Dyslipidemie je nejčastější metabolickou poruchou v západní společnosti a hlavním rizikovým faktorem pro rozvoj ischemické choroby srdeční (ICHS). Léčba dyslipidemie je stále nedostatečná a doporučené cíle LDL cholesterolu jsou dosahovány jen u malé části pacientů. Nejdůležitější skupinou léků pro léčbu dyslipidemie jsou statiny. Ačkoli jde zřejmě o jednu z nejbezpečnějších lékových skupin vůbec, terapie statiny může vést ke svalovým bolestem a ke zvýšenému riziku rozvoje diabetes mellitus (DM). Přerušení nebo ukončení léčby statiny je v klinické praxi časté, statiny jsou také často předmětem negativních sdělení v médiích. Inklisiran je modifikovaný oligonukleotid fungující na principu interference RNA. Inhibuje translaci mRNA pro proprotein konvertázu subtilisin/kexin typu 9 (PCSK9), což vede k dlouhodobému poklesu koncentrace LDL cholesterolu. Účinek inklisiranu se snižuje o přibližně 2 % měsíčně, takže efekt jediné dávky trvá zhruba dva roky. Při podávání jedenkrát za šest měsíců vede terapie tímto lékem k poklesu LDL cholesterolu o 50-55 %, u vybraných pacientů potom až o 65 %. Terapie inklisiranem není spojena se změnou počtu krevní destiček, lymfocytů, monocytů nebo neutrofilů, nevede ke změnám koncentrací cirkulujících cytokinů tumor nekrotizujícího faktoru alfa (TNFα) nebo interleukinu 6 (IL-6) a není spojena s indukcí tvorby protilátek proti tomuto léku. Nežádoucí reakce v místě vpichu tak zůstávají jediným relevantním nežádoucím účinkem této léčby. Inklisiran tak získává potenciál stát se široce preskribovaným lékem, který výrazně přispěje k léčbě dyslipidemie a v konečném důsledku povede ke snížení incidence a prevalence ICHS.
Dyslipidemia is the most frequent metabolic abnormality in western world population and a major risk factor for coronary artery disease (CAD) development. Dyslipidemia treatment is still insufficient and achieving target LDL-level infrequent. Statins are a cornerstone of dyslipidemia management. Although statins are one of the safest drugs on the market, statin therapy can be associated with muscle symptoms and increased risk of DM development. Statin discontinuation is frequent, often driven by negative media coverage. Inclisiran is a therapeutic oligonucleotide that employs RNA interference and inhibits the translation of PCSK9-mRNA leading to long-lasting LDL-cholesterol lowering. LDL-cholesterol-lowering effect of inclisiran is reversed at the rate of approximately 2% per month, so the effect of a single dose persists up to approximately two years. When administered once every six months, inclisiran therapy decreases the level circulating LDL-cholesterol by 50-55% and up to 65% in selected patient populations. Inclisiran therapy is not associated with alterations in platelet count, blood lymphocyte, monocyte or neu- trophil count, does not cause alterations in blood TNF-alpha or IL-6 concentrations and does not induce relevant anti-drug antibodies. The only relevant side effect is an adverse reaction at the injection site. In- clisiran thus has the potential to become widely prescribed drug that will greatly contribute to dyslipidemia management and further decrease of CAD incidence.
- Keywords
- inclisiran,
- MeSH
- Dyslipidemias * drug therapy MeSH
- Cardiology trends MeSH
- Cardiovascular Agents * administration & dosage pharmacology MeSH
- Cardiovascular Diseases drug therapy MeSH
- Cholesterol, LDL analysis drug effects MeSH
- Humans MeSH
- Oligonucleotides administration & dosage pharmacology MeSH
- PCSK9 Inhibitors administration & dosage pharmacology MeSH
- RNA Interference physiology MeSH
- RNA physiology MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- Keywords
- nusinersen,
- MeSH
- Heredodegenerative Disorders, Nervous System * diagnosis genetics therapy MeSH
- Diagnosis, Differential MeSH
- Humans MeSH
- Peripheral Nervous System Diseases diagnosis etiology therapy MeSH
- Neurologic Examination methods MeSH
- Oligonucleotides administration & dosage therapeutic use MeSH
- Muscular Atrophy, Spinal diagnosis genetics therapy MeSH
- Spinocerebellar Ataxias diagnosis genetics therapy MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
- Keywords
- nusinersen,
- MeSH
- Adult MeSH
- Humans MeSH
- Multicenter Studies as Topic MeSH
- Oligonucleotides administration & dosage pharmacology MeSH
- Muscular Atrophy, Spinal * etiology drug therapy genetics classification therapy MeSH
- Patient Care Team MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Publication type
- Review MeSH
BACKGROUND: Eluforsen is an antisense oligonucleotide designed to bind to the mRNA region around the F508-encoding deletion and restore the cystic fibrosis transmembrane conductance regulator (CFTR) protein function in the airway epithelium. We assessed the safety and tolerability, pharmacokinetics and exploratory measures of efficacy of inhaled eluforsen in cystic fibrosis (CF) patients homozygous for the F508del-CFTR mutation. METHODS: This randomised, double-blind, placebo-controlled, dose escalation 1b study recruited adult CF subjects with a FEV1 > 70% predicted in four single ascending dose cohorts and four multiple ascending dose cohorts. Primary objectives were safety and tolerability. Secondary endpoints included pharmacokinetics, percent predicted forced expiratory volume in 1 s (ppFEV1), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom Score (RSS). RESULTS: Single and multiple doses of inhaled eluforsen up to 50 mg were safe and well tolerated. A maximum tolerated dose was not established. Systemic exposure was low in all cohorts and lung function remained stable throughout the study. Three of four eluforsen-treated groups in the MAD study demonstrated an improvement in CFQ-R RSS at end of treatment with adjusted mean change from baseline values ranging from 6.4 to 12.7 points. In comparison, there was a mean decrease of 6.5 points in the placebo group from baseline to end of treatment. CONCLUSIONS: Inhaled eluforsen up to 50 mg dosed 3 times per week for 4 weeks was safe and well tolerated, showed low systemic exposure, and demonstrated improvement in CFQ-R RSS, a relevant measure of clinical benefit in CF patients.
