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A Phase 1/2, Randomized, Double-blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacodynamics, and Pharmacokinetics of Zilebesiran in Japanese Patients with Mild to Moderate Hypertension

A Study to Evaluate Zilebesiran in Japanese Patients with Mild to Moderate Hypertension

36

Demographics and baseline characteristics of enrolled patients Age(average) : 58 years old Sex: Male 24, Female 12 Participants with mild to moderate hypertension 24-hour Mean Blood Pressure by Ambulatory Blood Pressure Monitoring (ABPM) - Zilebesiran 300 mg: 12 participants Baseline Systolic Blood Pressure: 143.6mmHg Baseline Diastolic Blood Pressure: 87.2mmHg - Zilebesiran 600 mg: 12 participants Baseline Systolic Blood Pressure: 138.9mmHg Baseline Diastolic Blood Pressure: 86.6mmHg - Placebo: 12 participants Baseline Systolic Blood Pressure: 137.7mmHg Baseline Diastolic Blood Pressure: 85.6mmHg Mean Office Blood Pressure (OBP) - Zilebesiran 300 mg: 12 participants Baseline Systolic Blood Pressure: 139.8mmHg Baseline Diastolic Blood Pressure: 88.3mmHg - Zilebesiran 600 mg: 12 participants Baseline Systolic Blood Pressure: 134.3mmHg Baseline Diastolic Blood Pressure: 86.6mmHg - Placebo: 12 participants Baseline Systolic Blood Pressure: 133.9mmHg Baseline Diastolic Blood Pressure: 89.2mmHg

Reporting Groups Zilebesiran 300 mg: 12 participants were administered a single dose of zilebesiran 300 mg by subcutaneous(SC) injection on Day 1 of the 6-month Double-blind (DB) period. Withdrawal by 1 participant. After the DB period, 11 participants completed safety follow-up visits at Months 9 and 12. Zilebesiran 600 mg: 12 participants were administered a single dose of zilebesiran 600 mg by SC injection on Day 1 of the 6-month DB period. Withdrawal by 1 participant. After the DB period, 11 participants completed safety follow-up visits at Months 9 and 12. Placebo: 12 participants were administered a single dose of placebo by SC injection on Day 1 of the 6-month DB period. After the DB period, 12 participants completed safety follow-up visits at Months 9 and 12.

All-Cause Mortality - Zilebesiran 300 mg: 0.0% (0/12 participants) - Zilebesiran 600 mg: 0.0% (0/12 participants) - Placebo: 0.0% (0/12 participants) Serious Adverse Events - Zilebesiran 300 mg: 0.0% (0/12 participants) - Zilebesiran 600 mg: 0.0% (0/12 participants) - Placebo: 0.0% (0/12 participants) Treatment-emergent AEs - Zilebesiran 300 mg: 50% (6/12 participants) - Zilebesiran 600 mg: 50% (6/12 participants) - Placebo: 33.33% (4/12 participants) Related Treatment-emergent AEs, - Zilebesiran 300 mg: 0% (0/12 participants) - Zilebesiran 600 mg: 8.33% (1/12 participants) - Placebo: 8.33% (1/12 participants) Other Adverse Events - Zilebesiran 300 mg: COVID-19 8.33% (1 participant). Pharyngitis 16.67% (2 participants), ALT increased 8.33% (1 participant). Headache 16.67% (2 participants), Vaginal hemorrhage 8.33% (1 participant), Upper respiratory tract inflammation 8.33% (1 participant), Eczema 8.33% (1 participant) - Zilebesiran 600 mg: Eye pruritus 8.33% (1 participant), Influenza 16.67% (2 participants), ALP increased 8.33% (1 participant), Blood potassium increased 8.33% (1 participant), gamma-GTP increased 8.33% (1 participant), Spinal osteoarthritis 8.33% (1 participant), Headache 8.33% (1 participant), Upper respiratory tract inflammation 8.33% (1 participant) - Placebo: Gastralgia 8.33% (1 participant), Nausea 8.33% (1 participant), COVID-19 8.33% (1 participant), Glomerular filtration rate decreased 8.33% (1 participant), Periarthritis 8.33% (1 participant)

