Phase 1 study with siRNA targeting hepatic angiotensinogen synthesis in patients with hypertension

In a phase 1 study, a single dose of the siRNA zilebesiran reduced serum angiotensinogen levels and blood pressure in patients with hypertension up to 24 weeks.

Zilebesiran, an RNA Interference Therapeutic Agent for Hypertension
Literature - Desai AS, Webb DJ, Taubel J, et al. - N Engl J Med. 2023 Jul 20;389(3):228-238. doi: 10.1056/NEJMoa2208391

Introduction and methods

Background

Management of hypertension remains suboptimal [1-3]. The siRNA zilebesiran has been designed to specifically inhibit the production of hepatic angiotensinogen. Angiotensinogen is the sole precursor of angiotensin peptides. Zilebesiran may provide sustained reductions in blood pressure (BP) over a longer period of time, requiring only twice-yearly or quarterly subcutaneous injections.

Aim of the study

In this phase 1 study, the authors assessed the safety, pharmacokinetic, and pharmacodynamic profiles of zilebesiran in patients with hypertension. In addition, the effects of zilebesiran on BP under low- or high-salt diet conditions were evaluated, as well as the effects of zilebesiran in combination with irbesartan on safety outcomes and BP.

Methods

This phase 1 study with subcutaneous administration of zilebesiran was comprised of 4 parts, of which 3 parts were reported. Part A and B of the study were double-blind, randomized, placebo-controlled studies of a single ascending dose (Part A) and a single fixed dose during low- and high-salt diet conditions (Part B). Part E was an open-label study of a single dose of zilebesiran with daily irbesartan coadministration. A total of 107 patients (18 to 65 years old) with treated or untreated hypertension were included who had a mean seated systolic BP (SBP) as assessed by automated cuff of >130-165 mmHg (Parts A and B) or >135-165 mmHg (Part E) and a mean SBP of >130 mmHg as assessed by 24-h ambulatory BP monitoring after washout of antihypertensive medication. Key exclusion criteria were secondary hypertension, postural hypotension, diabetes, previous CV events, and current and anticipated treatment with betablockers.

In Part A, patients (n=84, 12 per cohort) were randomly assigned in a 2:1 ratio to receive a single dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo. In Part B, patients (n=12) followed a low-salt diet (0.23 g per day) for 1 week (days -21 through -8) followed by a high-salt diet (5.75 g per day) for 1 week, and subsequently randomly assigned in a 2:1 ratio to a single dose of 800 mg zilebesiran or placebo. Patients were rechallenged with the same dietary protocol at days 43 through 56. In Part E, all patients (n=16) received a single 800 mg dose of zilebesiran. Patients with SBP of ≥120 mmHg at week 6 as assessed by 24-h ambulatory BP monitoring received additional treatment with 300 mg irbesartan once daily for 2 weeks. All patients received instructions to limit their salt intake to 2.0 g/day, except during other diet instructions in part B. The treatment period was concluded at week 12, after which patients entered an extended safety follow-up period.

Outcomes

The primary outcome was the frequency of adverse events. Secondary outcomes were pharmacokinetic and pharmacodynamic characteristics, and changes in systolic and diastolic blood pressure, as measured by 24-h ambulatory BP monitoring.

Main results

Safety and adverse events

• In the overall study population, adverse events occurred in 72% of the patients receiving zilebesiran vs. 88% of the patients receiving placebo. Adverse events reported by at least 5% of participants included headache, injection-site reaction, and upper respiratory tract infection, and were mostly mild or moderate in severity. The only adverse event which was reported by more than 2 participants was injection-site reaction.
• Three serious adverse events were reported, which included a patient with ischemic optic neuropathy in the placebo group of Part A, a patient with prostate cancer resulting in surgery in the 200 mg zilebesiran group of Part A, and an patient with acute anemia as a complication of a procedure conducted during screening before the study agent was started in the zilebesiran and irbesartan group of Part E.
• There were no reports of hypotension, hyperkalemia, or renal adverse events requiring an intervention. Moreover, no clinically significant changes in the eGFR or in serum levels of potassium, sodium or creatinine were reported.

Pharmacokinetic and pharmacodynamic measurements

• In Part A, serum angiotensinogen levels were negatively correlated with the administered zilebesiran dose (r=-0.56 at week 8; 95%CI: -0,.69 to -0.39). Zilebesiran doses of ≥100 mg reduced serum angiotensinogen by ≥90% from week 3 through 12. Maintained reductions of ≥90% were observed in the 800 mg dose group through week 24.
• In Part B and E, comparable reductions of ≥90% in serum angiotensinogen levels were observed with the 800 mg zilebesiran dose at week 12.
• In Part E, treatment with irebesartan did not had an additional effect on the lowering of serum angiotensinogen levels.

Exploratory outcomes

• In Part A, there was a negative correlation between zilebesiran dose and the change from baseline in the mean 24-h SBP (r=-0.41 at week 8; 95%CI: -0.58 to -0.21). Decreases in SBP were correlated with decreases in serum angiotensinogen level (r=0.52; 95%CI: 0.42 to 0.61).
• In Part A, patients who received the 800 mg zilebesiran dose had a mean (±SE) change in SBP and DBP of -22.5±5.1 mmHg and -10.8±2.7 mmHg, respectively, at week 24.
• In Part B, mean changes (±SE) in 24-h SBP and DBP were -9.1±4.5 mmHg and -2.4±3.1 mmHg before initiation of zilebesiran treatment after a low-salt diet. After treatment with 800 mg zilebesiran was initiated, changes in 24-h SBP and DBP were -18.8±4.3 mmHg and -8.4±2.5 mmHg after a low-salt diet. The BP levels returned to baseline values during both conditions after exposure to a high-salt diet.
• In 6 patients of part E, SBP was reduced from baseline to week 6 by -21.8±2.9 mmHg after zilebesiran treatment and these patients did not receive additional treatment with irebesartan. 10 patients of part E had persistent ambulatory SBP of 120 mmHg or more at week 6 after zilebesiran treatment and received additional treatment with irbesartan. In these patients, treatment with irbesartan resulted incremental changes in mean (±SE) SBP (-6.3±3.1 mmHg) and DBP (-3.0±1.9 mmHg) at week 8.

Conclusion

References

Find this article online at N Engl J Med.