A Study to Evaluate ALN-AGT01 in Patients with Hypertension, v1.0
Research type
Research Study
Full title
A Phase 1, Randomized, Double-Blind, Placebo-Controlled Single Dose and Active Comparator-Controlled Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneously Administered ALN-AGT01 in Patients with Hypertension
IRAS ID
260551
Contact name
Jorg Taubel
Contact email
Sponsor organisation
Alnylam UK Limited
Eudract number
2019-000129-39
Clinicaltrials.gov Identifier
Duration of Study in the UK
2 years, 7 months, 1 days
Research summary
Research Summary
This is a study of an experimental drug known as ALN-AGT01 in patient volunteers with high blood pressure. ALN-AGT01 is being developed by Alnylam Pharmaceuticals Inc. as a strategy to lower blood pressure in patients with hypertension. This is a phase 1, randomized, double-blind, placebo-controlled single and multiple dose study. The aim is to evaluate the safety and tolerability of subcutaneously administered ALN-AGT01 in these patient volunteers as well as to assess the way ALN-AGT01 affects the body and is affected by the body.
ALN-AGT01 consists of a type of molecule called a small interfering ribonucleic acid (siRNA). This targets cells in the liver and reduces its ability to make a protein called angiotensinogen (AGT). AGT increases blood pressure by constricting blood vessels and increasing the volume of water in the blood. It is thought that ALN-AGT01 may reduce the production of angiotensinogen and therefore reduce high blood pressure.This study is planned to take place in four parts, as follows:
•Part A: Single ascending dose of ALN-AGT01 or placebo
•Part B: Single dose of ALN-AGT01 or placebo with controlled salt diet
•Part C: Multiple doses of ALN-AGT01 or established hypertensive agent
•Part D: Multiple doses of ALN-AGT01 or established hypertensive agent in obese patientsResearch Summary
The below summary is divided into 2 sections. The first section provides a summary of the primary analysis from the completed Treatment Periods of all parts of the study and available data from the ongoing Safety Follow-up Period, with a data cutoff date of 20 April 2022. The second section summarizes the final analysis of data from the Safety Follow-up Period after the 20 April 2022 through to the last patient’s last visit in the study (04 January 2023).Section 1 (data cut off 20 April 2022)
Efficacy Conclusions
• In Part A, zilebesiran treatment led to dose-dependent decreases in SBP and DBP, as measured by both 24-hour ABPM and office blood pressure. The dose-related reductions in both daytime and nighttime blood pressure, when assessed by 24-hour ABPM, were consistent when daytime and nighttime blood pressure periods were defined by either patient diaries or by European Society of Hypertension (ESH) guidance [O'Brien 2013].
• In Part B, zilebesiran treatment led to greater reductions in SBP and DBP during reduced sodium intake, relative to placebo, as measured by both 24-hour ABPM and office blood pressure. The blood pressure lowering response to zilebesiran was reduced, relative to placebo, in response to high sodium intake, demonstrating a dependence on RAAS activity for its antihypertensive efficacy.
• In Part D, zilebesiran treatment led to reductions in SBP and DBP in patients with Class II and III obesity, as measured by both 24-hour ABPM and office blood pressure.
• In Part E, co-administration of irbesartan led to additional reductions in SBP and DBP by both 24-hour ABPM and office blood pressure in patients whose initial blood pressure response after 6 weeks of zilebesiran treatment did not reach the target blood pressure level (ie, 24-hour ambulatory SBP ≥120 mmHg).
• Zilebesiran had no effect on body weight, body composition or biomarkers of metabolic syndrome after 24 weeks of treatment in obese patients in Part D.Pharmacodynamics Conclusions
• Zilebesiran treatment led to rapid and sustained reductions in serum AGT levels, an effect which was unaffected by altered sodium intake (low or high), body weight in patients with Class II/III obesity, or co-administration with irbesartan.
• Zilebesiran treatment generally led to dose-dependent increases from baseline in plasma renin and dose-dependent decreases in plasma renin activity, AngI, AngII, and aldosterone levels relative to placebo in Part A.
• Reduced sodium intake while receiving zilebesiran treatment led to additional increases in plasma renin. Conversely, high sodium intake, while receiving zilebesiran, led to decreases in plasma renin levels, similar to those observed prior to low salt intake (Day 43). These findings demonstrate the responsiveness of the RAAS to fluctuations in salt intake despite the presence of zilebesiran. The blood pressure lowering results observed with altered sodium intake may have been affected by low baseline values for RAAS biomarkers for patients in Part B, which were likely due to the high salt diet patients participated in prior to receiving zilebesiran.
