the antihypertensive effect of siran is not sufficient.DOI: 


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