RESUMEN
Inclisiran is a small interfering RNA molecule that has been shown to provide an effective and sustained reduction in low-density lipoprotein cholesterol levels. This study aimed to determine whether a supratherapeutic dose of inclisiran affects cardiac repolarization and conduction in healthy volunteers. A phase I, randomized, double-blind, double-dummy, placebo- and positive-controlled, three-way crossover study was performed in 48 healthy volunteers. Volunteers were assigned to three treatments in a randomized sequence: a supratherapeutic dose of inclisiran sodium (900 mg), placebo, or moxifloxacin 400 mg as a positive control, with a minimum 7-day washout period between treatments. Continuous electrocardiogram monitoring was performed from >60 min before dosing until 48 h after dosing. Pharmacokinetics, pharmacodynamics, and safety were also assessed. Inclisiran, at a supratherapeutic dose, did not show a clinically significant effect on the QT interval (Fridericia correction formula [QTcF]; maximal placebo- and baseline-corrected change: 2.5 ms [90% confidence interval: 0.6, 4.5]) near the maximal plasma concentrations at 4 h. In addition, inclisiran did not show any effects on other electrocardiogram intervals or ST- and T-wave morphology. The positive control, moxifloxacin, demonstrated the expected changes in QTcF interval, validating the adequate sensitivity of the study. A supratherapeutic dose of inclisiran sodium (900 mg) had no effect on the QTcF interval or other electrocardiogram parameters, providing additional insight and reassurance regarding the safety profile of inclisiran.
Asunto(s)
Fluoroquinolonas , Sodio , Humanos , Moxifloxacino/efectos adversos , ARN Interferente Pequeño , Fluoroquinolonas/efectos adversos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca , Método Doble Ciego , Voluntarios Sanos , Sodio/farmacologíaRESUMEN
Despite the development of new therapies to lower cardiovascular disease (CVD) risk in recent decades, the trend of reductions in CVD mortality has reversed. New therapies are essential for the prevention of first and recurrent CVD. The importance of lowering low-density lipoprotein cholesterol (LDL-C) in the management and prevention of atherosclerotic CVD (ASCVD) is widely reflected in clinical treatment guidelines; however, most patients with established ASCVD do not achieve guideline-recommended LDL-C targets. Common reasons include adherence challenges, public disinformation, statin tolerability issues, access barriers, and clinical inertia. Inclisiran is a novel small interfering ribonucleic acid (RNA) that lowers circulating LDL-C by â¼50% when added to maximally tolerated statins by mimicking the body's natural pathway of RNA interference to specifically prevent proprotein convertase subtilisin/kexin type 9 synthesis. The unique dosing regimen of inclisiran (initial, at 3 months, and then every 6 months) has the advantage of allowing for healthcare provider administration during recommended routine visits for patients with established ASCVD, which can circumvent adherence issues associated with currently available LDL-C-lowering therapies. Inclisiran has demonstrated favorable tolerability and safety for up to 3 years, and evidence from longer-term use is accumulating in ongoing studies. This review discusses the novel mechanism of action of inclisiran and its potential position in the clinical armamentarium.
