New RNA Interference-Based Therapy for Hypertension

This is a summarized version of the full in-depth article on Relias Media.

By Michael H. Crawford, MD, Editor

Introduction

Zilebesiran (Zbs) is a novel ribonucleic acid interference (RNAi) drug designed to inhibit hepatic synthesis of angiotensinogen, a key precursor in the renin-angiotensin system (RAS) responsible for regulating blood pressure (BP). A Phase I trial demonstrated a dose-dependent reduction in both angiotensinogen and 24-hour ambulatory BP over 24 weeks with a single subcutaneous (subq) dose of Zbs. This Phase II study further explores the efficacy and safety of different dosing regimens of Zbs in patients with mild to moderate hypertension (HTN) who were not on any antihypertensive medications.

Study Design and Methods

This Phase II, placebo-controlled, double-blind study randomized patients into five groups to assess the antihypertensive effects of Zbs. Patients received one of the following doses administered subcutaneously:

• 150 mg every six months

• 300 mg every six months

• 300 mg every three months

• 600 mg every six months

• Placebo every three months

Patients receiving Zbs every six months also received placebo injections at the three-month mark to maintain blinding. The primary endpoint was the change in 24-hour ambulatory systolic blood pressure (SBP) from baseline to three months. Secondary endpoints included changes in office BP, six-month BP changes, serum angiotensinogen levels, and safety outcomes. Subgroup analyses were also performed based on factors like age, baseline BP, and renal function.

Results

Study Population

A total of 377 patients were randomized, with 92% completing the six-month study. The mean age was 57 years, 44% were women, and 25% were Black. Baseline ambulatory BP was 142/82 mmHg.

Blood Pressure Reduction

• Primary Endpoint: At three months, the mean reduction in 24-hour ambulatory SBP was dose-dependent:

• 150 mg Zbs (every six months): -7 mmHg

• 300 mg Zbs (every three or six months): -10 mmHg

• 600 mg Zbs (every six months): -9 mmHg

• Placebo: +7 mmHg

• These reductions were statistically significant across all comparisons (P < 0.001) and consistent across prespecified subgroups.

Secondary Endpoints

• Office and six-month SBP changes mirrored the ambulatory SBP results, with significant reductions in all active treatment groups compared to placebo.

• Serum angiotensinogen levels were reduced by more than 90% in the 300 mg and 600 mg Zbs groups, with effects lasting six months post-dosing, supporting the proposed mechanism of BP reduction.

Safety and Adverse Effects

Zbs was well-tolerated with few serious adverse effects:

• Serious adverse events occurred in 4% of patients receiving Zbs and 7% of placebo patients, although none were attributed to the drug.

• The most common mild to moderate side effects in the Zbs groups were:

• Injection site reactions: 6%

• Hyperkalemia: 5%

• Hepatic reactions: 5% (compared to 1% in the placebo group), which were transient and resolved during therapy.

The authors concluded that Zbs significantly reduced SBP in patients with mild to moderate hypertension with a favorable safety profile across a range of dosing regimens.

Commentary and Interpretation

Strengths

This study showcases several strengths:

• The patient population represented typical adult hypertensives, including a significant proportion of obese individuals and those with comorbid conditions like type 2 diabetes.

• Ambulatory BP, the gold standard in hypertension research, was used as a primary outcome, enhancing the study's clinical relevance.

• Mechanistic validation was provided through significant reductions in serum angiotensinogen levels, aligning with the observed BP reductions.

• The study's double-blind design, with efforts to maintain blinding through placebo injections, ensured robust data collection and minimized bias.

Limitations

Several limitations were noted:

• The placebo group's increase in SBP may reflect delayed recovery from discontinuing previous antihypertensive therapies, potentially exaggerating the observed treatment effects.

• The study focused on patients with mild to moderate hypertension, making the applicability of these results to those with severe hypertension unclear.

• The trial duration of six months is relatively short, and longer studies are needed to confirm sustained efficacy and safety.

• Outcomes such as cardiovascular events were not assessed, although the SBP reductions achieved are known from other studies to reduce such risks.

Future Considerations

While Zbs presents a promising option for managing hypertension with quarterly or biannual dosing, several questions remain:

• Long-term safety and efficacy: Extended follow-up studies will be necessary to ensure that the antihypertensive effects persist without significant adverse events over time.

• Risk of refractory hypotension: There is a theoretical risk if large doses of Zbs attenuate the renin-angiotensin system’s response to stressors like volume depletion or sepsis. Developing a reversal agent for such cases could be essential.

• Drug interactions: Zbs' interactions with other antihypertensive therapies require further investigation, especially as it may not always be effective as monotherapy in every patient.

Summary

Zbs appears to be an effective and well-tolerated treatment option for mild to moderate hypertension, offering a potential alternative to daily antihypertensive regimens. Its long-acting nature, requiring administration only every three to six months, could significantly improve patient adherence and simplify long-term hypertension management. However, further studies are needed to assess its role in broader populations and its long-term safety profile.

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We discuss the new RNA interference-based therapy for hypertension in more detail in our full write-up on Relias Media.

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