Financiado en parte por Sanofi, Regeneron Pharmaceuticals
Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial
Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R, Wu R, Pordy R
Lancet (London, England) · 433 citas
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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
- Financiado por la industria
- Empresa
- Sanofi
- Empresa
- Regeneron Pharmaceuticals
Según 2 financiadores declarados.
Publicación
- Publicado
- 2012-05-25 · Lancet · vol. 380 · número 9836 · págs. 29–36
- Editorial
- Elsevier BV
- Citado
- 588 citas · más que el 100% de estudios similares · 91.4× el promedio de su campo
- Impacto
- Entre el 10 % más citado de su campo
- Referencias
- 21 trabajos
- Acceso
- De pago
- Áreas de investigación
- Lipoproteins and Cardiovascular Health · Lipid metabolism and disorders · Cholesterol and Lipid Metabolism
- Palabras clave
- PCSK9 inhibition, monoclonal antibodies, heterozygous familial hypercholesterolemia, LDL cholesterol lowering, statin therapy, ezetimibe, dosing interval, dose comparison, lipid-lowering therapy, safety and tolerability
- MeSH
- humans, azetidines, serine endopeptidases, proprotein convertases, antibodies, monoclonal, anticholesteremic agents, hydroxymethylglutaryl-coa reductase inhibitors, treatment outcome, analysis of variance, double-blind method, heterozygote, middle aged, female, male, hyperlipoproteinemia type ii, cholesterol, ldl, antibodies, monoclonal, humanized, ezetimibe, proprotein convertase 9
8 autores
- Evan A. Stein
- Dan Gipe🇺🇸Regeneron (United States)
- Jean Bergeron
- Daniel Gaudet
- Robert Weiss🇺🇸Maine Research Associates
- Robert Dufour🇨🇦Montreal Clinical Research Institute
- Richard Wu🇺🇸Regeneron (United States)
- Robert C. Pordy🇺🇸Regeneron (United States)
Resumen
El texto original del estudio, en el idioma en que se publicó.
Background
Inhibition of proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9) resulted in large reductions of low-density lipoprotein cholesterol (LDL-C) in phase 1 trials. We assessed the efficacy and safety of various doses and dosing intervals of REGN727, a monoclonal antibody to PCSK9, added to statins, to further lower LDL-C in patients with heterozygous familial hypercholesterolaemia.
Methods
This multicentre, randomised, placebo-controlled phase 2 trial was done at 16 lipid clinics in the USA and Canada. Between Jan 18, 2011, and Nov 7, 2011, we enrolled adults with heterozygous familial hypercholesterolaemia and LDL-C concentrations of 2·6 mmol/L or higher on stable diet and statin dose, with or without ezetimibe. Patients were randomly assigned to receive REGN727 150 mg, 200 mg, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks (ratio 1:1:1:1:1). Randomisation was stratified by concomitant use of ezetimibe at baseline. Investigators, study staff, and patients were masked to treatment group. Blinding was maintained by administration of placebo alternating with REGN727 for the groups of 4 week dosing. The primary endpoint was mean percent reduction in LDL-C from baseline at week 12 and was analysed in the modified intention-to-treat population with an analysis of covariance (ANCOVA) model with treatment group. This trial is registered in ClinicalTrials.gov, number NCT 01266876.
Findings
77 patients were randomly assigned to study groups (15-16 patients per group) and all were analysed. Least-squares (LS) mean LDL-C reduction from baseline to week 12 was 28·9% (SE 5·08) for 150 mg every 4 weeks (p=0·0113), 31·54% (4·91) for 200 mg every 4 weeks (p=0·0035), 42·53% (5·09) for 300 mg every 4 weeks (p<0·0001), and 67·90% (4·85) for 150 mg every 2 weeks (p<0·0001), compared with 10·65% (5·04) with placebo. One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment.
Interpretation
REGN727 was well tolerated and achieved substantial further LDL-C reduction in patients with heterozygous familial hypercholesterolaemia and elevated LDL-C treated with high-dose statins, with or without ezetimibe. REGN727 has the potential to provide optimum control of LDL-C in patients with this disorder.
Funding
Sanofi US and Regeneron Pharmaceuticals Incorporated.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial.
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