• Co-administration of irbesartan with zilebesiran in Part E led to additional reductions in blood pressure which may be explained by increases in plasma renin, but it had no effect on plasma renin activity confirming the effectiveness of zilebesiran to suppress serum AGT levels.Pharmacokinetics Conclusions
Plasma Cmax and AUC from time of dosing to the last measurable concentration (AUClast) were approximately dose-proportional across the 10 to 800 mg dose range, with a time to reach maximum concentration (tmax) of 4 to 12 hours and half-life (t1/2) of 5 to 8 hours.
• Plasma Cmax and AUClast were slightly lower (39% and 36%, respectively) in obese patients in Part D compared to non-obese patients in Part A (800 mg cohort), while the effect on PD was similar in obese and non-obese patients.
The metabolite to parent ratio for AUClast of the metabolite AS(N-1)3′ zilebesiran ranged from 0.131 to 0.143 across study parts at the 800 mg dose of zilebesiran. The t1/2 and tmax of the metabolite were similar to that of the parent.
• Renal excretion was a minor route of elimination, with approximately 9% to 22% of the administered dose excreted in urine as unchanged zilebesiran, while the fraction of dose excreted as AS(N-1)3′ zilebesiran was <3%.Antidrug Antibody Conclusions
• Two of 88 patients treated with zilebesiran in the study had transient treatment-emergent antidrug antibody (ADA) with low titers.Safety Conclusions
Zilebesiran had an acceptable safety profile for the treatment of patients with hypertension when administered up to the highest dose (800 mg) tested as single (Parts A, B, and E) and multiple (Part D) doses.
• Most patients had at least 1 treatment-emergent AE, and most treatment-emergent AEs were considered to be not related to study drug by the Investigator:
− Overall, in Part A, treatment-emergent AEs were reported in 75.0% of zilebesiran patients and 85.7% of placebo patients. The only treatment-emergent AE to be reported in ≥10% of zilebesiran patients was headache (17.9%), and the only treatment-emergent AEs to be reported in ≥10% of placebo patients were headache (46.4%) and upper respiratory tract infection (10.7%). Treatment-emergent AEs that were considered to be related to study drug by the Investigator occurred in 6 (10.7%) zilebesiran patients (4 patients had an injection site reaction [ISR] and 2 patients had at least 1 event of dizziness) and 4 (14.3%) placebo patients (head discomfort, headache, hypertension, libido decreased, and vertigo positional in 1 patient each).
− In Part B, treatment-emergent AEs were reported in 37.5% of zilebesiran patients and 100.0% of placebo patients. No treatment-emergent AE occurred in more than 1 patient in either treatment group. No treatment-emergent AEs were considered to be related to study drug by the Investigator.
− In Part D, treatment-emergent AEs were reported in 75.0% of zilebesiran patients and 100.0% of irbesartan patients. The only treatment-emergent AE to be reported in more than 1 patient in either treatment group was headache (37.5% of zilebesiran patients and 50.0% of irbesartan patients). One (12.5%) zilebesiran patient had a treatment-emergent AE (dizziness postural) that was considered to be related to study drug by the Investigator. No other patient had a treatment-emergent AE that was considered to be related to study drug by the Investigator.
− In Part E, before Day 43, treatment-emergent AEs were reported in 83.3% of zilebesiran only patients and 50.0% of zilebesiran + irbesartan patients. The only treatment-emergent AE reported in more than 1 patient in either treatment group was headache (33.3% of zilebesiran only patients and 30.0% of zilebesiran + irbesartan patients). Before Day 43, no treatment-emergent AEs were considered to be related to study drug by the Investigator.
− In Part E, on or after Day 43, treatment-emergent AEs were reported in 50.0% of zilebesiran only patients and 30.0% of zilebesiran + irbesartan patients. No treatment-emergent AE was reported in more than 1 patient. One (16.7%) zilebesiran only patient had a treatment-emergent AE (peripheral coldness) that was considered to be related to zilebesiran by the Investigator, which occurred on or after Day 43. No other patient had a treatment-emergent AE that was considered to be related to study drug by the Investigator.
• A total of 4 patients had treatment-emergent serious adverse events (SAEs) in Parts A, D, and E, which were considered to be not related to study drug by the Investigator:
− In Part A, 1 zilebesiran patient (200 mg cohort) had prostate cancer, and 1 placebo patient had optic ischemic neuropathy.
− In Part B, no patient had a treatment-emergent SAE.
− In Part D, 1 zilebesiran patient had a treatment-emergent SAE (ultrasound liver abnormal).