[Primary Outcome] Number of Participants With Adverse Events (AEs) Analysis Population: All participants who received any amount of Zilebesiran or placebo during the study. Details are shown in [Adverse events] section. Time Frame: Up to 12 months [Secondary Outcome(s)] Percent Change from Baseline in Serum Angiotensinogen (AGT) at Month 3 and Month 6. Unit of measure: Percent Change Analysis Population: Number analyzed is the number of participants with data available for analysis at the specified time-points. Time Frame: Baseline and Month 3 and Month 6 Month 3 (% Change from Baseline) Mean (Standard Deviation). - Zilebesiran 300 mg: 11 participants -96.85 (1.45) - Zilebesiran 600 mg: 12 participants -96.85 (2.32) - Placebo: 12 participants 6.93 (21.93) Month 6 (% Change from Baseline) Mean (Standard Deviation) - Zilebesiran 300 mg: 11 participants -95.36 (2.17) - Zilebesiran 600 mg: 12 participants -95.79 (3.21) - Placebo: 12 participants -2.74 (12.75) 2.Change from Baseline at Month 3 and Month 6 in 24-hour Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed by Ambulatory Blood Pressure Monitoring (ABPM) Unit of measure: mmHg Analysis Population: Number analyzed is the number of participants with data available for analysis at the specified time-points. Time Frame: Baseline and Month 3 and Month 6 Month 3 SBP(Change from Baseline) Mean (Standard Deviation). - Zilebesiran 300 mg: 11 participants -15.2 (9.0) - Zilebesiran 600 mg: 12 participants -17.8 (11.8) - Placebo: 12 participants 0.4 (7.8) Month 6 SBP(Change from Baseline) Mean (Standard Deviation) - Zilebesiran 300 mg: 10 participants -12.6 (4.8) - Zilebesiran 600 mg: 12 participants -12.2 (11.7) - Placebo: 12 participants -6.5 (11.0) Month 3 DBP(Change from Baseline) Mean (Standard Deviation) - Zilebesiran 300 mg: 11 participants -8.6 (6.0) - Zilebesiran 600 mg: 12 participants -9.2 (6.5) - Placebo: 12 participants 0.3 (5.3) Month 6 DBP(Change from Baseline) Mean (Standard Deviation) - Zilebesiran 300 mg: 10 participants -7.1 (2.4) - Zilebesiran 600 mg: 12 participants -8.2 (6.0) - Placebo: 12 participants -3.9 (6.6) 3.Change from Baseline at Month 3 and Month 6 in SBP and DBP Assessed by Office Blood Pressure. Unit of measure: mmHg Analysis Population: Number analyzed is the number of participants with data available for analysis at the specified time-points. Time Frame: Baseline and Month 3 and Month 6 1) SBP Month 3 SBP (Change from Baseline) Mean (Standard Deviation) - Zilebesiran 300 mg: 11 participants -14.4 (21.0) - Zilebesiran 600 mg: 12 participants -14.4 (12.3) - Placebo: 12 participants 4.4 (5.0) Month 6 SBP (Change from Baseline) Mean (Standard Deviation) - Zilebesiran 300 mg: 11 participants -10.3 (12.9) - Zilebesiran 600 mg: 12 participants -6.8 (9.6) - Placebo: 12 participants 1.2 (13.3) 2) DBP Month 3 DBP (Change from Baseline) Mean (Standard Deviation) - Zilebesiran 300 mg: 11 participants -7.8 (10.4) - Zilebesiran 600 mg: 12 participants -7.4 (8.0) - Placebo: 12 participants 0.1 (5.2) Month 6 DBP (Change from Baseline) Mean (Standard Deviation) - Zilebesiran 300 mg: 11 participants -4.5 (7.9) - Zilebesiran 600 mg: 12 participants -1.7 (6.8) - Placebo: 12 participants -2.2 (7.1) 4. PK; The maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), elimination half-life (t1/2), area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration (AUClast), and urinary excretion rate (Fe) for Zilebesiran and the metabolite [AS (N-1) 3' Zilebesiran]. Analysis Population: All participants who received at least 1 full dose of Zilebesiran and had at least 1 evaluable postdose PK assessment. Cmax (ng/mL) Geometric Mean (Geometric Coefficient of Variation) Time Frame: Predose and 30 minutes, 1, 2, 3, 4, 6, 8, 12, 16, 24 and 48 hours post-dose. - Zilebesiran 300 mg: 12 participants 1024 (53.5%) , Metabolite [AS (N-1) 3'] 12 participants 101.4 (72.1%) - Zilebesiran 600 mg: 12 participants 2445 (42.4%) , Metabolite [AS (N-1) 3'] 12 participants 288.2 (49.7%) Tmax (hours) Median (Full Range) Time Frame: Predose and 30 minutes, 1, 2, 3, 4, 6, 8, 12, 16, 24 and 48 hours post-dose. - Zilebesiran 300 mg: 12 participants 3.53 (1.00 to 12.0) , Metabolite [AS (N-1) 3'] 12 participants 8.01 (3.00 to 16.0) - Zilebesiran 600 mg: 12 participants 6.00 (1.00 to 16.0) , Metabolite [AS (N-1) 3'] 12 participants 16.00 (4.00 to 16.0) t1/2(hours)Geometric Mean (Geometric Coefficient of Variation) Time Frame: Predose and 30 minutes, 1, 2, 3, 4, 6, 8, 12, 16, 24 and 48 hours post-dose. - Zilebesiran 300 mg: 10 participants 5.83 (65.3%) , Metabolite [AS (N-1) 3'] 7 participants 9.42 (120.8%) - Zilebesiran 600 mg: 11 participants 5.56 (36.9%) , Metabolite [AS (N-1) 3'] 5 participants 5.48 (25.6%) AUClast (ng*h/mL) Geometric Mean (Geometric Coefficient of Variation) Time Frame: Predose and 30 minutes, 1, 2, 3, 4, 6, 8, 12, 16, 24 and 48 hours post-dose. - Zilebesiran 300 mg: 12 participants 16150 (43.5%) , Metabolite [AS (N-1) 3'] 12 participants 1587 (73.8%) - Zilebesiran 600 mg: 12 participants 41260 (32.2%) , Metabolite [AS (N-1) 3'] 12 participants 4906 (47.5%) Pooled Urine PK (fe) (%) Geometric Mean (Geometric Coefficient of Variation) Time Frame: Predose and 2 to 6, 6 to 12, and 12 to 24 hours post-dose. - Zilebesiran 300 mg: 12 participants 23.62 (21.2%) , Metabolite [AS (N-1) 3'] 12 participants 2.68 (42.7%) - Zilebesiran 600 mg: 12 participants 30.08 (16.1%) , Metabolite [AS (N-1) 3'] 12 participants 3.85 (28.3%)