Asunto(s)
Anticolesterolemiantes , Aterosclerosis , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , LDL-Colesterol , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , ARN Interferente Pequeño/uso terapéutico , Colesterol , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Aterosclerosis/tratamiento farmacológico , Anticolesterolemiantes/uso terapéuticoRESUMEN
BACKGROUND: There is a lack of large-scale data on the clinical and genotype characteristics of homozygous familial hypercholesterolemia (HoFH) patients in Asia. OBJECTIVE: To define the characteristics of phenotypic and genetic HoFH probands from mainland China. METHODS: We collected data from patients with suspected HoFH from ten clinical hospitals across mainland China from 2003 to 2019. Clinical data and DNA testing were obtained in all patients. The Kaplan-Meier method was used to generate survival curves, and the groups were compared with the log-rank test. RESULTS: A total of 108 unrelated probands with suspected HoFH (mean age 14.9 years) were included. The three most common variants were W483X (c.1448 G>A), A627T (c.1879 G>A), H583Y (c.1747 C>T). The majority (64.8%) were compound heterozygotes (n = 70), 23 (21.3%) were true HoFH patients. True HoFH showed higher LDL-C levels compared to compound HoFH (16.8±3.6 mmol/L vs. 15.0±3.1 mmol/L, P = 0.022). During follow-up, only 21.2% patients exhibited an LDL-C reduction of more than 50%. Kaplan-Meier analysis showed that the true HoFH probands had significantly worse survival rates compared to other genotype probands (13-year survival; 20.3% vs. 76.7%, respectively; P = 0.016). In addition, true HoFH shows that 2.8-fold (P = 0.022) increase any death and 3.0-fold (P = 0.023) increase cardiovascular death risk in relative to other FH. CONCLUSIONS: This report shows that HoFH has devastating consequences, and that patients are often only diagnosed after they have been exposed to severely elevated LDL-C for years. Systematic screening and early intensive treatment are an absolute requirement for these young individuals with HoFH.
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Anticolesterolemiantes , Hipercolesterolemia Familiar Homocigótica , Hiperlipoproteinemia Tipo II , Adolescente , Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/genética , Estudios de Cohortes , Homocigoto , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , FenotipoRESUMEN
BACKGROUND: Inclisiran, a small interfering RNA molecule, reduces low-density lipoprotein cholesterol (LDL-C) by inhibiting production of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the liver. OBJECTIVE: To investigate the pharmacokinetics, pharmacodynamics, and safety of inclisiran in patients with mild or moderate hepatic impairment (HI) vs participants with normal hepatic function (NHF). METHODS: In this single-center, open-label, parallel-group study, patients with mild (Child-Pugh A) or moderate (Child-Pugh B) HI and with NHF, matched by age, body mass index, sex, and race (if possible), received a single subcutaneous therapeutic dose of inclisiran (300â¯mg). Pharmacokinetic profiles, pharmacodynamic endpoints (PCSK9 and LDL-C), and safety were assessed. RESULTS: Twenty-eight participants completed the study (mild HI: nâ¯=â¯10; moderate HI: nâ¯=â¯6; NHF: nâ¯=â¯12). Inclisiran achieved maximum plasma concentration at 4-6 h and was undetectable in plasma at 48 h in most participants, irrespective of liver function. Inclisiran exposure was 1.24-fold higher in the mild HI vs NHF groups (90% confidence interval [CI] 1.01-1.53) and 2.03-fold higher in the moderate HI vs NHF groups (90% CI 1.60-2.58). LDL-C and PCSK9 plasma levels decreased from baseline up to the last assessment on Day 60 in all groups, with a similar response in NHF and mild HI groups but a less pronounced and more varied decrease in the moderate HI group. Inclisiran was generally safe and well tolerated. CONCLUSION: The pharmacokinetic exposure of inclisiran increased by up to two fold in patients with moderate HI compared with those with NHF, while pharmacodynamic effects remained relatively unchanged. Inclisiran is generally safe and well tolerated in patients with mild or moderate HI, with no dose adjustment needed. However, a larger, long-term clinical trial would help to further evaluate the long-term safety profile of inclisiran in patients with liver disease.
Asunto(s)
Hepatopatías , ARN Interferente Pequeño , LDL-Colesterol , Humanos , Hepatopatías/tratamiento farmacológico , Proproteína Convertasa 9/genética , ARN Interferente Pequeño/efectos adversos , ARN Interferente Pequeño/farmacocinética , ARN Interferente Pequeño/farmacologíaRESUMEN
PURPOSE: AT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations. METHODS: This phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77-196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks. RESULTS: The most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was -7.2% (95% CI [-10.4 to -3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%. CONCLUSIONS: Although both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development. TRIAL REGISTRATION: EudraCT: 2015-001719-11. ClinicalTrials.gov Identifier: NCT02508896.
