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Clinical Trial
. 2024 May 14;331(18):1534-1543.
doi: 10.1001/jama.2024.4504.

Single Ascending and Multiple-Dose Trial of Zerlasiran, a Short Interfering RNA Targeting Lipoprotein(a): A Randomized Clinical Trial

Steven E Nissen  1 , Kathy Wolski  1 , Gerald F Watts  2 , Michael J Koren  3 , Henry Fok  4 , Stephen J Nicholls  5 , David A Rider  4 , Leslie Cho  1 , Steven Romano  4 , Carrie Melgaard  1 , Curtis Rambaran  4
Affiliations
Clinical Trial

Single Ascending and Multiple-Dose Trial of Zerlasiran, a Short Interfering RNA Targeting Lipoprotein(a): A Randomized Clinical Trial

Steven E Nissen et al. JAMA. .

Abstract

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Nissen reported receiving grants with competing drugs from Novartis, Eli Lilly, and New Amsterdam Pharmaceuticals during the conduct of the study and receiving grants from AbbVie, AstraZeneca, Arrowhead Pharmaceuticals, Bristol Myers Squibb, Esperion Pharmaceuticals, and Medtronic outside the submitted work. Dr Watts reported receiving grants from Amgen, Arrowhead, and Novartis outside the submitted work and receiving personal fees from Esperion and Novo Nordisk outside the submitted work. Dr Koren reported receiving grants from the Jacksonville Center for Clinical Research during the conduct of the study and that he is an employee of an independent research organization that receives study grants and consulting fees from multiple manufacturers of lipid disorder treatments. Dr Fok, an employee of Silence Therapeutics, reported holding stock options in Silence Therapeutics. Dr Nicholls reported receiving consulting fees paid to his institution from Silence Therapeutics, the study sponsor; receiving grants paid to his institution from AstraZeneca, Amgen, Anthera, CSL Behring, Cerenis, Cyclarity, Eli Lilly, Esperion, Resverlogix, New Amsterdam Pharma, Novartis, InfraReDx, and Sanofi-Regeneron; and receiving personal fees paid to his institution from Amgen, Akcea, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Kowa, Merck, Takeda, Pfizer, Sanofi- Regeneron, Vaxxinity, CSL Seqirus, and Novo Nordisk outside the submitted work. Dr Rider, an employee of Silence Therapeutics, is an inventor of issued patent rights owned and controlled by Silence Therapeutics covering SLN360 (zerlasiran) sequences and has held stock options in Silence Therapeutics during the conduct of the study. Dr Romano, an employee of Silence Therapeutics, reported receiving stock options in Silence Therapeutics as part of compensation during the conduct of the study. Dr Rambaran, an employee of Silence Therapeutics, reported holding stock options in Silence Therapeutics during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Disposition of Healthy Participants in the Single-Dose Cohort and Patients With Atherosclerotic Cardiovascular Disease in the Multiple-Dose Cohort
aPrimary analysis reported previously. bOne participant in the 300-mg dose group only had follow-up to day 180 of the planned 365 days and then declined further participation. cOne participant in the single-dose pooled placebo group did not consent to 365 days of follow-up. dOne participant did not complete day-60 dosing and was excluded from the efficacy analyses but included in the safety assessments.
Figure 2.
Figure 2.. Percent Change in Lipoprotein(a) Serum Concentrations Following Zerlasiran Administration
A, Dashed lines indicate previously reported data for change in lipoprotein(a) concentrations during the first 150 days following administration. Observed lipoprotein(a) values and absolute changes are reported in eFigure 4 and eTable 2, respectively, in Supplement 3. B, Observed lipoprotein(a) values and absolute changes are reported in eFigure 5 and eTable 3, respectively, in Supplement 3.
Figure 3.
Figure 3.. Waterfall Plot Showing Distribution of Lipoprotein(a) Responses
aPatient did not complete day-60 dosing.
See this image and copyright information in PMC

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