− In Part E, 1 zilebesiran + irbesartan patient had a treatment-emergent SAE (anemia) on Day 1 (ie, after receiving zilebesiran and before receiving irbesartan); no other patient had a treatment-emergent SAE in Part E.
• Overall, most treatment-emergent AEs were mild or moderate in severity. Treatment-emergent severe AEs occurred in 2 patients who received zilebesiran (prostate cancer in Part A and ultrasound liver abnormal in Part D) and 1 patient who received placebo (optic ischemic neuropathy in Part A); these events were also SAEs and were considered to be not related to study drug by the Investigator.
• There were no deaths.
• In Part D, 1 (12.5%) zilebesiran patient discontinued study drug and withdrew from the study during the Treatment period due to an SAE of ultrasound liver abnormal that was considered to be severe and not related to study drug by the Investigator. No other patients discontinued study drug (in Parts D or E) or withdrew from the study due to an AE during the Treatment period.
• During the Safety Follow-up period, which is still ongoing, there were no deaths or related SAEs in any part.
• Overall, 6 zilebesiran patients (5 patients in Part A, 1 patient in Part D, and no patients in Parts B or E) had a treatment-emergent AE of ISR; all ISRs were transient, mild in intensity, and resolved without intervention.
• Overall, treatment-emergent hepatic AEs occurred in 3 zilebesiran patients (liver function test [LFT] increased in 1 zilebesiran patient [25 mg cohort] in Part A, alanine aminotransferase [ALT] increased in 1 zilebesiran patient in Part D, and gamma glutamyltransferase [GGT] increased followed by ultrasound liver abnormal in 1 zilebesiran patient in Part D) and 1 placebo patient (LFT increased in 1 placebo patient in Part B); all hepatic AEs were considered to be not related to study drug by the Investigator. Most hepatic AEs were mild or moderate in intensity and none were associated with concurrent hyperbilirubinemia.
• Overall, no patient had a treatment-emergent AE of hypotension. In Part D, 1 (12.5%) zilebesiran patient had an AE of dizziness postural that was considered to be related to study drug by the Investigator; the lowest office SBP reading associated with this event was 105 mmHg (Day 57). None of the other treatment-emergent AEs potentially suggestive of low blood pressure were associated with low office SBP.
Additionally, no patient required a medical therapy intervention to add, adjust, or change any oral medications for low blood pressure.
• No clinically significant changes in renal function, hematologic or chemistry parameters, vital signs, physical examinations, or ECG parameters were reported. There were no instances of rebound hypertension following the last dose of study drug.
• No significant impact on the safety profile was observed due to the coronavirus disease 2019 COVID-19 pandemic.
• No pregnancies were reported during the study.Conclusion:
Zilebesiran had an acceptable safety profile for the treatment of patients with hypertension when administered up to the highest dose (800 mg) tested as single and multiple doses, and was effective at reducing serum AGT, SBP, and DBP in patients with hypertensionSection 2 (data cut off 04 Jan 2023)
Safety Conclusions
Zilebesiran had an acceptable safety profile for the treatment of patients with hypertension when administered up to the highest dose (800 mg) tested as single (Parts A, B, and E) and multiple (Part D) doses.
• Since CSR1, no deaths or SAEs were reported in any study part.
• No clinically significant changes in renal function, hematologic or chemistry parameters, vital signs, physical examinations, or ECG parameters were reported. There were no instances of rebound hypertension following the last dose of study drug.
• No pregnancies were reported during the studyDISCUSSION AND OVERALL CONCLUSIONS
Reductions in blood pressure as assessed by ABPM were maintained for at least 6 months after the last dose of zilebesiran in Part D.
In Part D, zilebesiran administered as 2 doses of 800 mg each administered 3 months apart resulted in rapid and sustained reductions in serum AGT levels through Month 15.
Zilebesiran had an acceptable safety profile when administered as single SC doses of 10 to 800 mg or 2 doses of 800 mg administered 3 months apart, and no new safety signals were observed during the Safety Follow-up period after CSR1. No clinically significant changes in renal function, hematologic or chemistry parameters, vital signs, physical examinations, or ECG parameters were reported. There were no instances of rebound hypertension following the last dose of study drug.
In conclusion, zilebesiran had an acceptable safety profile for the treatment of patients with hypertension when administered up to the highest dose (800 mg) tested as single and multiple doses, and was effective at reducing serum AGT, SBP, and DBP in patients with hypertension.REC name
London - London Bridge Research Ethics Committee
REC reference
19/LO/0264
Date of REC Opinion
5 Apr 2019
REC opinion
Favourable Opinion