- MeSH
- Oligonucleotides, Antisense administration & dosage adverse effects MeSH
- Administration, Inhalation MeSH
- Cystic Fibrosis * drug therapy genetics physiopathology MeSH
- Adult MeSH
- Double-Blind Method MeSH
- Cross-Over Studies MeSH
- Humans MeSH
- Drug Monitoring methods MeSH
- Mutation MeSH
- Oligonucleotides * administration & dosage adverse effects MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator genetics MeSH
- Respiratory Function Tests methods MeSH
- Symptom Assessment methods MeSH
- Treatment Outcome MeSH
- Dose-Response Relationship, Drug * MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: REG1 is a novel anticoagulation system consisting of pegnivacogin, an RNA aptamer inhibitor of coagulation factor IXa, and anivamersen, a complementary sequence reversal oligonucleotide. We tested the hypothesis that near complete inhibition of factor IXa with pegnivacogin during percutaneous coronary intervention, followed by partial reversal with anivamersen, would reduce ischaemic events compared with bivalirudin, without increasing bleeding. METHODS: We did a randomised, open-label, active-controlled, multicentre, superiority trial to compare REG1 with bivalirudin at 225 hospitals in North America and Europe. We planned to randomly allocate 13,200 patients undergoing percutaneous coronary intervention in a 1:1 ratio to either REG1 (pegnivacogin 1 mg/kg bolus [>99% factor IXa inhibition] followed by 80% reversal with anivamersen after percutaneous coronary intervention) or bivalirudin. Exclusion criteria included ST segment elevation myocardial infarction within 48 h. The primary efficacy endpoint was the composite of all-cause death, myocardial infarction, stroke, and unplanned target lesion revascularisation by day 3 after randomisation. The principal safety endpoint was major bleeding. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, identifier NCT01848106. The trial was terminated early after enrolment of 3232 patients due to severe allergic reactions. FINDINGS: 1616 patients were allocated REG1 and 1616 were assigned bivalirudin, of whom 1605 and 1601 patients, respectively, received the assigned treatment. Severe allergic reactions were reported in ten (1%) of 1605 patients receiving REG1 versus one (<1%) of 1601 patients treated with bivalirudin. The composite primary endpoint did not differ between groups, with 108 (7%) of 1616 patients assigned REG1 and 103 (6%) of 1616 allocated bivalirudin reporting a primary endpoint event (odds ratio [OR] 1·05, 95% CI 0·80-1·39; p=0·72). Major bleeding was similar between treatment groups (seven [<1%] of 1605 receiving REG1 vs two [<1%] of 1601 treated with bivalirudin; OR 3·49, 95% CI 0·73-16·82; p=0·10), but major or minor bleeding was increased with REG1 (104 [6%] vs 65 [4%]; 1·64, 1·19-2·25; p=0·002). INTERPRETATION: The reversible factor IXa inhibitor REG1, as currently formulated, is associated with severe allergic reactions. Although statistical power was limited because of early termination, there was no evidence that REG1 reduced ischaemic events or bleeding compared with bivalirudin. FUNDING: Regado Biosciences Inc.
- MeSH
- Anticoagulants therapeutic use MeSH
- Aptamers, Nucleotide therapeutic use MeSH
- Factor IXa antagonists & inhibitors MeSH
- Hirudins MeSH
- Coagulants administration & dosage MeSH
- Percutaneous Coronary Intervention * MeSH
- Hemorrhage epidemiology MeSH
- Drug Hypersensitivity epidemiology MeSH
- Middle Aged MeSH
- Humans MeSH
- Oligonucleotides administration & dosage MeSH
- Peptide Fragments therapeutic use MeSH
- Early Termination of Clinical Trials MeSH
- Recombinant Proteins therapeutic use MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Geographicals
- Europe MeSH
- North America MeSH
- MeSH
- Adenosine analogs & derivatives administration & dosage adverse effects MeSH
- Rhinitis, Allergic immunology therapy MeSH
- Anti-Allergic Agents pharmacology therapeutic use MeSH
- Asthma immunology therapy MeSH
- Molecular Targeted Therapy MeSH
- Desensitization, Immunologic methods MeSH
- Phenylacetates administration & dosage adverse effects MeSH
- Clinical Trials as Topic MeSH
- Humans MeSH
- Lipid A analogs & derivatives administration & dosage adverse effects MeSH
- Oligodeoxyribonucleotides administration & dosage adverse effects MeSH
- Oligonucleotides administration & dosage adverse effects MeSH
- Toll-Like Receptors agonists immunology MeSH
- Vaccines administration & dosage adverse effects MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Review MeSH
- Keywords
- imuregen,
- MeSH
- Diet methods MeSH
- Research Support as Topic MeSH
- Ileum drug effects MeSH
- Mice MeSH
- Oligonucleotides administration & dosage pharmacology MeSH
- Polynucleotides administration & dosage pharmacology MeSH
- Intestinal Mucosa drug effects MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