Asunto(s)
Hipercolesterolemia/tratamiento farmacológico , Proproteína Convertasa 9/inmunología , Vacunas de Subunidad/uso terapéutico , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Método Simple Ciego , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/efectos adversos , Adulto JovenRESUMEN
AIMS: Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported. Here, we present the pre-specified safety analysis from ORION-1 evaluating platelets, immune cells, immunological markers, antidrug antibodies, and clinical immunogenicity adverse events (AEs) under PCSK9 siRNA treatment with inclisiran. METHODS AND RESULTS: The pre-specified safety analysis from ORION-1 was performed in six different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single dose (SD: 200 mg, n = 60; 300 mg, n = 62 or 500 mg, n = 66) or double-dose starting regimen (DD: 100 mg, n = 62; 200 mg, n = 63; or 300 mg, n = 61 on days 1 and 90) of inclisiran or placebo (SD: n = 65; DD: n = 62). The effects of inclisiran on haematological parameters including platelet counts, lymphocytes, and monocytes as well as on the immune markers interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were examined after 180 days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADAs) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity AEs as part of the pharmacovigilance strategy. At day 180, no significant alterations of platelet counts were observed in any of the dosing groups (change from baseline, SD: 200 mg: 0.8%; 300 mg: -0.5%; 500 mg: -1.8%; DD: 100 mg: 1.3%; 200 mg: -0.5%; 300 mg: 1.0%; no significant difference for any group as compared with placebo). No significant effects on other immune cells, including leucocytes, monocytes, or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-α) with either the SD or DD regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity AEs in none of the treatment regimens. CONCLUSION: In this pre-specified safety analysis of ORION-1 for the siRNA therapeutic inclisiran, no adverse effects on measures of inflammation or immune activation nor adverse effects on platelets or clinical immunogenicity AEs were observed over at least 6-month treatment. These safety findings in the largest analysis of an RNAi study in humans to date provide strong reassurance about the safety of inclisiran and the potential of cardiovascular RNA-targeted therapies.
Asunto(s)
Plaquetas/efectos de los fármacos , LDL-Colesterol/sangre , Dislipidemias/terapia , Leucocitos/efectos de los fármacos , Proproteína Convertasa 9/metabolismo , ARN Interferente Pequeño/uso terapéutico , Tratamiento con ARN de Interferencia , Anticuerpos/sangre , Biomarcadores/sangre , Plaquetas/metabolismo , Método Doble Ciego , Regulación hacia Abajo , Dislipidemias/sangre , Dislipidemias/genética , Dislipidemias/inmunología , Humanos , Interleucina-6/sangre , Leucocitos/inmunología , Proproteína Convertasa 9/genética , ARN Interferente Pequeño/efectos adversos , ARN Interferente Pequeño/inmunología , Tratamiento con ARN de Interferencia/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/sangreAsunto(s)
LDL-Colesterol/biosíntesis , Terapia Genética , Hiperlipoproteinemia Tipo II/terapia , Terapia Molecular Dirigida , Inhibidores de PCSK9 , Interferencia de ARN , ARN Interferente Pequeño/uso terapéutico , Anticolesterolemiantes/uso terapéutico , Ezetimiba/uso terapéutico , Técnicas de Silenciamiento del Gen , Homocigoto , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/metabolismo , Proyectos Piloto , Prueba de Estudio Conceptual , Proproteína Convertasa 9/biosíntesis , Proproteína Convertasa 9/genética , ARN Interferente Pequeño/efectos adversos , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the pharmacodynamic properties of inclisiran, a small interfering RNA targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), in individuals with normal renal function and renal impairment (RI). PATIENTS AND METHODS: The analysis included participants with normal renal function and mild, moderate, and severe RI from the phase 1 ORION-7 renal study (n=31) and the phase 2 ORION-1 study (n=247) who received 300 mg of inclisiran sodium or placebo. RESULTS: In ORION-7, PCSK9 values were reduced at day 60 in the normal renal function group (68.1%±12.4%), mild RI group (74.2%±12.3%), moderate RI group (79.8%±4.9%), and severe RI group (67.9%±16.4%) (P<.001 vs placebo in all groups). Low-density lipoprotein cholesterol levels were significantly reduced versus placebo: normal renal function, 57.6%±10.7%; mild RI, 35.1%±13.5%; moderate RI, 53.1%±21.3%; severe RI, 49.2%±26.6% (P<.001 for all). In ORION-1, PCSK9 level reductions at day 180 were 48.3% to 58.6% in the 300-mg single-dose groups and 67.3% to 73.0% in the 300-mg 2-dose groups (P<.001 vs placebo in all groups). The corresponding low-density lipoprotein cholesterol level reductions were 35.7% to 40.2% in the 300-mg single-dose groups and 50.9% to 58.0% in the 300 mg 2-dose groups (P<.001 vs placebo in all groups). In ORION-7, exposure to inclisiran was proportionally greater in individuals with increasing RI; inclisiran was undetectable in plasma 48 hours after administration in any group. CONCLUSION: The pharmacodynamic effects and safety profile of inclisiran were similar in study participants with normal and impaired renal function. Dose adjustments of inclisiran are not required in these patients. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT02597127 and NCT03159416.