Overall, single doses of 300 or 600 mg zilebesiran had an acceptable safety profile and provided clinically meaningful reductions in blood pressure in Japanese patients with mild-to-moderate hypertension.

Yes

Access to Anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the US and/or the EU. Access to data may be declined where there is likelihood a patient could be identified or other feasibility issue, where there is a potential conflict of interest, a planned business activities or an actual or potential competitive risk. Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Timeframes for data access may vary and can take up to 6 months or more.

https://jrct.mhlw.go.jp/latest-detail/jRCT2071240016

Clinical Trial Information

Alnylam Japan K.K.

Pacific Century Place Marunouchi 11th Floor, 1-11-1 Marunouchi, Chiyoda-ku, Tokyo

JPTiken@alnylam.com

Clinical Trial Information

CMIC Co., Ltd.(ICCC)

1-1-1 Shibaura Minato-ku, Tokyo

+81-3-6779-8000

ClinicalTrialInformation@cmic.co.jp

Complete

June. 07, 2024

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1.18 Years to 75 Years (Adult, Older Adult)
2.Must have been born in Japan, and their biological parents and grandparents must have been of Japanese origin.
3.Has untreated hypertension or newly diagnosed with hypertension (not taking antihypertensive medication) or is on stable therapy with up to 2 antihypertensive medications.
4.Mean sitting SBP of >130 and =<165 mmHg by automated office blood pressure measurement, with a minimum of 3 week washout prior to office blood pressure measurement.
5.24-hour mean SBP >=130 mmHg by ABPM, after a minimum of 3 weeks washout if taking hypertensive medication.

1.Secondary hypertension
2.History of orthostatic hypotension or orthostatic hypotension during screening
3.ALT or AST >2 x ULN
4.Elevated serum potassium >5 mmol/L.
5.eGFR of <60 mL/min/1.73m2 (calculation will be based on the Modification of Diet in Renal Disease formula with a Japanese coefficient of 0.808).
6.Received an investigational agent within the last 30 days before randomization or are in follow-up of another clinical study prior to study enrollment.
7.Type 1 diabetes mellitus, poorly controlled Type 2 diabetes mellitus (hemoglobin A1c:HbA1c >9.0%), or laboratory evidence of diabetes during screening (HbA1c >=7.0%) without known diagnosis of diabetes.
8.History of any cardiovascular event
9.History of intolerance to SC injection(s)

Both

Mild to Moderate Hypertension

Patients will be administered a single dose of zilebesiran or placebo as an SC injection on Day 1.

High blood pressure, Hypertension, Hypertensive, SiRNA, Angiotensinogen, AGT

Frequency of Adverse Events (AEs)

1.Percent Change from Baseline in Serum Angiotensinogen (AGT) at Month 3 and Month 6
2.Change from Baseline at Month 3 and Month 6 in 24-hour Mean Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) Assessed by Ambulatory Blood Pressure Monitoring (ABPM)
3.Change from Baseline at Month 3 and Month 6 in SBP and DBP Assessed by Office Blood Pressure
4.Maximum Observed Plasma Concentration (Cmax) of Zilebesiran Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) for Zilebisiran: Fraction of Zilebisiran Excreted in the Urine (fe)

+81-92-283-7701

May. 09, 2024

none