Can siRNA Improve Compliance in Patients With Hypertension?

Aude Lecrubier

January 13, 2023

PARIS — How can the problem of poor treatment compliance in patients with hypertension be resolved? A new therapeutic approach could be a game-changer.

Many approaches have been explored in recent years to make life easier for patients living with chronic conditions that require them to take daily medication: subcutaneous implantable devices, nanogels, and, more specifically in the case of hypertension, renal denervation or small interfering RNA (siRNA) with a long half-life.

It's these siRNA that Michel Azizi, MD, PhD, head of the blood pressure clinic at Georges Pompidou European Hospital (HEGP) in Paris, discussed at the International Meeting of the French Society of Hypertension (JHTA).

These small molecules have already shown their worth in treating rare diseases such as transthyretin amyloidosis. More recently, treating hypercholesterolemia with the PCSK9 inhibitor inclisiran has proven effective. "One subcutaneous injection of inclisiran reduces LDL cholesterol by 50% for a period of 210 days," said Azizi.

The benefit of a new therapeutic siRNA — zilebesiran, administered subcutaneously — in treating hypertension is currently the subject of a phase II clinical trial.

This is a double-stranded RNA. One of the strands is linked to a sugar, N-acetylgalactosamine (GalNAc), which protects these highly fragile siRNA and binds with a very strong affinity in the liver. The second strand binds to a specific area of the RNA to prevent synthesis of the precursor peptide of angiotensin, angiotensinogen. The resulting effect is suppression of the production of angiotensin I and II, which leads to a long-lasting lowering of blood pressure.

Lasting Efficacy

Phase I studies with zilebesiran have demonstrated a long-term effect, with a reduction of >90% in circulating angiotensinogen over 6 months after a single subcutaneous dose (800 mg). The peak in reduction of circulating angiotensinogen occurs after approximately 3 weeks.

"It's extremely powerful," said Azizi.

Lasting reductions in blood pressure have also been observed, with 24-hour ambulatory blood pressure monitoring showing a reduction in systolic BP of >15 mm Hg 8 weeks after administration of a single dose of zilebesiran (800 mg).

Zilebesiran was also well tolerated, with only mild to moderate reactions at the site of the injection (n = 5/56) and no serious treatment-related adverse events, no hypotension, or significant changes in kidney or liver function.

"In terms of benefits, the effect is ongoing. Zilebesiran leads to reduced medication use and causes less variability in blood pressure response. Nevertheless, interfering RNA acts slowly, meaning that zilebesiran would not be suitable for people presenting with a hypertensive crisis. The fact that it blocks the renin-angiotensin system [RAS] for a very long period of time also poses the question of how to reverse its hypotensive effects," said Azizi.

Unanswered Questions

The lasting RAS antagonist and blood pressure–lowering effects pose a potential safety problem in circumstances involving patients in a state of hypovolemia and hypotension who require rapid blood pressure–raising interventions to prevent morbidity and mortality.

In recent studies, Uijl et al have thus examined strategies to counteract the blood pressure–lowering effect of siRNA in spontaneously hypertensive rats.

Fludrocortisone and a high-salt diet were both successful in gradually increasing blood pressure, which returned to its baseline levels on days 5 and 7, respectively. Yet this rate of response would be wholly inadequate in an urgent clinical situation.

However, midodrine could not reduce blood pressure to normal levels, whether administered subcutaneously or orally.

A rapid and short-lasting increase in blood pressure was observed with bolus doses of vasopressors, but clinically, these would need to be administered intravenously to achieve a lasting effect. Such administration would require hospitalization, close monitoring, and the use of human resources and additional healthcare provisions.

Encouragingly, the laboratory that created this molecule, Alnylam Pharmaceuticals, has come up with an antidote, Reversir. It is a GalNAc-conjugated, single-stranded, high-affinity oligonucleotide complementary to the zilebesiran strand that achieves effective reversal of siRNA activity in 24 hours.

In the future, after the phase 2 trials have been completed (see box below), whether or not zilebesiran reduces the incidence of cardiovascular events and mortality remains to be seen. But as for Azizi, the director of HEGP's blood pressure clinic in Paris, he has no doubt that "this approach is about to shake up how we treat patients in the cardiovascular field."

On the Horizon

Zilebesiran is being studied in phase 2 trials in patients with mild to moderate hypertension not taking antihypertensive drugs (KARDIA-1: 375 patients; double-blind, placebo-controlled, five-arm trial; zilebesiran at 150, 300, and 600 mg twice per year and 300 mg once every 3 months) and in patients whose blood pressure is not controlled (KARDIA-2: 800 patients; initial open-label start-up period of 4 weeks with indapamide/amlodipine/olmesartan, followed by a double-blind, placebo-controlled study over 6 months, then an open-label extension study for up to 12 additional months; zilebesiran at 600 mg on the first day of the initial double-blind period, then every 6 months during the open-label extension period).

This article was translated from the Medscape French edition.

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