Asunto(s)
LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria , ARN Interferente Pequeño , Insuficiencia Renal , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Monitoreo de Drogas/métodos , Femenino , Humanos , Hipolipemiantes/administración & dosificación , Hipolipemiantes/efectos adversos , Hipolipemiantes/farmacocinética , Pruebas de Función Renal/métodos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Inhibidores de PCSK9 , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/efectos adversos , ARN Interferente Pequeño/farmacocinética , Insuficiencia Renal/diagnóstico , Insuficiencia Renal/fisiopatología , Resultado del TratamientoRESUMEN
Importance: Sustained reductions in low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies that require frequent dosing are reliant on patient adherence, and poor adherence is associated with worse clinical outcomes. Objective: To determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen. Design, Setting, and Participants: Prespecified analysis of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial. Participants were followed up monthly for LDL-C levels and proprotein convertase subtilisin-kexin type 9 (PCSK9) measurements as well as safety until their LDL-C levels had returned to within 20% of their change from baseline (maximum 360 days). The study included patients with elevated LDL-C despite maximally tolerated statin therapy. Data were analyzed between January 11, 2016, and June 7, 2017. Interventions: One dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo. Main Outcomes and Measures: Duration of time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year. Results: At baseline, among the 501 participants, 65% were men (n = 326 of 501), mean age was 63 years, 6% had familial hypercholesterolemia (n = 28 of 501), and 69% had established ASCVD (n = 347 of 501). Baseline LDL-C was 128 mg/dL among 501 randomized participants. The percentage of participants who were followed up to day 360 because their LDL-C levels had not returned to within 20% of their change from baseline ranged from 48.3% to 65.0% for those receiving a single dose and between 55.9% and 83.1% of those receiving 2 doses, with similar effects observed for PCSK9. Time-averaged reduction in LDL-C levels over 1 year after a single dose ranged from 29.5% to 38.7% (P < .001 between groups) and from 29.9% to 46.4% (P < .001 between groups) for those who received 2 doses. The 2-dose 300-mg regimen produced the highest proportion of responders at day 360 and the greatest mean reduction in LDL-C over 1 year. Incidence of adverse events was similar through to 1 year. Conclusions and Relevance: Treatment with inclisiran resulted in durable reductions in LDL-C over 1 year. Inclisiran may offer a novel approach to LDL-C reduction with the convenience of infrequent dosing. Trial Registration: ClinicalTrials.gov identifier: NCT02597127.
