Zerlasiran-A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial
Nissen SE, Wang Q, Nicholls SJ, Navar AM, Ray KK, Schwartz GG, Szarek M, Stroes ESG, Troquay R, Dorresteijn JAN, Fok H, Rider DA, Romano S, Wolski K, Rambaran C
JAMA · 98 citas
Etiquetas de revisión
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Cómo se estudió
- Diseño
- Ensayo controlado aleatorizado (indexado por PubMed)
- Estudiado en
- Personas
- Resultado principal
- Marcadores de salud y funcionamiento
Quién lo pagó
- Financiación
- Financiación no declarada
Publicación
- Publicado
- 2024-11-18 · JAMA · vol. 332 · número 23 · pág. 1992
- Editorial
- American Medical Association
- Citado
- 150 citas · más que el 100% de estudios similares · 57.3× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 21 trabajos
- Acceso
- Acceso abierto (copia en repositorio) · OTHER-OA
- Áreas de investigación
- Lipoproteins and Cardiovascular Health · Lipid metabolism and disorders · Cholesterol and Lipid Metabolism
- Palabras clave
- lipoprotein(a), siRNA, apolipoprotein(a), atherosclerotic cardiovascular disease, aortic stenosis, RNA interference, dose comparison, treatment safety, adverse events, drug discontinuation, cardiovascular risk reduction, hypercholesterolemia, hypertriglyceridemia
- MeSH
- liver, humans, lipoprotein(a), rna, small interfering, injections, subcutaneous, double-blind method, aged, middle aged, female, male, atherosclerosis
15 autores
- Steven E. Nissen🇺🇸 · autor de correspondenciaCleveland Clinic
- Qiuqing Wang🇺🇸Cleveland Clinic
- Stephen James Nicholls🇦🇺Monash University
- Ann Marie Návar🇺🇸The University of Texas Southwestern Medical Center
- Kausik Kumar Ray🇬🇧Imperial College London
- Gregory G. Schwartz🇺🇸University of Colorado Anschutz
- Michael J. Szarek🇺🇸SUNY Downstate Health Sciences University; University of Colorado Anschutz
- Erik S.G. Stroes🇳🇱Amsterdam UMC Location University of Amsterdam; Amsterdam University Medical Centers
- Roland P.T. Troquay🇳🇱VieCuri Medisch Centrum
- Jannick A N Dorresteijn🇳🇱University Medical Center Utrecht
- Henry Fok🇬🇧Silence Therapeutics (United Kingdom)
- David A. Rider🇬🇧Silence Therapeutics (United Kingdom)
- Steven Romano🇬🇧Silence Therapeutics (United Kingdom)
- Kathy Wolski🇺🇸Cleveland Clinic
- Curtis Rambaran🇬🇧Silence Therapeutics (United Kingdom)
Resumen
El texto original del estudio, en el idioma en que se publicó.
Importance
Elevated lipoprotein(a) increases the risk of atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis.
Objective
To evaluate the effects of zerlasiran, a small-interfering RNA targeting hepatic synthesis of apolipoprotein(a), on lipoprotein(a) serum concentration.
Design, setting, and participants
A multicenter trial in patients with stable ASCVD with serum lipoprotein(a) concentrations greater than or equal to 125 nmol/L at 26 sites in Europe and South Africa between January 3, 2023, and April 27, 2023, with last follow-up on July 1, 2024.
Interventions
Participants randomized to receive a subcutaneous dose of placebo every 16 weeks for 3 doses (n = 23) or every 24 weeks for 2 doses (n = 24) or zerlasiran 450 mg every 24 weeks for 2 doses (n = 45), 300 mg every 16 weeks for 3 doses (n = 42), or 300 mg every 24 weeks for 2 doses (n = 44).
Main outcome and measures
The primary outcome was the time-averaged percent change in lipoprotein(a) concentration from baseline to 36 weeks, with follow-up to 60 weeks.
Results
Among 178 patients, mean (SD) age was 63.7 (9.4) years, 46 (25.8%) were female, with a median (IQR) baseline lipoprotein(a) concentration of 213 (177-282) nmol/L; 172 patients completed the trial. Compared with the pooled placebo group, the least-squares mean time-averaged percent change in lipoprotein(a) concentration from baseline to week 36 was -85.6% (95% CI, -90.9% to -80.3%), -82.8% (95% CI, -88.2% to -77.4%), and -81.3% (95% CI, -86.7% to -76.0%) for the 450 mg every 24 weeks, 300 mg every 16 weeks, and 300 mg every 24 weeks groups, respectively. Median (IQR) percent change in lipoprotein(a) concentration at week 36 was -94.5% (-97.3% to -84.2%) for the 450 mg every 24 weeks group, -96.4% (-97.7% to -92.3%) for the 300 mg every 16 weeks group, and -90.0% (-93.7% to -81.3%) for the 300 mg every 24 weeks group. The most common treatment-related adverse effects were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration. There were 20 serious adverse events in 17 patients, none considered related to the study drug.
Conclusions
Zerlasiran was well-tolerated and reduced time-averaged lipoprotein(a) concentration by more than 80% during 36 weeks of treatment in patients with ASCVD.
Trial registration
ClinicalTrials.gov Identifier: NCT05537571.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial.
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