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Isolation of High-density Lipoproteins for Non-coding Small RNA Quantification
Published on: November 28, 2016
Single Ascending and Multiple-Dose Trial of Zerlasiran, a Short Interfering RNA Targeting Lipoprotein(a): A
Steven E Nissen1, Kathy Wolski1, Gerald F Watts2
1Cleveland Clinic Center for Clinical Research, Cleveland, Ohio.
Insights
Zerlasiran, a novel RNA therapy, effectively lowers lipoprotein(a) levels in individuals with atherosclerotic cardiovascular disease. This treatment was well-tolerated, offering a promising new option for managing cardiovascular risk.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Genetics and Molecular Biology
Background:
- Lipoprotein(a) is a significant, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis.
- Current therapeutic options for managing elevated lipoprotein(a) levels are limited, highlighting the need for novel pharmacological interventions.
- Zerlasiran targets the hepatic synthesis of apolipoprotein(a) using short interfering RNA (siRNA) technology.
Purpose of the Study:
- To evaluate the safety and tolerability of zerlasiran in healthy participants and patients with stable ASCVD.
- To assess the impact of zerlasiran on serum concentrations of lipoprotein(a).
- To determine the efficacy of different dosing regimens for zerlasiran.
Main Methods:
- A Phase 1, randomized, single- and multiple-dose study involving healthy volunteers and ASCVD patients with elevated lipoprotein(a) (>150 nmol/L).
- Participants received placebo or varying doses of zerlasiran via subcutaneous injection.
- Safety, tolerability, serum zerlasiran levels, and lipoprotein(a) concentrations were monitored.
Main Results:
- Zerlasiran demonstrated a favorable safety and tolerability profile, with no serious adverse events reported.
- Single doses of zerlasiran led to significant reductions in lipoprotein(a) levels (up to 30% at 300 mg).
- Multiple doses resulted in substantial and sustained reductions in lipoprotein(a), with maximal median percent changes reaching up to 99%.
Conclusions:
- Zerlasiran is a well-tolerated siRNA therapeutic that effectively reduces elevated lipoprotein(a) concentrations.
- Infrequent administration of zerlasiran shows promise for long-term management of cardiovascular risk associated with high lipoprotein(a).
- These findings support further investigation of zerlasiran in larger clinical trials for ASCVD prevention.
Importance:
Lipoprotein(a) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, with no pharmacological treatments approved by regulatory authorities.
Objectives:
To assess the safety and tolerability of zerlasiran, a short interfering RNA targeting hepatic synthesis of apolipoprotein(a), and effects on serum concentrations of lipoprotein(a).
Design, Setting, And Participants:
Single- and multiple-dose study in healthy participants and patients with stable ASCVD, respectively, with lipoprotein(a) serum concentrations greater than 150 nmol/L, conducted at 7 research sites in the US, the Netherlands, UK, and Australia between November 18, 2020, and February 8, 2023, with last follow-up on August 23, 2023.
Interventions:
Participants were randomized to receive (1) a single subcutaneous dose of placebo (n = 8), zerlasiran 300 mg (n = 6) or 600 mg (n = 6); or (2) 2 doses of placebo (n = 9), zerlasiran 200 mg (n = 9) at a 4-week interval or 300 mg (n = 9) or 450 mg (n = 9) at an 8-week interval.
Main Outcomes Measures:
The primary outcome was safety and tolerability. Secondary outcomes included serum levels of zerlasiran and effects on lipoprotein(a) serum concentrations.
Results:
Among 37 patients in the multiple-dose group (mean age, 56 [SD, 10.4] years; 15 [42%] women), 36 completed the trial. Among 14 participants with extended follow-up after single doses, 13 completed the trial. There were no serious adverse events. Median baseline lipoprotein(a) concentrations in the multiple-dose group were 288 (IQR, 199-352) nmol/L. Median changes in lipoprotein(a) concentration at 365 days after single doses were 14% (IQR, 13% to 15%) for the placebo group, -30% (IQR, -51% to -18%) for the 300 mg of zerlasiran group, and -29% (IQR, -39% to -7%) for the 600-mg dose group. After 2 doses, maximal median changes in lipoprotein(a) concentration were 19 (IQR, -17 to 28) nmol/L for the placebo group, -258 (IQR, -289 to -188) nmol/L for the 200 mg of zerlasiran group, -310 (IQR, -368 to -274) nmol/L for the 300-mg dose group, and -242 (IQR, -343 to -182) nmol/L for the 450-mg dose group, with maximal median percent change of 7% (IQR, -4% to 21%), -97% (IQR, -98% to -95%), -98% (IQR, -99% to -97%), and -99% (IQR, -99% to -98%), respectively, attenuating to 0.3% (IQR, -2% to 21%), -60% (IQR, -71% to -40%), -90% (IQR, -91% to -74%), and -89% (IQR, -91% to -76%) 201 days after administration.
Conclusions:
Zerlasiran was well tolerated and reduced lipoprotein(a) concentrations with infrequent administration.
Trial Registration:
ClinicalTrials.gov Identifier: NCT04606602.
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