Asunto(s)
LDL-Colesterol/sangre , LDL-Colesterol/efectos de los fármacos , Hipercolesterolemia/tratamiento farmacológico , Seguridad del Paciente , ARN Interferente Pequeño/administración & dosificación , Anciano , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Hipercolesterolemia/diagnóstico , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , ARN Interferente Pequeño/efectos adversos , Medición de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Statin therapy has delivered tremendous value to society by improving the burden of atherosclerotic cardiovascular disease. Nonetheless, atherosclerotic cardiovascular disease remains the leading cause of death globally. Technological advances such as in the field of genomics have revolutionized drug discovery and development and have revealed novel therapeutic targets to lower low-density lipoprotein cholesterol (LDL-C), as well as other detrimental lipids and lipoproteins. Therapeutic LDL-C lowering prevents atherosclerotic cardiovascular disease with an effect size proportional to absolute LDL-C reductions and time of exposure. This understanding supports the notion that reducing cumulative LDL-C exposure should be a key therapeutic target. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibiting monoclonal antibodies provides the possibility of reducing LDL-C to very low levels. Novel therapeutic platforms such as RNA inhibition present opportunities to combine robust lipid lowering with infrequent dosing regimens, introducing therapies with vaccine-like properties. The position of lipid-lowering therapies with targets other than LDL-C, such as Lp(a) [lipoprotein(a)], TRL (triglyceride-rich lipoproteins), and remnant cholesterol, will likely be determined by the results of ongoing clinical trials. Current evidence suggests that reducing Lp(a) or TRLs could attenuate atherosclerotic cardiovascular disease risk in specific categories of patients. This review provides an overview of the latest therapeutic developments, focusing on their mechanisms, efficacy, and safety.
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Dislipidemias/tratamiento farmacológico , Hipolipemiantes/uso terapéutico , Animales , Aterosclerosis/etiología , Aterosclerosis/prevención & control , Ensayos Clínicos como Asunto , Diseño de Fármacos , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Dislipidemias/complicaciones , Ácido Eicosapentaenoico/uso terapéutico , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Hipolipemiantes/farmacología , Terapia Molecular Dirigida , Oligonucleótidos Antisentido/farmacología , Oligonucleótidos Antisentido/uso terapéutico , PPAR alfa/efectos de los fármacosRESUMEN
Inclisiran is a novel drug that inhibits PCSK9 synthesis specifically in the liver, harnessing the natural mechanism of RNAi. Phase I and II data show that inclisiran lowers low-density lipoprotein cholesterol levels on average by >50% with a duration of effect that enables twice-yearly dosing. Phases I, II and emerging Phase III data support inclisiran's safety, tolerability and risk-benefit profile. The ongoing ORION program includes Phase III trials that will provide robust evidence of inclisiran's safety and efficacy in individuals at high risk of atherosclerotic cardiovascular disease (ASCVD), including established ASCVD and familial hypercholesterolemia. In addition, the ORION-4 trial will assess the impact of inclisiran on cardiovascular outcomes in approximately 15,000 ASCVD subjects.
Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Desarrollo de Medicamentos , ARN Interferente Pequeño/farmacología , Ensayos Clínicos como Asunto , HumanosRESUMEN
Clinical trials have unequivocally shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) efficaciously and safely prevents cardiovascular events by lowering levels of LDL cholesterol. PCSK9 in the circulation is derived mainly from the liver, but the protein is also expressed in the pancreas, the kidney, the intestine and the central nervous system. Although PCSK9 modulates cholesterol metabolism by regulating LDL receptor expression in the liver, in vitro and in vivo studies have suggested that PCSK9 is involved in various other physiological processes. Although therapeutic PCSK9 inhibition could theoretically have undesired effects by interfering with these non-cholesterol-related processes, studies of individuals with genetically determined reduced PCSK9 function and clinical trials of PCSK9 inhibitors have not revealed clinically meaningful adverse consequences of almost completely eradicating PCSK9 from the circulation. The clinical implications of PCSK9 functions beyond lipid metabolism in terms of wanted or unwanted effects of therapeutic PCSK9 inhibition therefore appear to be limited. The objective of this Review is to describe the physiological role of PCSK9 beyond the LDL receptor to provide a rational basis for monitoring the effects of PCSK9 inhibition as these drugs gain traction in the clinic.
