Medication compliance is a major problem around the world, especially for people with high blood pressure who typically need to take daily pills to control their conditions. In fact, almost 80 percent of high blood pressure patients do not meet guideline-recommended blood pressure targets, according to a 2017-2020 survey from the Centers for Disease Control and Prevention (1). But now, scientists have reported that two yearly injections of a new RNAi drug called zilebesiran significantly reduced systolic blood pressure in participants in a placebo-controlled Phase 2 clinical trial (2). If approved, zilebesiran may offer a solution to the problem of blood pressure medication adherence, which contributes significantly to poor health outcomes around the world.

People say, ‘I don’t want to take pills.’ You tell them they have to lose weight, exercise, cut back on alcohol, and have a healthy diet, and they say, ‘Can’t you replace that with a pill?’ It gets really hard to argue with people over medication adherence. 
- Ernesto Schiffrin, McGill University

“People say, ‘I don’t want to take pills.’ You tell them they have to lose weight, exercise, cut back on alcohol, and have a healthy diet, and they say, ‘Can’t you replace that with a pill?’ It gets really hard to argue with people over medication adherence,” said Ernesto Schiffrin, a hypertension researcher at McGill University who was not involved in the clinical research.

The renin-angiotensin hormonal system regulates blood pressure by creating the protein angiotensinogen in the liver. Angiotensinogen then metabolizes into angiotensin II, a peptide hormone that binds to its receptors throughout the body to increase blood pressure. 

Researchers at the RNAi therapeutics company Alnylam Pharmaceuticals designed zilebesiran to block production of angiotensinogen in the liver, reducing its circulating levels in the body to lower blood pressure. Zilebesiran, which is administered via injection, is an RNAi molecule directed against angiotensinogen mRNA that is linked to a small molecule that targets the drug to the liver. 

“We know that the renin-angiotensin system is active in regulating blood pressure in the broad population and in different ethnic groups and races and with different comorbidities,” said coauthor Weinong Guo, senior vice president for clinical research at Alnylam Pharmaceuticals. 

In this study, the researchers randomized people with high blood pressure to receive either zilebesiran or placebo following a period after they stopped taking other antihypertensive drugs. Of the 302 people who received a dose of zilebesiran every three or six months, all of them experienced a decrease in systolic blood pressure. For the 77 individuals given the placebo, systolic blood pressure increased considerably. Zilebesiran reduced the plasma level of angiotensinogen by more than 90 percent for up to six months.

Modulating blood pressure, however, is not risk-free. “What happens if three months later the person bleeds or is in an accident and has trauma or becomes dehydrated through vomiting or diarrhea? Will their blood pressure be very difficult to maintain?” Schiffrin said.

When the investigators measured the participants for drug-related adverse events such as injection site reaction, high blood potassium levels (hyperkalemia), and blood pressure changes, they found that only 16.9 percent of zilebesiran-treated patients had nonserious adverse reactions to the drug. These included injection site reactions and mild hyperkalemia.

The researchers plan to report subgroup analyses next month at the American College of Cardiology annual meeting. The data will break down outcomes by age, race, baseline blood pressure, and region, Guo said.

“There are lots of treatment options for these patients, but these are all oral drugs. Our technology offers a great opportunity for treatment once quarterly or biannually by a single subcutaneous shot. This is a potentially ground-breaking development in managing patients with hypertension,” said Guo.

References                                                                                               

1. National Center for Health Statistics, Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey (NHANES), 2017–2020. Accessed: April 10, 2024.
2. Bakris, G., Saxena, M., Gupta, A. et al. RNA interference with Zilebesiran for mild to moderate hypertension: the KARDIA-1 randomized clinical trial. JAMA  331, 740-749 (2024).