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LDL-Colesterol/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Proproteína Convertasa 9/efectos de los fármacos , Proproteína Convertasa 9/metabolismo , Receptores de LDL/efectos de los fármacos , Biomarcadores/metabolismo , Enfermedades Cardiovasculares/prevención & control , LDL-Colesterol/efectos de los fármacos , Femenino , Humanos , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/prevención & control , Masculino , Receptores de LDL/metabolismo , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: The ORION-1 trial (Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol [LDL-C]) demonstrated that inclisiran, an siRNA therapeutic that targets protease proprotein convertase subtilisin/kexin type 9 mRNA within hepatocytes, produces significant low-density lipoprotein cholesterol reduction. The effects of inclisiran on other lipids are less well described. METHODS: ORION-1 was a phase 2 trial assessing 6 different inclisiran dosing regimens versus placebo. Participants with elevated low-density lipoprotein cholesterol despite receiving maximally tolerated statin therapy received a single-dose (200, 300, or 500 mg) or 2-dose starting regimen (100, 200, or 300 mg on days 1 and 90) of inclisiran or placebo. This prespecified analysis reports the percentage reductions in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein (apo) B, very-low-density lipoprotein cholesterol, lipoprotein(a), triglycerides, HDL-C, and apo A1 at the primary efficacy time point (day 180) with mixed-effect models for repeated measures. Additional prespecified analyses report time course of changes from baseline at each visit to day 210, interindividual variation in response, and lipid goal attainment. RESULTS: The mean age of the 501 participants was 63 years, 65% were male, 69% had atherosclerotic cardiovascular disease, 73% used statins, and mean low-density lipoprotein cholesterol was 128 mg/dL. A single dose of inclisiran reduced apo B, non-HDL-C, and very-low-density lipoprotein cholesterol over 210 days. A second dose of inclisiran provided additional lowering of these lipids. At day 180, non-HDL-C was lowered dose-dependently: by 25% from 148±43 to 110±45 mg/dL in the 200-mg single-dose group and by 46% from 161±58 to 91±58 mg/dL in the 2-dose 300-mg group. For the same dosing regimens, apo B was reduced by 23% from 101±23 to 78±29 mg/dL and by 41% from 106±31 to 65±33 mg/dL ( P<0.001 for all groups versus placebo). In the 300-mg 2-dose group, all individuals experienced apo B and non-HDL-C reductions. There was larger interindividual variation in very-low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) reductions. In the 300-mg 2-dose group, the percentages of patients achieving guideline-recommended apo B goals for high- and very-high-risk patients at day 180 were 78% and 90%; 68% and 83% of participants achieved non-HDL-C <100 and <130 mg/dL. CONCLUSIONS: Inclisiran produces significant and prolonged reductions in atherogenic lipoproteins, suggesting that inhibiting the synthesis of protease proprotein convertase subtilisin/kexin type 9 through siRNA may be a viable alternative to other approaches that target protease proprotein convertase subtilisin/kexin type 9. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02597127.
Asunto(s)
Dislipidemias/terapia , Lípidos/sangre , Proproteína Convertasa 9/genética , ARN Interferente Pequeño/administración & dosificación , Tratamiento con ARN de Interferencia/métodos , Anciano , Apolipoproteína A-I/sangre , Apolipoproteína B-100/sangre , Biomarcadores/sangre , Colesterol/sangre , Método Doble Ciego , Dislipidemias/sangre , Dislipidemias/diagnóstico , Dislipidemias/genética , Femenino , Humanos , Lipoproteína(a)/sangre , Masculino , Persona de Mediana Edad , Proproteína Convertasa 9/metabolismo , ARN Interferente Pequeño/efectos adversos , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Tratamiento con ARN de Interferencia/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Triglicéridos/sangreRESUMEN
PURPOSE OF REVIEW: This review describes the pivotal role of genetic insights and technologies in the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the rapid development of PCSK9 inhibitors - a revolutionary new class of lipid-lowering agents. RECENT FINDINGS: PCSK9 was discovered as a the third gene implicated in familial hypercholesterolemia. Population genetics studies, enabled by technological advances, were instrumental in validating PCSK9 as a therapeutic target. Monoclonal antibodies against PCSK9 were introduced in the clinic after an unprecedently rapid development path, in which clinical trial results confirmed that these drugs robustly lower cholesterol and improve clinical outcomes regardless of disease indication or background therapy. New strategies to PCSK9 inhibition are underway and have delivered promising preliminary results, including inhibition of PCSK9 synthesis by targeting the cellular gene expression machinery and vaccination. The future will tell whether directly targeting the genome through editing techniques will ultimately enable us to virtually eliminate many of the traditional CVD risk factors. SUMMARY: The extraordinary PCSK9 narrative highlights the opportunities offered by genetics-driven drug development and holds valuable lessons for future development programs.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Colesterol/sangre , ADN/genética , Terapia Genética/métodos , Hipercolesterolemia , Mutación , Proproteína Convertasa 9/genética , Ensayos Clínicos como Asunto , Análisis Mutacional de ADN , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/genética , Hipercolesterolemia/terapia , Proproteína Convertasa 9/metabolismo , Factores de RiesgoRESUMEN
OBJECTIVE: Conflicting evidence exists on the effects of hyperbaric oxygen therapy (HBOT) in the treatment of chronic ischemic leg ulcers. The aim of this trial was to investigate whether additional HBOT would benefit patients with diabetes and ischemic leg ulcers. RESEARCH DESIGN AND METHODS: Patients with diabetes with an ischemic wound (n = 120) were randomized to standard care (SC) without or with HBOT (SC+HBOT). Primary outcomes were limb salvage and wound healing after 12 months, as well as time to wound healing. Other end points were amputation-free survival (AFS) and mortality. RESULTS: Both groups contained 60 patients. Limb salvage was achieved in 47 patients in the SC group vs. 53 patients in the SC+HBOT group (risk difference [RD] 10% [95% CI -4 to 23]). After 12 months, 28 index wounds were healed in the SC group vs. 30 in the SC+HBOT group (RD 3% [95% CI -14 to 21]). AFS was achieved in 41 patients in the SC group and 49 patients in the SC+HBOT group (RD 13% [95% CI -2 to 28]). In the SC+HBOT group, 21 patients (35%) were unable to complete the HBOT protocol as planned. Those who did had significantly fewer major amputations and higher AFS (RD for AFS 26% [95% CI 10-38]). CONCLUSIONS: Additional HBOT did not significantly improve complete wound healing or limb salvage in patients with diabetes and lower-limb ischemia.
Asunto(s)
Diabetes Mellitus Tipo 2/terapia , Oxigenoterapia Hiperbárica , Isquemia/terapia , Recuperación del Miembro , Úlcera/terapia , Cicatrización de Heridas , Anciano , Anciano de 80 o más Años , Amputación Quirúrgica , Índice de Masa Corporal , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Tamaño de la Muestra , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: In clinical trials, protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors robustly lowered LDL-cholesterol (LDL-c) and had a favorable tolerability and safety profile. Based on these findings, PCSK9 inhibitors are incorporated in updates of clinical treatment guidelines. However, trial results do not necessarily predict the effectiveness under real-world conditions. The aim of the current study is to determine the efficacy and tolerability of PCSK9 inhibitors in routine outpatient care. METHODS: The cohort comprised all patients who were prescribed evolocumab or alirocumab at the outpatient clinic of a large university hospital in the Netherlands. Eligible patients required additional lipid-lowering despite maximally tolerated statin therapy and ezetimibe, or were statin intolerant. Data were systematically collected during routine outpatient visits. RESULTS: The study included 238 patients of whom 67.2% had familial hypercholesterolemia (FH) and 42.9% were statin intolerant. The mean LDL-c reduction was 55.0% from a baseline of 4.4 mmol/L. LDL-c goals were attained by 62.3% of patients. Side effects were reported by 15.5% of patients and 2.5% discontinued treatment. No meaningful differences in efficacy or tolerability were observed between patients with FH or statin intolerance, or across treatment regimens. CONCLUSIONS: The observed lipid reductions and side effects profile of PCSK9 inhibitors in a routine care setting were comparable to observations in clinical trials.